.
Search for "inclusion body myositis" English only.
[There is always overlap in these lists but they should be inclusive as a result]
1: Neurosci Lett. 2007 Dec 15 [Epub ahead of print]
Casein kinase 1 alpha associates with the tau-bearing lesions of inclusion body myositis.
Kannanayakal TJ, Mendell JR, Kuret J.
Center for Molecular Neurobiology, Department of Molecular and Cellular
Biochemistry, College of Medicine, The Ohio State University, 1060 Carmack Road,
Columbus, OH 43210, United States.
Inclusion body myositis and Alzheimer's disease are age-related disorders
characterized in part by the appearance of intracellular lesions composed of
filamentous aggregates of the microtubule-associated protein tau. Abnormal tau
phosphorylation accompanies tau aggregation and may be an upstream pathological
event in both diseases. Enzymes implicated in tau hyperphosphorylation in
Alzheimer's disease include members of the casein kinase 1 family of
phosphotransferases, a group of structurally related protein kinases that
frequently function in tandem with the ubiquitin modification system. To
determine whether casein kinase 1 isoforms associate with degenerating muscle
fibers of inclusion body myositis, muscle biopsy sections isolated from sporadic
disease cases were subjected to double-label fluorescence immunohistochemistry
using selective anti-casein kinase 1 and anti-phospho-tau antibodies. Results
showed that the alpha isoform of casein kinase 1, but not the delta or epsilon
isoforms, stained degenerating muscle fibers in all eight inclusion body myositis
cases examined. Staining was almost exclusively localized to phospho-tau-bearing
inclusions. These findings, which extend the molecular similarities between
inclusion body myositis muscle and Alzheimer's disease brain, implicate casein
kinase 1 alpha as one of the phosphotransferases potentially involved in tau
hyperphosphorylation.
PMID: 18191026 [PubMed - as supplied by publisher]
2: Neuromuscul Disord. 2007 Dec 19 [Epub ahead of print]
Sporadic inclusion body myositis: a continuing puzzle.
Needham M, Mastaglia FL.
Centre for Neuromuscular and Neurological disorders, Level 4, A Block, Australian
Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, University
of Western Australia, Perth, WA 6009, Australia.
There is now compelling evidence that sporadic inclusion body myositis (sIBM)
is
a muscle-specific autoimmune disease in which both T and B-cells play a part
and
in which both cytotoxic muscle fibre necrosis and degeneration occur. However
the
factors responsible for breakdown of immune tolerance and the nature of the
target antigens expressed by muscle fibres remain unknown. Genetic factors are
known to contribute to susceptibility, in particular MHC haplotyes which may
influence antigenic presentation, and could also operate through genetic
variations in muscle fibre constituents or immune effector mechanisms. Viral
infection may act as a trigger mechanism, as in cases of HIV-associated sIBM.
Our
understanding of the mechanisms leading to the degenerative changes in muscle
fibres is still incomplete. Protein misfolding and proteasomal dysfunction rather
than defective transcriptional control is likely to underlie the abnormal
accumulation of multiple proteins in the muscle fibre inclusions. However,
aberrant transcription is thought to be the basis for the accumulation of
potentially toxic mutant protein forms (e.g. UBB(+1)). The origin of the multiple
clonally expanded somatic mtDNA mutations in COX-negative segments of muscle
fibres remains uncertain but may be linked to the effects of oxidative stress.
It
is proposed that the disproportionate involvement of certain muscles in sIBM
may
be due to the existence of muscle group-specific transcriptomes which are
differentially affected by the disease process and that the male predominance
of
the disease may indicate the influence of genes preferentially expressed in
males. There is a need to develop better animal models of sIBM in which the
relationship between the inflammatory and degenerative components of the disease
as well as the gender difference in susceptibility and differential vulnerability
of different muscle groups can be more critically investigated.
PMID: 18160291 [PubMed - as supplied by publisher]
3: J Neuropathol Exp Neurol. 2008 Jan;67(1):41-49.
Inclusion Body Myositis Associated With Human T-Lymphotropic Virus-Type I
Infection: Eleven Patients From an Endemic Area in Japan.
Matsuura E, Umehara F, Nose H, Higuchi I, Matsuoka E, Izumi K, Kubota R, Saito
M,
Izumo S, Arimura K, Osame M.
From the Department of Neurology and Geriatrics (E Matsuura, FU, HN, IH, E
Matsuoka, KI, KA, MO) and Division of Molecular Pathology (RK, SI), Center for
Chronic Viral Diseases, Graduate School of Kagoshima University, Kagoshima;
and
Department of Microbiology (MS), Kanazawa Medical University, Ishikawa, Japan.
The objective of this study was to investigate the association of human
T-lymphotropic virus-type I (HTLV-I) infection with sporadic inclusion body
myositis in 11 patients from an endemic area in Japan. The clinical features
were
consistent with sporadic inclusion body myositis, and anti-HTLV-I antibodies
were
present in the sera of all patients. Their muscle biopsies showed the diagnostic
features of inclusion body myositis, including endomysial T-cell infiltration,
rimmed vacuoles, deposits of phosphorylated tau, and abnormal filaments in the
nuclei and cytoplasm of the myofibers. The fibers expressed major
histocompatibility complex class I antigens and were invaded by CD8 and CD4
cells. In a single human leukocyte antigen-A2-positive patient, in situ human
leukocyte antigen-A*0201 / Tax11-19-pentamer staining showed pentamer-positive
cells surrounding the muscle fibers. Double-immunogold silver staining and
polymerase chain reaction in situ hybridization revealed that HTLV-I proviral
DNA
was localized on helper-inducer T cells, but not on muscle fibers. Human
T-lymphotropic virus-type I proviral loads in peripheral blood mononuclear cells
from each patient were similar to those in HTLV-I-associated myelopathy/tropical
spastic paraparesis. This study suggests that HTLV-I infection may be one of
the
causes of sporadic inclusion body myositis, as has been reported in human
immunodeficiency virus type-1 infection.
PMID: 18091562 [PubMed - as supplied by publisher]
4: Best Pract Res Clin Rheumatol. 2007 Dec;21(6):1051-70.
Diagnostic uncertainty in the inflammatory myopathies.
Verity MA.
David Geffen School of Medicine, University of California at Los Angeles, 10833
Le Conte Avenue, Los Angeles, CA 90095, USA.
A group of case histories with appropriate muscle biopsy findings is presented
to
demonstrate some atypical presentations of the inflammatory myopathies.
Differential diagnostic possibilities are considered in presentations of
idiopathic polymyositis, statin myotoxicity, the inflammatory component with
the
dysferlinopathies, treated dermatomyositis, a necrotizing myopathy with pipe-stem
microvascular change, an inflammatory myopathy with abundant macrophages,
inclusion-body myositis, and the differential diagnosis of problems with
eosinophilic infiltration in the muscle biopsy. Attention is given to the role
of
membrane attack complex deposition in the microvasculature and the role of major
histiocompatibility complex-1-expressing muscle fibers indicating activation
of
the endoplasmic reticulum stress response.
PMID: 18068861 [PubMed - in process]
5: Neuromuscul Disord. 2007 Nov 28 [Epub ahead of print]
Apolipoprotein epsilon alleles in sporadic inclusion body myositis: A
reappraisal.
Needham M, Hooper A, James I, van Bockxmeer F, Corbett A, Day T, Garlepp MJ,
Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, Queen Elizabeth II Medical Centre, Perth, Australia.
Previous studies have differed as to whether APOE epsilon4 is a susceptibility
factor for developing sporadic inclusion body myositis (sIBM), with a positive
association being found only in an Australian cohort of cases. We have now
re-examined this in a larger cohort of 57 sIBM cases and have also carried out
a
meta-analysis of all the published studies looking for evidence of a risk
association or effect of APOE alleles on disease expression. Our findings argue
against a specific role for any APOE alleles in conferring susceptibility to
sIBM
but have demonstrated a non-significant trend towards an earlier age-of-onset
in
patients with the epsilon2 allele.
PMID: 18060780 [PubMed - as supplied by publisher]
6: Acta Neurol Scand. 2007 Nov 14 [Epub ahead of print]
Expression of transglutaminase 2 does not differentiate focal myositis from
generalized inflammatory myopathies.
Macaione V, Aguennouz M, Mazzeo A, De Pasquale MG, Russo M, Toscano A, De Luca
G,
Di Giorgio RM, Vita G, Rodolico C.
Department of Biochemical, Physiological and Nutritional Sciences, University
of
Messina, Messina, Italy.
Objectives - Idiopathic inflammatory myopathies (IIM), including dermatomyositis
(DM), polymyositis (PM), sporadic inclusion-body myositis (s-IBM) and focal
myositis (FM) are a heterogeneous group of autoimmune disorders of skeletal
muscle. An increased transglutaminase 2 (TG2) expression has been found in DM,
PM
and s-IBM. The aim of our study was to investigate TG2 expression in FM in
comparison with other IIM. Materials and methods - We re-examined tissue material
we have gathered in the course of our previous studies on IIM, investigating
muscle expression of TG2 in patients with FM in comparison with DM, PM and s-IBM
using immunocytochemistry and real-time RT-PCR. Results - Immunocytochemistry
revealed an increased TG2 signal in endomysial vessels, in atrophic and
degenerating/regenerating muscle fibres in PM, DM, s-IBM and FM; in s-IBM, some
vacuoles were immunostained too. Real-time RT-PCR study confirmed a significantly
increased expression of TG2 in all IIM muscles examined. Conclusions - Our study
demonstrates the presence of TG2 in FM muscles. The study suggests that TG2
expression does not represent a distinctive marker to differentiate FM from
generalized IIM. TG2 over-expression in inflamed skeletal muscle does not seem
have a pathogenetic role in such a disease, but it could represent a way to
contain the inflammatory process.
PMID: 18005224 [PubMed - as supplied by publisher]
7: Front Biosci. 2008 Jan 1;13:2548-77.
Chemokines in idiopathic inflammatory myopathies.
De Paepe B, Creus KK, De Bleecker JL.
Department of Neurology, Ghent University Hospital, Ghent, Belgium.
The idiopathic inflammatory myopathies (IIM) represent a heterogeneous group
of
acquired muscle diseases. The three best-studied subgroups: dermatomyositis
(DM),
polymyositis (PM), and sporadic inclusion body myositis (IBM), differ
considerably both clinically and pathophysiologically. DM is a chiefly humoral
endotheliopathy often associated with characteristic skin manifestations. In
PM
and IBM nonnecrotic muscle fibers are invaded by auto-aggressive cytotoxic
T-cells and macrophages. IBM presents with additional structural abnormalities
of
myofibers, including rimmed vacuoles and depositions of ectopic proteins. Data
accumulates implicating the chemokines in the immunopathogenesis of the different
IIM. This review bundles current knowledge of the chemokine and chemokine
receptor expression in the skeletal muscle of DM, PM and IBM patients. The IIM
are characterized by a general increase of specific chemokines, while the
chemokine distribution reflects the two different immune responses represented
within these muscle diseases: (I) The endotheliopathy of DM is characterized
by
increased levels of CXCL12 and CCL2 in the affected blood vessels, (II) In the
myocytotoxic immune response of PM and IBM, active invasion of nonnecrotic
myofibers by inflammatory cells is associated with CXCL10 and CCL2 upregulation.
The ever accumulating data illustrates the important role of the chemokine system
in IIM, indicating the therapeutic potential of interfering agents. This raises
hopes for future treatments for DM and PM with fewer side effects, and the
possible establishment of a therapy suited for IBM, a myopathy which has proven
unresponsive to all available immuno-modulating interventions up till now.
Publication Types:
Review
PMID: 17981734 [PubMed - indexed for MEDLINE]
8: Arthritis Rheum. 2007 Nov;56(11):3784-92.
Type I interferon-inducible gene expression in blood is present and reflects
disease activity in dermatomyositis and polymyositis.
Walsh RJ, Kong SW, Yao Y, Jallal B, Kiener PA, Pinkus JL, Beggs AH, Amato AA,
Greenberg SA.
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
OBJECTIVE: To apply gene expression profiling to the study of peripheral blood
mononuclear cells from patients with inflammatory myopathies, in order to provide
insight into disease pathogenesis and identify potential biomarkers associated
with disease activity. METHODS: We used Affymetrix whole-genome microarrays
to
measure the expression of approximately 38,500 genes in 65 blood and 15 muscle
samples from 44 patients with dermatomyositis (DM), polymyositis (PM), inclusion
body myositis (IBM), myasthenia gravis, or genetically determined myopathies
and
from 12 healthy volunteers. In 9 patients, 2 samples were obtained at different
time points, when disease was either active or improving, and these paired blood
samples were also compared. Bioinformatics techniques were used to identify
genes
with significant differential expression among diagnostic categories and in
relation to disease activity. We corroborated the microarray data with
quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS:
Most patients with active DM or PM, but not patients with IBM, had significant
and high up-regulation of the type I interferon-alpha/beta
(IFNalpha/beta)-inducible genes in blood. Furthermore, the up-regulation of
these
genes correlated with disease activity in DM and PM, with down-regulation
occurring when disease was controlled with treatment. CONCLUSION: DM and PM
are
diseases characterized by the systemic overexpression of IFNalpha/beta-inducible
genes. The magnitude of the overexpression of these genes is higher in DM and
correlates with disease activity in both disorders. Although PM and IBM have
been
modeled as having similar immunologic processes occurring within muscle, there
are substantial differences in the expression of IFNalpha/beta-inducible genes
in
blood in these diseases.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17968926 [PubMed - indexed for MEDLINE]
9: Neurology. 2007 Oct 23;69(17):1672-9.
T cell receptor profiling in muscle and blood lymphocytes in sporadic inclusion
body myositis.
Salajegheh M, Rakocevic G, Raju R, Shatunov A, Goldfarb LG, Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
BACKGROUND: Sporadic IBM (sIBM) is characterized by invasion of non-necrotic
MHC-I class-expressing muscle fibers by clonally expanded CD8+ cells. Whether
the
endomysial cells expand in situ or are recruited from the circulation is unclear.
METHODS: We used CDR3 spectratyping of the T cell receptor (TCR) V beta chains
to
determine clonal expansion of T cells in simultaneously obtained muscle and
peripheral blood lymphocytes (PBL) from 12 patients with sIBM, and compared
the
difference between the two compartments. To determine whether the identified
clones belonged to autoinvasive T cells, we performed immunohistochemistry on
the
same muscle specimens. Spectratyping was repeated in four muscle biopsies 1
year
after the first. RESULTS: In control PBL, all 24 TCR V beta subfamilies had
a
polyclonal or Gaussian distribution. In sIBM PBL, 5% of the V beta subfamilies
demonstrated a single and 16% up to three peaks. In contrast, in their
corresponding muscles, 27% (p = 0.0003) of the V beta subfamilies demonstrated
a
single and 71% (p < 0.0001) up to three peaks. Among the amplified subfamilies,
V
beta 9, 10, 11, 16, 18, 23, and 24 showed the highest degree of restriction
within muscle. Immunohistochemistry demonstrated that the clonally expanded
CD8+
cells were autoinvasive. In follow-up biopsies the clonality persisted with
an
unchanged degree of restriction, but not always of the same subfamilies,
suggesting epitope spreading. CONCLUSION: In sporadic inclusion body myositis,
the endomysial T cells are specifically recruited to the muscle or expand in
situ. The restriction of multiple V beta subfamilies and their change over time
suggests recognition of various local antigens and epitope spreading.
Publication Types:
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
PMID: 17954782 [PubMed - indexed for MEDLINE]
10: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17016-21. Epub 2007 Oct 17.
Distinctive patterns of microRNA expression in primary muscular disorders.
Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, Lidov HG, Kang
PB, North KN, Mitrani-Rosenbaum S, Flanigan KM, Neely LA, Whitney D, Beggs AH,
Kohane IS, Kunkel LM.
Howard Hughes Medical Institute, Program in Genomics, Division of Genetics,
Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
The primary muscle disorders are a diverse group of diseases caused by various
defective structural proteins, abnormal signaling molecules, enzymes and proteins
involved in posttranslational modifications, and other mechanisms. Although
there
is increasing clarification of the primary aberrant cellular processes
responsible for these conditions, the decisive factors involved in the secondary
pathogenic cascades are still mainly obscure. Given the emerging roles of
microRNAs (miRNAs) in modulation of cellular phenotypes, we searched for miRNAs
regulated during the degenerative process of muscle to gain insight into the
specific regulation of genes that are disrupted in pathological muscle
conditions. We describe 185 miRNAs that are up- or down-regulated in 10 major
muscular disorders in humans [Duchenne muscular dystrophy (DMD), Becker muscular
dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular
dystrophies types 2A and 2B, Miyoshi myopathy, nemaline myopathy, polymyositis,
dermatomyositis, and inclusion body myositis]. Although five miRNAs were found
to
be consistently regulated in almost all samples analyzed, pointing to possible
involvement of a common regulatory mechanism, others were dysregulated only
in
one disease and not at all in the other disorders. Functional correlation between
the predicted targets of these miRNAs and mRNA expression demonstrated tight
posttranscriptional regulation at the mRNA level in DMD and Miyoshi myopathy.
Together with direct mRNA-miRNA predicted interactions demonstrated in DMD,
some
of which are involved in known secondary response functions and others that
are
involved in muscle regeneration, these findings suggest an important role of
miRNAs in specific physiological pathways underlying the disease pathology.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17942673 [PubMed - indexed for MEDLINE]
11: Clin Genet. 2007 Nov;72(5):420-6.
Novel VCP mutations in inclusion body myopathy associated with Paget disease
of
bone and frontotemporal dementia.
Watts GD, Thomasova D, Ramdeen SK, Fulchiero EC, Mehta SG, Drachman DA, Weihl
CC,
Jamrozik Z, Kwiecinski H, Kaminska A, Kimonis VE.
Division of Genetics, Children's Hospital Boston, Harvard Medical School, Boston,
MA, USA.
Inclusion body myopathy associated with Paget disease of bone and frontotemporal
dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense
mutations in valosin-containing protein (VCP). We report novel VCP mutations
N387H and L198W in six individuals from two families who presented with proximal
muscle weakness at a mean age of diagnosis of 40 years, most losing the ability
to walk within a few years of onset. Electromyographic studies in four
individuals were suggestive of 'myopathic' changes, and neuropathic pattern
was
identified in one individual in family 1. Muscle biopsy in four individuals
showed myopathic changes characterized by variable fiber size, two individuals
showing rimmed vacuoles and IBM-type cytoplasmic inclusions in muscle fibers,
and
electron microscopy in one individual revealing abundant intranuclear inclusions.
Frontotemporal dementia associated with characteristic behavioral changes
including short-term memory loss, language difficulty, and antisocial behavior
was observed in three individuals at a mean age of 47 years. Detailed brain
pathology in one individual showed cortical degenerative changes, most severe
in
the temporal lobe and hippocampus. Abundant ubiquitin-positive tau-,
alpha-synuclein-, polyglutamine repeat-negative neuronal intranuclear inclusions
and only rare intracytoplasmic VCP positive inclusions were seen. These new
mutations may cause structural changes in VCP and provide some insight into
the
functional effects of pathogenic mutations.
Publication Types:
Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17935506 [PubMed - indexed for MEDLINE]
12: Neurology. 2007 Nov 20;69(21):2008-19. Epub 2007 Oct 10.
Comment in:
Neurology. 2007 Nov 20;69(21):1966-7.
Proposed immunologic models of the inflammatory myopathies and potential
therapeutic implications.
Greenberg SA.
Department of Neurology, Brigham and Womens Hospital, Harvard Medical School,
Boston, MA 02115, USA. sagreenberg@partners.org
Several immune system cell types and processes have been recently identified
in
muscle in inclusion body myositis, dermatomyositis, and polymyositis.
Plasmacytoid dendritic cells, the immune system's professional producer of the
type 1 interferons alpha and beta, are present in dermatomyositis muscle and
skin. These tissues also show high expression of transcripts and proteins from
genes that are induced by interferon alpha and beta. Myeloid dendritic cells,
which contribute to an immunologic synapse responsible for activation of the
adaptive immune system, are abundant within muscle in inclusion body myositis
and
polymyositis. B cells and plasma cells, effector cells of the humoral immune
system, have been stimulated by antigen to transcribe immunoglobulins and produce
antibodies in muscle in all three of these diseases. The presence of these immune
cells and processes suggests revisions in models of the pathogenesis of the
inflammatory myopathies and provides rationales for future therapeutic
approaches.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17928577 [PubMed - indexed for MEDLINE]
13: Curr Opin Rheumatol. 2007 Nov;19(6):550-9.
Inclusion-body myositis, a multifactorial muscle disease associated with aging:
current concepts of pathogenesis.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles,
California 90017-1912, USA. askanas@usc.edu
PURPOSE OF REVIEW: Sporadic inclusion-body myositis, the most common muscle
disease of older persons, has no known cause or persistently beneficial
treatment. The unfolding pathogenesis could lead to new treatment strategies
and
it is now of growing interest among clinicians and basic scientists. About 100
papers related to the subject were published in 2006 and the first part of 2007
(we cite only articles most relevant to this review). RECENT FINDINGS: This
review focuses on the current concepts of the pathogenesis of sporadic
inclusion-body myositis. Both degeneration and mononuclear-cell inflammation
are
components of the pathology, but how each relates to the pathogenesis remains
unclear. We suggest that an intramuscle fiber degenerative component is primary,
leading to muscle-fiber destruction, while the lymphocytic inflammatory component
may only slightly contribute to sporadic inclusion-body myositis muscle-fiber
damage. Intracellular accumulation of amyloid-beta precursor protein,
amyloid-beta, and amyloid-beta oligomers in an aging muscle-fiber cellular
milieu, and other abnormalities, appear to be key pathogenic factors. We
summarize intracellular molecular events and their consequences, and correlate
findings in sporadic inclusion-body myositis muscle biopsies with inclusion-body
myositis experimental models in tissue culture and in transgenic mice. SUMMARY:
Treatment of sporadic inclusion-body myositis remains a challenge.
Antiinflammatory approaches used so far are without major or enduring benefit.
Possible new treatment avenues are suggested.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17917534 [PubMed - in process]
14: Curr Opin Rheumatol. 2007 Nov;19(6):536-41.
A gene expression approach to study perturbed pathways in myositis.
Greenberg SA.
Division of Neuromuscular Disease, Department of Neurology, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
sagreenberg@partners.org
PURPOSE OF REVIEW: To review new insights into the disease mechanisms of
dermatomyositis, inclusion body myositis, and polymyositis gained from
large-scale microarray gene expression studies of patient tissue samples. RECENT
FINDINGS: The detection of unexpected gene transcripts using microarrays in
inflammatory myopathy tissue has led to the discovery of new types and roles
of
immune system cells present in muscle in these diseases. Plasmacytoid dendritic
cells, the immune system's professional producer of the type 1 interferons alpha
and beta, are prominent in dermatomyositis muscle. Plasma cells and myeloid
dendritic cells are abundant in polymyositis and inclusion body myositis muscle.
Type 1 interferon induction is the single most upregulated pathological pathway
genome-wide in dermatomyositis muscle and blood. In individual patients with
dermatomyositis and some with polymyositis, a blood type 1 interferon-signature
correlates with disease activity. SUMMARY: The identification of new cells and
pathways in inflammatory myopathies has led to deeper mechanistic understanding
of these diseases and potential therapeutic approaches. Through insights gained
in gene expression studies, a strong scientific rationale has developed for
blockade of the type 1 interferon pathway for treatment of dermatomyositis.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17917532 [PubMed - in process]
15: Ann N Y Acad Sci. 2007 Sep;1110:285-96.
Treatment of autoimmune disease with rabbit anti-T lymphocyte globulin: clinical
efficacy and potential mechanisms of action.
Lytton SD, Denton CP, Nutzenberger AM.
SeraDiaLogistics, Hertlingstr 1, 81545 München, Germany. simon.lytton@t-online.de
The rabbit anti-T lymphocyte globulins (rATGs) are immune-suppressive anti-T
cell
agents with beneficial effects in solid organ and hematological transplantation.
The present review evaluates the potential mechanisms of rATGs and their impact
on pilot and exploratory studies of diffuse cutaneous systemic sclerosis
(scleroderma-SSc), inclusion body myositis (IBM), vasculitis, and type 1 diabetes
mellitus (T1DM). The rATGs are associated with improvements in well-defined
parameters of clinical autoimmunity: insulin usage, tissue inflammation, and
systemic organ functions. Meta-analysis of a retrospective database of SSc,
N =
196 and two prospective randomized pilot studies; IBM, N = 11 and T1DM, N =
17
shows a two- to ninefold increase in the relative response to treatments with
intravenous infusions of rATG. The rATGs deplete T cells and are associated
with
increases in the percentage of CD25+ T cell subsets. This may underlie the
apparent long-lasting immunomodulation associated with these agents. The future
optimization of rATG adjunct therapy requires statistically powered-controlled
prospective trials of rATG dose-finding and timing of administration. The
potential mechanisms of rATGs:depletion of autoreactive T cells, generation
CDCD25+Foxp3+ regulatory T cells (Tregs), and the acquisition of regulatory
immune cell functions, need to be examined in patients prior to rATG infusion
and
at time intervals following rATG treatment to identify those mechanisms relevant
to the improvement of their clinical outcome.
PMID: 17911443 [PubMed - indexed for MEDLINE]
16: Clin Neuropathol. 2007 Sep-Oct;26(5):232-40.
Brain imaging and neuropsychology in late-onset dementia due to a novel mutation
(R93C) of valosin-containing protein.
Krause S, Göhringer T, Walter MC, Schoser BG, Reilich P, Linn J, Pöpperl
GE,
Frölich L, Hentschel F, Lochmüller H, Danek A.
Neurologische Klinik, Ludwig-Maximilians-Universität München, Germany.
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
(IBMPFD, MIM 167320) is a recently identified autosomal dominant disorder due
to
mutations in the valosin-containing protein (VCP) that affects muscle, bone
and
brain. Brain involvement and neuropsychological findings of IBMPFD have not
been
described in detail. A patient carried a novel heterozygous base pair change,
47832C>T, in the VCP gene that resulted in substitution of an arginine residue
by
cysteine at position 93 (R93C). He presented first with myopathy while bone
involvement remained subclinical. The patient developed behavioral abnormalities
in his 60s and showed frank personality change with fluent empty speech at the
age of 74 years. This syndrome was best classified as semantic dementia. Magnetic
resonance imaging disclosed slight but progressive cerebral atrophy with
prominent callosal and frontal white matter loss. Positron emission tomography
demonstrated glucose hypometabolism of the frontal and temporal lobes
disproportionate to their structural involvement. This first comprehensive
clinical and neuroimaging study in IBMPFD may raise the awareness among
clinicians as well as basic scientists for this exemplary genetic model of
dementia.
Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
PMID: 17907600 [PubMed - indexed for MEDLINE]
17: Neuromuscul Disord. 2007 Sep 19 [Epub ahead of print]
Histone H1 is released from myonuclei and present in rimmed vacuoles with DNA
in
inclusion body myositis.
Nakano S, Shinde A, Fujita K, Ito H, Kusaka H.
Department of Neurology, Kansai Medical University, Moriguchi 570-8507, Japan.
To investigate myonuclear alterations in sporadic inclusion body myositis
(s-IBM), we immuno-localized histones in muscles in 11 patients. The examination
showed that vacuolar rims were frequently positive for histone H1. In
triple-color fluorescence study, the H1-positive products were found on the
inner
side of an emerin-positive circle with DNA. Moreover, H1-positive materials
appeared to be released into the cytoplasm in some vacuoles and myonuclei. The
localization of H1 was different from phosphorylated Elk-1, which is a nuclear
protein, but abnormally accumulated in the cytoplasm in s-IBM. The results
strongly support the hypothesis that rimmed vacuoles are derived from the
nucleus. The cytoplasmic H1-release suggests dysfunction of nuclear membranes
in
an early phase of the nuclear disintegration. We hypothesize that, in s-IBM
muscles, compromised nuclear envelope may permit release of some nuclear
components such as histone H1 and cannot facilitate the incorporation of others
to the nucleus as in pElk-1.
PMID: 17888663 [PubMed - as supplied by publisher]
18: J Cardiovasc Med (Hagerstown). 2007 Oct;8(10):859-63.
Apical ballooning (Takotsubo syndrome) in mitochondrial disorder during
mechanical ventilation.
Finsterer J, Stöllberger C, Sehnal E, Valentin A, Huber J, Schmiedel J.
Krankenanstalt Rudolfstiftung, Vienna, Austria. duarte@aonmail.at
Takotsubo syndrome may be associated with neuromuscular disorders, but has
never
been described in a patient with mitochondrial disorder. A 75-year-old woman
developed muscle cramps, ptosis, fasciculations and slowly progressive weakness
and wasting of all four limbs, starting 2.5 years earlier. After exclusion of
various differential diagnoses, including non-specific granulomatous myositis,
inclusion body myositis, and motor neuron disease, mitochondrial disorder was
assumed. Muscle weakness progressed to respiratory insufficiency, requiring
mechanical ventilation. Five days after intubation, she developed hypotension,
torsades de pointes, ST-segment elevation, and negative T waves. Echocardiography
revealed apical ballooning with akinesia of the left ventricular anteroseptal,
apical, apicolateral and inferior segments. Coronary angiography was normal,
and
ventriculography confirmed apical hypokinesia and ballooning. Takotsubo syndrome
was diagnosed, resolving completely within 7 weeks under bisoprolol.This case
shows that Takotsubo syndrome occurs also in mitochondrial disorder and under
mechanical ventilation, and may be triggered by stress from respiratory
insufficiency, intubation, pain from tracheostomy, stress from mechanical
ventilation, medication, or from the uncertain prognosis.
PMID: 17885529 [PubMed - in process]
19: Neurology. 2007 Dec 26 [Epub ahead of print]
Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic
IBM.
Chahin N, Engel AG.
From the Department of Neurology, Mayo Clinic, Rochester, MN.
OBJECTIVE: To correlate muscle biopsy findings with prebiopsy and postbiopsy
clinical course and response to therapy in polymyositis (PM) and sporadic
inclusion body myositis (IBM). BACKGROUND: Existence of pure PM has recently
been
questioned; subsequently, the definition and criteria for diagnosing PM were
debated. METHODS: Patient records, follow-up information, and muscle biopsies
were analyzed in 107 patients whose biopsies were initially read as PM and IBM.
RESULTS: The patients fell into three groups by combined biopsy and clinical
criteria: PM, 27 patients; IBM, 64 patients; PM/IBM, 16 patients with biopsy
diagnosis of PM but clinical features of IBM. For the three groups, the
respective mean periods from disease onset to end of follow-up were 5.9, 8.5,
and
9.6 years. Another autoimmune disease was present in 4 of 27 PM, 8 of 64 IBM,
and
1 of 16 PM/IBM cases. An autoimmune serologic marker occurred in one-third of
each group. Nineteen PM patients had no associated autoimmune disease or marker.
Nonnecrotic fiber invasion by mononuclear cells appeared in all IBM, 17 of 27
PM,
and 13 of 16 PM/IBM patients. The density of both invaded fibers and cytochrome-c
oxidase-negative fibers was higher in IBM and PM/IBM than in PM. Immunotherapy
improved 22 of 27 PM patients but had only transient beneficial effects in 2
of
32 IBM and 1 of 14 PM/IBM patients. CONCLUSIONS: 1) Sixteen of 43 patients (37%)
with biopsy features of polymyositis (PM) had clinical features of inclusion
body
myositis (IBM). 2) Absence of canonical biopsy features of IBM from clinically
affected muscles of IBM patients challenges biopsy criteria for IBM, or the
IBM
markers appear late in some patients, or their distribution in muscle is patchy
and restricted compared with that of the inflammatory exudate. 3) The muscle
biopsy is a reliable instrument in the diagnosis of PM and IBM in close to 85%
of
the patients. Errors of diagnosis in the remaining 15% can be avoided or reduced
by combined evaluation of the clinical and pathologic findings.
PMID: 17881720 [PubMed - as supplied by publisher]
20: J Immunol. 2007 Oct 1;179(7):4939-44.
Autoantibodies in canine masticatory muscle myositis recognize a novel myosin
binding protein-C family member.
Wu X, Li ZF, Brooks R, Komives EA, Torpey JW, Engvall E, Gonias SL, Shelton GD.
Department of Pathology, University of California, San Diego 92101, USA.
Inflammatory myopathies are a group of autoimmune diseases that affect muscles.
In humans, the most common inflammatory myopathies are polymyositis,
dermatomyositis, and inclusion body myositis. Autoantibodies may be found in
humans with inflammatory myopathies, and these play an important role in
diagnosis and disease classification. However, these Abs are typically not muscle
specific. Spontaneously occurring canine inflammatory myopathies may be good
parallel disorders and provide insights into human myositis. In dogs with
inflammatory myopathy, muscle-specific autoantibodies have been found, especially
in masticatory muscle myositis. We have identified the major Ag recognized by
the
autoantibodies in canine masticatory muscle myositis. This Ag is a novel member
of the myosin binding protein-C family, which we call masticatory myosin binding
protein-C (mMyBP-C). mMyBP-C is localized not only within the masticatory muscle
fibers, but also at or near their cell surface, perhaps making it accessible
as
an immunogen. The gene for mMyBP-C also exists in humans, and mMyBP-C could
potentially play a role in certain human inflammatory myopathies. Understanding
the role of mMyBP-C in this canine inflammatory myopathy may advance our
knowledge of mechanisms of autoimmune inflammatory muscle diseases, not only
in
dogs, but also in humans.
PMID: 17878394 [PubMed - indexed for MEDLINE]
21: J Neurol Sci. 2008 Jan 15;264(1-2):77-86. Epub 2007 Sep 12.
Non-pathogenic protein aggregates in skeletal muscle in MLF1 transgenic mice.
Li ZF, Wu X, Jiang Y, Liu J, Wu C, Inagaki M, Izawa I, Mizisin AP, Engvall
E,
Shelton GD.
Burnham Institute for Medical Research, 10901 N. Torrey Pines Road. La Jolla,
CA
92037, United States.
Protein aggregate formation in muscle is thought to be pathogenic and associated
with clinical weakness. Over-expression of either wild type or a mutant form
of
myeloid leukemia factor 1 (MLF1) in transgenic mouse skeletal muscle and in
cultured cells resulted in aggregate formation. Aggregates were detected in
MLF1
transgenic mice at 6 weeks of age, and increased in size with age. However,
histological examination of skeletal muscles of MLF1 transgenic mice revealed
no
pathological changes other than the aggregates, and RotaRod testing did not
detect functional deficits. MLF1 has recently been identified as a protein that
could neutralize the toxicity of intracellular protein aggregates in a Drosophila
model of Huntington's disease (HD). We also demonstrate that MLF1 interacts
with
MRJ, a heat shock protein, which can independently neutralize the toxicity of
intracellular protein aggregates in the Drosophila HD model. Our data suggest
that over-expression of MLF1 has no significant impact on skeletal muscle
function in mice; that progressive formation of protein aggregates in muscle
are
not necessarily pathogenic; and that MLF1 and MRJ may function together to
ameliorate the toxic effects of polyglutamine or mutant proteins in
myodegenerative diseases such as inclusion body myositis and oculopharyngeal
muscular dystrophy, as well as neurodegenerative disease.
PMID: 17854834 [PubMed - in process]
22: Ann N Y Acad Sci. 2007 Aug;1109:441-53.
Chemokine profile of different inflammatory myopathies reflects humoral versus
cytotoxic immune responses.
De Paepe B, Creus KK, De Bleecker JL.
Department of Neurology, Ghent University Hospital, Belgium.
The idiopathic inflammatory myopathies (IM) are subdivided into dermatomyositis
(DM), polymyositis (PM), and sporadic inclusion body myositis (IBM). These
autoimmune muscle diseases represent different immunopathological entities.
DM is
a humoral endotheliopathy initiated by complement deposition in intramuscular
blood vessels, and characterized by perimysial inflammation and muscle fiber
atrophy in perifascicular regions. In PM and IBM, nonnecrotic muscle fibers
are
actively invaded by autoaggressive macrophages and cytotoxic T cells. Chemokines
are key mediators of inflammatory disease as they regulate leukocyte recruitment
to tissue target sites. We studied a large selection of alpha/beta-chemokines
and
receptors in normal controls and in the IM using immunohistochemistry,
immunofluorescence, in situ hybridization, and Western blotting. We showed that
the chemokine array of normal myocytes was limited, while the blood vessels
in
normal skeletal muscle tissue displayed a broad chemokine profile. The IM were
characterized by a general increase of specific chemokines and chemokine
receptors, while chemokine distribution reflected the two different immune
responses represented within these muscle diseases. In DM, endothelial expression
of CCL2 and CXCL12beta was highly increased. In PM and IBM, macrophages and
cytotoxic T cells actively invading nonnecrotic muscle fibers expressed highest
levels of CXCL10 and CCL2. Some chemokines were selectively expressed by
different IM infiltrates: CCL4 was present only in the perimysial inflammatory
foci of a subset of DM biopsies, while CXCL1, CXCL2, CXCL3, and CCL7-positive
cells were exclusively detected in endomysial infiltrates of a number of PM
and
IBM samples. The chemokine receptor profile of the IM indicated the predominance
of Th1-mediated immune responses in all three IM. Our studies identified three
ligand-receptor pairs, namely CXCL10/CXCR3, CXCL12/CXCR4, and CCL2/CCR2, as
potential targets for chemokine-based therapy in IM.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17785333 [PubMed - indexed for MEDLINE]
23: Acta Neuropathol. 2007 Nov;114(5):517-26. Epub 2007 Aug 31.
NOGO is increased and binds to BACE1 in sporadic inclusion-body myositis and
in A
beta PP-overexpressing cultured human muscle fibers.
Wojcik S, Engel WK, Yan R, McFerrin J, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Ave,
Los Angeles, CA 90017-1912, USA.
Increased amyloid-beta precursor protein (A beta PP) and amyloid-beta (A beta)
accumulation appear to be upstream steps in the pathogenesis of sporadic
inclusion-body myositis (s-IBM). BACE1, participating in A beta production is
also increased in s-IBM muscle fibers. Nogo-B and Nogo-A belong to a family
of
integral membrane reticulons, and Nogo-B binding to BACE1 blocks BACE1 access
to
A beta PP, decreasing A beta production. We studied Nogo-B and Nogo-A in s-IBM
muscle and in our IBM muscle culture models, based on A beta PP-overexpression
or
ER-stress-induction in cultured human muscle fibers (CHMFs). We report that:
(1)
in biopsied s-IBM fibers, Nogo-B is increased, accumulates in aggregates, is
immuno-co-localized with BACE1, and binds to BACE1; Nogo-A is undetectable.
(2)
In CHMFs, (a) A beta PP overexpression increases Nogo-B, Nogo-A, and BACE1,
(b)
ER stress increases BACE1 but decreases Nogo-B and Nogo-A, (c) Nogo-B and Nogo-A
associate with BACE1. Accordingly, two novel mechanisms, A beta PP overexpression
and ER stress, are involved in Nogo-B and Nogo-A expression in human muscle.
We
propose that in s-IBM muscle the Nogo-B increase may represent an attempt by
muscle fiber to decrease A beta production. However, the increase of Nogo-B
seems
insufficient because A beta continues to accumulate and the disease progresses.
We propose that manipulations, which increase Nogo-B in s-IBM muscle might offer
a new therapeutic opportunity.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17764014 [PubMed - in process]
24: Arthritis Rheum. 2007 Sep;56(9):3112-24.
A possible mechanism for endogenous activation of the type I interferon system
in
myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies.
Eloranta ML, Helmers SB, Ulfgren AK, Rönnblom L, Alm GV, Lundberg IE.
Uppsala University, Uppsala, Sweden.
OBJECTIVE: To investigate type I interferon (IFN) system activation and its
correlation with autoantibodies and organ manifestations in polymyositis (PM),
dermatomyositis (DM), and inclusion body myositis. METHODS: Sera from 30 patients
and 16 healthy controls, or purified IgG, were combined with material released
from necrotized cells to stimulate IFNalpha production by peripheral blood
mononuclear cells (PBMCs) from healthy blood donors. Muscle biopsy specimens
from
25 patients and 7 healthy controls were investigated for blood dendritic cell
antigen 2 (BDCA-2)-positive plasmacytoid dendritic cells (PDCs) and
IFNalpha/beta-inducible myxovirus resistance 1 (MX-1) protein. RESULTS: Sera
from
13 patients who were positive for anti-Jo-1 or anti-Ro 52/anti-Ro 60
autoantibodies induced IFNalpha production in PBMCs when combined with necrotic
cell material. In addition, IgG prepared from anti-Jo-1-positive PM sera induced
IFNalpha with necrotic material, but not when the latter was treated with RNase.
BDCA-2 expression in PDCs in muscle tissue was increased in PM patients with
anti-Jo-1 autoantibodies, while MX-1 staining in capillaries was increased in
DM
patients, compared with healthy individuals. IFNalpha-inducing capacity
correlated with interstitial lung disease, while MX-1 expression in the
capillaries correlated with DM. CONCLUSION: Immune complexes containing anti-Jo-1
or anti-Ro 52/anti-Ro 60 autoantibodies and RNA may act as endogenous IFNalpha
inducers that activate IFNalpha production in PDCs. These PDCs could be of
importance for inducing myositis, whereas in DM patients without autoantibodies
the presence of MX-1 protein in capillaries suggests another cellular IFNalpha
source and induction mechanism. Consequently, the type I IFN system may be of
importance in both PM and DM, but via different pathways.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17763410 [PubMed - indexed for MEDLINE]
25: Eur J Neurol. 2007 Sep;14(9):e14-5.
Hereditary inclusion body myopathy with a novel mutation in the GNE gene
associated with proximal leg weakness and necrotizing myopathy.
Motozaki Y, Komai K, Hirohata M, Asaka T, Ono K, Yamada M.
Publication Types:
Case Reports
Letter
PMID: 17718674 [PubMed - indexed for MEDLINE]
26: Neurology. 2007 Aug 14;69(7):655-9.
GNE protein expression and subcellular distribution are unaltered in HIBM.
Krause S, Aleo A, Hinderlich S, Merlini L, Tournev I, Walter MC, Argov Z,
Mitrani-Rosenbaum S, Lochmüller H.
Friedrich Baur Institute and Department of Neurology, Ludwig Maximilians
University, Munich, Germany.
Mutations in GNE encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine
kinase (GNE) cause hereditary inclusion body myopathy (HIBM). To define the
role
of GNE mutations in HIBM pathogenesis, GNE protein expression was analyzed.
GNE
protein is expressed at equal levels in HIBM patients and normal control
subjects. Immunofluorescence detection of GNE did not reveal any mislocalization
of GNE in skeletal muscle. We conclude that impaired GNE function, not lack
of
expression, may be the key pathogenic factor in HIBM. For diagnostic purposes,
direct genetic analysis of the GNE gene in patients with IBM will remain the
mainstay and is not aided by immunohistochemistry or immunoblotting using
antibodies against the GNE protein.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17698786 [PubMed - indexed for MEDLINE]
27: Muscle Nerve. 2007 Oct;36(4):447-54.
Nuclear localization of valosin-containing protein in normal muscle and muscle
affected by inclusion-body myositis.
Greenberg SA, Watts GD, Kimonis VE, Amato AA, Pinkus JL.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's
Hospital, and Harvard Medical School, Boston, MA 02115, USA.
sagreenberg@partners.org
Inclusion-body myopathy with Paget's disease and frontotemporal dementia (IBMPFD)
is a disease of muscle, bone, and brain that results from mutations in the gene
encoding valosin-containing protein (VCP). The mechanism of disease resulting
from VCP mutations is unknown. Previous studies of VCP localization in normal
human muscle samples have found a capillary and perinuclear distribution, but
not
a nuclear localization. Here we demonstrate that VCP is present in both myonuclei
and endothelial cell nuclei in normal human muscle tissue. The immunodetection
of
VCP varies with acetone or paraformaldehyde fixation. Within the nucleus, VCP
associates with the nucleolar protein fibrillarin and Werner syndrome protein
(Wrnp) in normal and IBMPFD muscle. In patients with inclusion-body myositis
(IBM), normal nuclear localization is present and some rimmed vacuoles are lined
with VCP. These findings suggest that impairment in the nuclear function of
VCP
might contribute to the muscle pathology occurring in IBMPFD.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17626287 [PubMed - indexed for MEDLINE]
28: Arch Pathol Lab Med. 2007 Jul;131(7):1070-6.
Major histocompatibility complex class I and II detection as a diagnostic tool
in
idiopathic inflammatory myopathies.
Jain A, Sharma MC, Sarkar C, Bhatia R, Singh S, Handa R.
Department of Pathology, All India Institute of Medical Sciences, New Delhi,
India.
CONTEXT: Muscle biopsy is at present the gold standard for the diagnosis of
idiopathic inflammatory myopathies (IIMs), which include dermatomyositis,
polymyositis, and inclusion body myositis. Currently, there is no definite
diagnostic marker that helps in the discrimination of different subgroups of
IIMs
and the discrimination of IIMs from other clinical and morphologic mimics. Major
histocompatibility complex (MHC) class I and II antigens are not expressed on
normal muscle fibers. OBJECTIVE: To determine the diagnostic utility of MHC
class
I and II antigen expression on the muscle biopsies from patients with various
neuromuscular disorders and to validate its addition in the existing diagnostic
armamentarium. DESIGN: Expression of MHC class I and II antigen was studied
on
126 muscle biopsies, of which 62 were IIMs and 64 were controls (taken from
patients with other neuromuscular disorders). RESULTS: When compared with
controls, the sensitivity of MHC class I expression for diagnosis of IIMs was
88.7% (100%, 81.6%, and 100% for dermatomyositis, polymyositis, and inclusion
body myositis, respectively), with a specificity of 89.1%. The specificity of
MHC
class II expression was 100% for all IIMs. CONCLUSION: Detection of MHC class
I
and II antigen expression is extremely helpful in the diagnosis of IIMs and
has
high sensitivity and specificity, especially in dermatomyositis. This expression
can be used as a diagnostic tool in discriminating IIMs from other muscle
diseases in which it is either absent or weakly expressed.
PMID: 17616993 [PubMed - indexed for MEDLINE]
29: Best Pract Res Clin Rheumatol. 2007 Jun;21(3):581-96.
Future perspectives: pathogenesis of chronic muscle pain.
Staud R.
Department of Medicine, University of Florida College of Medicine, Gainesville,
FL 32610-0221, USA. staudr@ufl.edu
Chronic painful muscle conditions include non-inflammatory and inflammatory
illnesses. This review is focused on chronic non-inflammatory pain conditions
such as myofascial pain syndrome (MPS) and fibromyalgia syndrome (FM), and will
not discuss metabolic, genetic or inflammatory muscle diseases such as McArdle's
disease, muscular dystrophy, polymyositis, dermatomyositis, or inclusion body
myositis.
Publication Types:
Review
PMID: 17603001 [PubMed - indexed for MEDLINE]
30: Joint Bone Spine. 2007 Jul;74(4):316-8. Epub 2007 May 24.
Biologics in the treatment of primary inflammatory myositis.
Wendling D.
Publication Types:
Editorial
PMID: 17590371 [PubMed - indexed for MEDLINE]
31: Lancet Neurol. 2007 Jul;6(7):620-31.
Inclusion body myositis: current pathogenetic concepts and diagnostic and
therapeutic approaches.
Needham M, Mastaglia FL.
Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, Queen Elizabeth II Medical Centre, Perth, Australia.
Inclusion body myositis is the most common acquired muscle disease in older
individuals, and its prevalence varies among countries and ethnic groups. The
aetiology and pathogenesis of sporadic inclusion body myositis are still poorly
understood; however genetic factors, ageing, and environmental triggers might
all
have a role. Unlike other inflammatory myopathies, sporadic inclusion body
myositis causes slowly progressing muscular weakness and atrophy, it has a
distinctive pattern of muscle involvement, and is unresponsive to conventional
forms of immunotherapy. This review covers the clinical presentation, diagnosis,
treatment, and the latest information on genetic susceptibility and pathogenesis
of sporadic inclusion body myositis.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17582362 [PubMed - indexed for MEDLINE]
32: J Neuroimmunol. 2007 Jul;187(1-2):166-74. Epub 2007 Jun 18.
Upregulation of thrombospondin-1(TSP-1) and its binding partners, CD36 and
CD47,
in sporadic inclusion body myositis.
Salajegheh M, Raju R, Schmidt J, Dalakas MC.
The Division of Neuromuscular Disease, Department of Neurology, Brigham and
Women's Hospital, 75 Francis Street, Tower 5D, Boston, MA 02115, USA.
The TSP1/CD36/CD47-complex is involved in T cell expansion and inflammatory
responses to beta-amyloid, both relevant to IBM. We report on the mRNA and
protein expression of TSP1/ CD36 /CD47-complex in IBM muscles and in human
myoblasts after cytokine stimulation. The TSP1/CD36 /CD47 was upregulated in
IBM.
TSP1 immunolocalized to the connective tissue contiguous to inflammation and
CD36/CD47 on the myofibers and CD8+ cells. Further, TNF-alpha upregulated the
production of TSP1 and CD47 by myoblasts. The TSP-complex is another inflammatory
mediator associated with chronic inflammation in IBM that may perpetuate the
immune responses to local antigens in response to TNF-alpha.
Publication Types:
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
PMID: 17572512 [PubMed - indexed for MEDLINE]
33: Clin Exp Rheumatol. 2007 Mar-Apr;25(2):246-51.
Treatment of inclusion body myositis with cyclosporin-A or tacrolimus: successful
long-term management in patients with earlier active disease and concomitant
autoimmune features.
Quartuccio L, De Marchi G, Scott CA, Ferraccioli G, Beltrami CA, De Vita S.
Clinic of Rheumatology, DPMSC, University of Udine, Italy.
OBJECTIVE: Sporadic inclusion body myositis (s-IBM) is a chronic, progressive,
inflammatory myopathy of unknown aetiology, generally resistant to
immunosuppressive therapy. Given that lymphocyte infiltrates in s-IBM muscle
tissue are CD8+ T cells, targeting these cells may represent a valid approach.
PATIENTS AND METHODS: Three patients with biopsy-proven s-IBM, high creatine
kinase levels at diagnosis, two of whom with associated immune disorders, were
treated with either cyclosporin-A (CyA) or tacrolimus, in combination with high
doses of corticosteroids (CS), followed by rapid CS tapering. Clinical assessment
and laboratory evaluation were performed every three months for the first year
and then every six months for the second year. RESULTS: Based on muscle strength
assessment and muscle enzyme serum levels, a major clinical response was observed
at month +3 in two out of the three patients. A complete clinical response and
major clinical response were obtained at month +6, in two and one patient,
respectively. Normalization of serum muscle enzymes was observed in all. Steroids
could be tapered to very low doses in all patients and were suspended early
in
one. Laboratory, but not clinical relapse occurred in one patient and was
controlled by increasing the CyA dose. Treatment was well tolerated, with no
serious adverse events occurring. All three patients are maintaining
immunosuppressive therapy. CONCLUSION: Calcineurin inhibitors may represent
a
useful option for the long-term management of s-IBM, possibly in a subset
characterized by a short duration with high disease activity or associated
autoimmune manifestations.
Publication Types:
Case Reports
PMID: 17543149 [PubMed - indexed for MEDLINE]
34: Clin Neurophysiol. 2007 Jul;118(7):1563-8. Epub 2007 May 15.
Single-fiber electromyography in sporadic inclusion body myopathy.
Hatanaka Y, Oh SJ.
Department of Neurology, The University of Alabama at Birmingham, The Veterans
Affair Medical Center, UAB Station, Birmingham, AL 35294, USA.
OBJECTIVE: To report the SFEMG findings in sporadic inclusion body myopathy
(S-IBM). METHODS: We have analyzed the SFEMG data in 25 patients (mean age:
63;
16 males) with S-IBM which was diagnosed by the presence of classical rimmed
vacuoles in the muscle biopsy together with clinical, laboratory, and
electrophysiological findings. RESULTS: All patients had fibrillations, positive
sharp waves, and small-amplitude short-duration motor unit potentials (MUPs)
in
the needle EMG. High-amplitude MUPs were observed in eight (32%) patients, two
of
whom had long-duration MUPs. SFEMG was abnormal in 17 (68%) cases: mean "mean
consecutive difference (MCD)" was increased beyond the age-adjusted normal
limit
in 16 cases, and more than 10% of potential pairs (PP) had MCD longer than the
upper normal limit of an individual MCD in one case. Mean fiber density (FD)
was
2.16, with maximum FD being 4.15. Increased FD was noted in 11 (44%) cases.
In
four cases, more than 10% of PP had blocking, but there was no neurogenic
blocking in any PP. As expected, MCD increased linearly (r=0.85) with the
percentage of PP beyond the normal upper limit. CONCLUSIONS: The SFEMG findings
in S-IBM are typical of the classical pattern of myopathy. SIGNIFICANCE: Our
findings support the consensus that S-IBM is a myopathy.
PMID: 17507289 [PubMed - indexed for MEDLINE]
35: Electromyogr Clin Neurophysiol. 2007 Mar-Apr;47(2):97-104.
Serial quantitative electrophysiologic studies in sporadic inclusion body
myositis.
Barkhaus PE, Nandedkar SD.
Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA.
Sporadic inclusion body myositis (S-IBM) is a progressive, acquired myopathic
process of unknown etiology. No known, successful or proven treatment exists.
Quantitative EMG studies including concentric needle motor unit action
potentials, interference pattern, macro-EMG and fiber density have allowed
different measures to be made of the motor unit. These different measures allow
inferences to be made in how the muscle fibers are distributed within both the
normal and diseased motor unit. The present study is an effort to use multiple
quantitative EMG measurements from the biceps brachii on a serial basis in order
to study chronic changes in the motor unit with disease progression. Twenty-eight
studies from 9 patients over a four-year period are shown. We conclude that
while
the concentric needle electrode is most helpful for diagnosing abnormality,
the
less selective macro-EMG and surface electrodes are better suited to monitor
disease progression, especially in very weak muscles. These observations have
practical applications for monitoring disease progression, or conversely,
response to treatment.
Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
PMID: 17479726 [PubMed - indexed for MEDLINE]
36: Autophagy. 2007 Jul-Aug;3(4):396-8. Epub 2007 Jul 12.
Erratum in:
Autophagy. 2007 Nov-Dec;3(6):674.
Comment on:
Hum Mol Genet. 2007 Jan 15;16(2):115-28.
Autophagy in a mouse model of distal myopathy with rimmed vacuoles or hereditary
inclusion body myopathy.
Malicdan MC, Noguchi S, Nishino I.
Department of Neuromuscular Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy
(hIBM) is an autosomal recessive disorder clinically characterized by weakness
that initially involves the distal muscles, although other muscles can be
affected as well. Pathological hallmarks include the presence of rimmed vacuoles
(RVs) and intracellular Congo red-positive depositions in vacuolated or
nonvacuolated fibers. Mutations in the UDP-N-acetylglucosamine
2-epimerase/N-acetylmannosamine kinase (GNE) gene, which encodes the
rate-limiting enzyme in sialic acid biosynthesis, are causative of DMRV/hIBM.
Recently, we have generated a mouse model (Gne(-/-)hGNEV572L-Tg) for this
disease, and have shown that these mice exhibit hyposialylation and intracellular
amyloid deposition before the characteristic RVs are detected, indicating that
autophagy is a downstream phenomenon to hyposialylation and amyloid deposition
in
DMRV/hIBM.
Publication Types:
Comment
Research Support, Non-U.S. Gov't
PMID: 17471014 [PubMed - indexed for MEDLINE]
37: Ann Neurol. 2007 May;61(5):476-83.
Comment in:
Autophagy. 2007 Jul-Aug;3(4):384-6.
Beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis.
Lünemann JD, Schmidt J, Schmid D, Barthel K, Wrede A, Dalakas MC, Münz C.
Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology
and Immune Diseases, The Rockefeller University, New York, NY 10021, USA.
OBJECTIVE: Sporadic Inclusion Body Myositis (sIBM) is the most common acquired
muscle disease in patients above 50 years of age. Apart from inflammation in
the
skeletal muscle, overexpression of amyloid precursor protein (APP) and
intracellular accumulation of its proteolytic fragment beta-amyloid play a
central role in the pathogenesis of sIBM. In neurodegenerative disorders, similar
aggregations of aberrant proteins have recently been shown to be susceptible
to
autophagic degradation. Therefore, we analyzed macroautophagy of APP in human
muscle cell lines and sIBM muscle biopsies. METHODS: Colocalization of APP with
the essential autophagy protein Atg8/LC3, which associates with preautophagosomal
and autophagosomal membranes via lipidation, was analyzed in the CCL-136 muscle
cell line and muscle biopsies by immunofluorescence. While APP was visualized
with specific antibodies in the muscle cell line and in tissue sections. Atg8/LC3
localization was analyzed after GFP-Atg8/LC3 transfection or with an Atg8/LC3
specific antiserum, respectively. RESULTS: We demonstrate here that Atg8/LC3
colocalizes with APP in cultured human muscle cells. In addition,
APP/beta-amyloid-containing autophagosomes can be observed at increased frequency
in muscle fibers of sIBM muscle biopsies, but not in non-myopathic muscle or
non-vacuolated myopathic controls. APP/beta-amyloid and Atg8/LC3 double-positive
compartments were almost exclusively observed in degenerating muscle fibers
of
the type II (fast-twitching) and were in part associated with overexpression
of
major histocompatibility complex (MHC) class I and II on myofibers and invasion
by CD4(+) and CD8(+) cells. INTERPRETATION: These findings indicate that
APP/beta-amyloid is targeted for lysosomal degradation via macroautophagy and
suggest that the autophagy pathway should be explored for its potential
therapeutic merit in sIBM.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17469125 [PubMed - indexed for MEDLINE]
38: Muscle Nerve. 2007 Nov;36(5):721-5.
Myositis with sensory neuronopathy.
França MC Jr, Faria AV, Queiroz LS, Nucci A.
Department of Neurology, School of Medical Sciences, Campinas State University,
Zeferino Vaz, Campinas, SP 13083-970, Brazil.
Inflammatory myopathies (IM) are a heterogeneous group of diseases characterized
by immune-mediated damage to skeletal muscle. Sensory abnormalities are rare
in
patients with IM. We report two patients, one with dermatomyositis and the other
with inclusion-body myositis, who presented with unexpected sensory abnormalities
due to probable immune-mediated damage to dorsal root ganglia. We emphasize
the
importance of combined neuroimaging and neurophysiological assessment for proper
diagnosis.
Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
PMID: 17469107 [PubMed - indexed for MEDLINE]
39: Acta Neuropathol. 2007 Jul;114(1):55-61. Epub 2007 Apr 25.
Valosin-containing protein and the pathogenesis of frontotemporal dementia
associated with inclusion body myopathy.
Guinto JB, Ritson GP, Taylor JP, Forman MS.
Department of Pathology and Laboratory Medicine, University of Pennsylvania
School of Medicine, 422 Curie Blvd., 605B Stellar-Chance Building, Philadelphia,
PA, 19104-6140, USA.
Frontotemporal dementia with inclusion body myopathy and Paget's disease of
bone
(IBMPFD) is a rare, autosomal dominant disorder caused by mutations in the gene
valosin-containing protein (VCP). The CNS pathology is characterized by a novel
pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal
lobar degeneration with ubiquitin-positive inclusions without VCP mutations.
Yet,
the ubiquitin-positive inclusions in IBMPFD also stain for TAR DNA binding
protein, a feature that links this rare disease with the pathology associated
with the majority of sporadic FTD as well as disease resulting from different
genetic alterations. VCP, a member of the AAA-ATPase gene family, associates
with
a plethora of protein adaptors to perform a variety of cellular processes
including Golgi assembly/disassembly and regulation of the ubiquitin-proteasome
system. However, the mechanism whereby mutations in VCP lead to CNS, muscle,
and
bone disease is largely unknown. In this report, we review current literature
on
IBMPFD, focusing on the pathology of the disease and the biology of VCP with
respect to IBMPFD.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 17457594 [PubMed - indexed for MEDLINE]
40: Autophagy. 2007 Jul-Aug;3(4):384-6. Epub 2007 Jul 9.
Comment on:
Ann Neurol. 2007 May;61(5):476-83.
Macroautophagy as a pathomechanism in sporadic inclusion body myositis.
Lünemann JD, Schmidt J, Dalakas MC, Münz C.
Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology
and Immune Diseases, The Rockefeller University, New York, New York 10021, USA.
Skeletal muscle fibers show a high level of constitutive and starvation-induced
macroautophagy. Sporadic Inclusion Body Myositis (sIBM) is the most common
acquired skeletal muscle disease in patients above the age of 50 years and is
characterized by inflammation and intracellular accumulation of aggregate-prone
proteins such as amyloid precursor protein (APP)/beta-amyloid,
hyperphosphorylated tau, and presenilin. In a recent study, we found that muscle
fibers of sIBM patients show increased frequencies of Atg8/LC3(+) autophagosomes
and that intracellular APP/beta-amyloid colocalized with Atg8/LC3 in degenerating
fibers. Colocalization of APP/beta-amyloid with LC3(+) autophagosomes was further
associated with upregulation of major histocompatibility complex (MHC) class
I
and class II molecules and T cell infiltration. These findings indicate that
APP/beta-amyloid is a substrate for autophagy in skeletal muscle fibers and
suggest that degradation of aggregate-prone proteins via macroautophagy can
be
linked with both immune-mediated and degenerative tissue damage. A better
understanding of this pathway in skeletal muscle and in the inflammatory
environment of sIBM might provide a rationale for novel therapeutic strategies
targeting pathogenic protein aggregation.
Publication Types:
Comment
PMID: 17438365 [PubMed - indexed for MEDLINE]
41: Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6800-5. Epub 2007 Apr 9.
Inducible overexpression of wild-type prion protein in the muscles leads to
a
primary myopathy in transgenic mice.
Huang S, Liang J, Zheng M, Li X, Wang M, Wang P, Vanegas D, Wu D, Chakraborty
B,
Hays AP, Chen K, Chen SG, Booth S, Cohen M, Gambetti P, Kong Q.
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106,
USA.
The prion protein (PrP) level in muscle has been reported to be elevated in
patients with inclusion-body myositis, polymyositis, dermatomyositis, and
neurogenic muscle atrophy, but it is not clear whether the elevated PrP
accumulation in the muscles is sufficient to cause muscle diseases. We have
generated transgenic mice with muscle-specific expression of PrP under extremely
tight regulation by doxycycline, and we have demonstrated that
doxycycline-induced overexpression of PrP strictly limited to muscles leads
to a
myopathy characterized by increased variation of myofiber size, centrally located
nuclei, and endomysial fibrosis, in the absence of intracytoplasmic inclusions,
rimmed vacuoles, or any evidence of a neurogenic disorder. The PrP-induced
myopathy correlates with accumulation of an N-terminal truncated PrP fragment
in
the muscle, and the muscular PrP displayed consistent mild resistance to protease
digestion. Our findings indicate that overexpression of wild-type PrP in skeletal
muscles is sufficient to cause a primary myopathy with no signs of peripheral
neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP
and/or PrP aggregation.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 17420473 [PubMed - indexed for MEDLINE]
42: Mayo Clin Proc. 2007 Apr;82(4):441-7.
Dysphagia in inflammatory myopathy: clinical characteristics, treatment
strategies, and outcome in 62 patients.
Oh TH, Brumfield KA, Hoskin TL, Stolp KA, Murray JA, Bassford JR.
Department of Physical Medicine and Rehabilitation, College of Medicine, Mayo
Clinic, 200 First St SW, Rochester, MN 55905, USA. oh.terry@mayo.edu
OBJECTIVE: To assess the clinical characteristics, treatment, and outcome of
patients with inflammatory myopathy-associated dysphagia. PATIENTS AND METHODS:
We retrospectively reviewed the medical records of all patients with inflammatory
myopathy-associated dysphagia seen at the Mayo Clinic in Rochester, Minn, between
January 1, 1997, and December 31, 2001. RESULTS: A total of 783 patients were
diagnosed as having inflammatory myopathy during the 5-year study period. Of
these, 62 patients (41 women and 21 men; mean age, 68.6 years) had inflammatory
myopathy-associated dysphagia: 26 with inclusion body myositis (IBM), 18 with
dermatomyositis, 9 with polymyositis, and 9 with overlap syndrome. Dysphagia
was
a presenting symptom in 13 patients (21%), with the highest incidence in the
IBM
group. Videofluoroscopic examinations revealed pharyngeal pooling and impaired
oropharyngeal and cricopharyngeal function. The benefits of swallowing
compensation techniques and exercises were difficult to establish. Interventional
procedures were performed in 24 patients (39%) and most frequently (62%) in
patients with IBM, with cricopharyngeal myotomy being most beneficial. Patients
with IBM had the least symptomatic improvement. Overall, 11 patients died during
the median follow-up of 38 months, with respiratory failure due to aspiration
pneumonia as the most common cause. Mortality was high in patients who required
percutaneous endoscopic gastrostomy (7/11, 64%), and 1- year mortality was
highest (31%) in those with dermatomyositis. CONCLUSION: Dysphagia is a serious
and at times presenting problem in patients with inflammatory myopathy. It occurs
most frequently and appears to be most refractory in patients with IBM. The
mortality rate was high in patients who required percutaneous endoscopic
gastrostomy, and the 1-year mortality rate was the highest in patients with
dermatomyositis.
PMID: 17418072 [PubMed - indexed for MEDLINE]
43: Acta Neuropathol. 2007 Nov;114(5):537-42. Epub 2007 Mar 29.
Myopathy with tubulin-reactive inclusions in two cats.
Shelton GD, Sturges BK, Lyons LA, Williams DC, Aleman M, Jiang Y, Mizisin AP.
Department of Pathology 0709, University of California, San Diego, La Jolla,
CA
92093-0709, USA. gshelton@ucsd.edu
Many types of inclusions have been described in human myopathies including
but
not limited to nemaline rod bodies, cylindrical spirals, tubular aggregates,
cytoplasmic bodies, reducing bodies, and fingerprint bodies, and hyaline
inclusions in myofibrillar myopathy and inclusion body myositis. There are very
few reports describing inclusions in spontaneously occurring myopathies in cats,
and these reports are limited to nemaline rod myopathy. A myopathy with
tubulin-reactive crystalline inclusions has recently been reported in a human
patient with a clinical presentation of myalgia and fatigue. Similarly, a
myopathy with chronic, slowly progressive muscle weakness has been identified
here in two unrelated cats. Inclusions were the only pathological change in
skeletal muscle biopsies and, ultrastructurally, groups of crystalline structures
were evident that had a subsarcolemmal or central location, rhomboid or
rectangular shapes, lacked orientation, and were not membrane bound. The
crystalline structures reacted positively with an antibody against tubulin.
This
feline myopathy may be the equivalent of the human myopathy with tubulin-positive
crystalline inclusions.
PMID: 17393175 [PubMed - in process]
44: Arthritis Res Ther. 2007;9(2):208.
Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies.
Grundtman C, Malmström V, Lundberg IE.
Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna,
Karolinska Institutet, SE-171 76 Stockholm, Sweden. cecilia.grundtman@ki.se
Idiopathic inflammatory myopathies (IIMs), comprising polymyositis,
dermatomyositis, and inclusion-body myositis, are characterized by inflammatory
cell infiltrates in skeletal muscle tissue, muscle weakness, and muscle fatigue.
The cellular infiltrates often consist of T lymphocytes and macrophages but
also,
in some cases, B lymphocytes. Emerging data have led to improved phenotypic
characterization of the inflammatory cells, including their effector molecules,
in skeletal muscle, peripheral blood, and other organs that are frequently
involved, such as skin and lungs. In this review we summarize the latest findings
concerning the role of T lymphocytes, B lymphocytes, dendritic cells, and other
antigen-presenting cells in the pathophysiology of IIMs.
Publication Types:
Review
PMID: 17389031 [PubMed - indexed for MEDLINE]
45: Ann Neurol. 2007 May;61(5):466-75.
Inclusion body myositis with human immunodeficiency virus infection: four cases
with clonal expansion of viral-specific T cells.
Dalakas MC, Rakocevic G, Shatunov A, Goldfarb L, Raju R, Salajegheh M.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
OBJECTIVE: Sporadic inclusion body myositis (sIBM), a common adult-onset
myositis, is characterized by an antigen-driven inflammatory response and
vacuolar degeneration. The cause is unknown. We report the association of sIBM
with human immunodeficiency virus (HIV) infection and explore the clonality
and
viral specificity of the autoinvasive T cells. METHODS: Clinicopathological
studies in four HIV-infected patients with IBM were performed. The clonal
restriction of endomysial T cells, compared with peripheral blood, was examined
by spectratyping. Immunohistochemical studies using human leukocyte antigen-A*
0201-gag tetramers and the most dominant Vb families were performed in serial
muscle biopsy sections to examine whether clonally expanded autoinvasive T cells
are viral specific and invade muscle fibers expressing the allele-specific
monomorphic major histocompatibility complex class I antigen. RESULTS: Prominent
clonal restriction of certain Vb families was noted among the endomysial T cells
with evidence of in situ expansion. Approximately 10% of the autoinvasive CD8(+)
cells were human leukocyte antigen-A* 0201-HIV-gag specific and invaded muscle
fibers expressing the specific human leukocyte antigen-A* 0201 allele. These
cells belonged to restricted Vb families. The HIV gag antigen was present on
several endomysial macrophages but not within the muscle fibers. INTERPRETATION:
sIBM develops in patients who harbor HIV. In HIV-IBM, a subset of CD8(+) T cells
surrounding muscle fibers are viral specific and may play a role in the disease
mechanism by cross-reacting with antigens on the surface of muscle fibers. This
study provides a paradigm that a chronic viral infection in genetically
susceptible individuals can trigger viral specific T cell clones that persist
within the muscle and lead to development of sIBM.
Publication Types:
Case Reports
Research Support, N.I.H., Intramural
PMID: 17366634 [PubMed - indexed for MEDLINE]
46: Muscle Nerve. 2007 May;35(5):549-61.
Genetics of inclusion-body myositis.
Needham M, Mastaglia FL, Garlepp MJ.
Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, Level 4, A Block, Queen Elizabeth II Medical Centre, Nedlands, Western
Australia 6009, Australia. Needhm01@student.uwa.edu.au
Sporadic inclusion-body myositis (sIBM) is the most common acquired muscle
disease in Caucasians over the age of 50 years. Pathologically it is marked
by
inflammatory, degenerative, and mitochondrial changes that interact in a
yet-unknown way to cause progressive muscle degeneration and weakness. The cause
of the disease is unknown, but it is thought to involve a complex interplay
between environmental factors, genetic susceptibility, and aging. The strongest
evidence for genetic susceptibility comes from studies of the major
histocompatibility complex (MHC), where different combinations of alleles have
been associated with sIBM in different ethnic groups. The rare occurrence of
familial cases of inclusion-body myositis (fIBM) adds additional evidence for
genetic susceptibility. Other candidate genes such as those encoding some of
the
proteins accumulating in muscle fibers have been investigated, with negative
results. The increased understanding of related disorders, the hereditary
inclusion-body myopathies (hIBM), may also provide clues to the underlying
pathogenesis of sIBM, but to date there is no indication that the genes
responsible for these conditions are involved in sIBM. This review summarizes
current understanding of the contribution of genetic susceptibility factors
to
the development of sIBM.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17366591 [PubMed - indexed for MEDLINE]
47: Neuropathol Appl Neurobiol. 2007 Apr;33(2):238-42.
Myostatin precursor protein is increased and associates with amyloid-beta
precursor protein in inclusion-body myositis culture model.
Wojcik S, Nogalska A, McFerrin J, Engel WK, Oledzka G, Askanas V.
Publication Types:
Letter
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17359364 [PubMed - indexed for MEDLINE]
48: Hum Mol Genet. 2007 Apr 15;16(8):919-28. Epub 2007 Feb 28.
Transgenic expression of inclusion body myopathy associated mutant p97/VCP
causes
weakness and ubiquitinated protein inclusions in mice.
Weihl CC, Miller SE, Hanson PI, Pestronk A.
Department of Neurology, Washington University School of Medicine, 660 S. Euclid
Avenue, Saint Louis, MO 63110, USA. weihlc@neuro.wustl.edu
Mutations in p97/VCP cause the autosomal-dominant, inherited syndrome inclusion
body myopathy (IBM) associated with Paget's disease of the bone and
frontotemporal dementia (IBMPFD) (Watts, G.D., Wymer, J., Kovach, M.J., Mehta,
S.G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M.P. and Kimonis, V.E. (2004)
Inclusion body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein. p97/VCP is a
multi-functional protein with a role in the ubiquitin-proteasome system (UPS)
(Wang, Q., Song, C. and Li, C.C. (2004) Molecular perspectives on p97-VCP:
progress in understanding its structure and diverse biological functions. To
understand how mutations in this protein lead to a myopathy, we generated several
lines of transgenic mice expressing p97/VCP-WT (TgVCP-WT) or the most common
IBMPFD mutant, p97/VCP R155H (TgVCP-RH), under a muscle-specific promoter.
TgVCP-RH animals, but not controls, became progressively weaker in a
dose-dependent manner starting at 6 months of age. Abnormal muscle pathology,
which included coarse internal architecture, vacuolation and disorganized
membrane morphology with reduced caveolin-3 expression at the sarcolemma
developed coincident with the onset of weakness. These changes were not
associated with alterations in sarcolemmal integrity as measured by muscle fiber
uptake of Evan's blue dye. Even before animals displayed measurable weakness,
there was an increase in ubiquitin-containing protein inclusions and
high-molecular-weight ubiquitinated proteins, markers of UPS dysfunction. We
suggest that this early and persistent increase in ubiquitinated proteins induced
by IBMPFD mutations in p97/VCP may ultimately lead to animal weakness and the
observed muscle pathology. TgVCP-RH animals will be a valuable tool for
understanding the pathogenesis of IBM and the role of the UPS in skeletal muscle.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 17329348 [PubMed - indexed for MEDLINE]
49: J Neuropathol Exp Neurol. 2007 Feb;66(2):152-7.
TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene
mutations.
Neumann M, Mackenzie IR, Cairns NJ, Boyer PJ, Markesbery WR, Smith CD, Taylor
JP,
Kretzschmar HA, Kimonis VE, Forman MS.
Center for Neuropathology and Prion Research, Ludwig-Maximilians University,
Munich, Germany.
Frontotemporal dementia with inclusion body myopathy and Paget disease of bone
is
a rare, autosomal-dominant disorder caused by mutations in the gene
valosin-containing protein (VCP). The CNS pathology is characterized by a novel
pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal
lobar degeneration with ubiquitin-positive inclusions (FTLD-U) without VCP
mutations. TAR DNA binding protein 43 (TDP-43) was recently identified as a
major
disease protein in the ubiquitin-positive inclusions of sporadic and familial
FTLD-U. To determine whether the ubiquitin pathology associated with mutations
in
VCP is characterized by the accumulation of TDP-43, we analyzed TDP-43 in the
CNS
pathology of five patients with VCP gene mutations. Accumulations of TDP-43
colocalized with ubiquitin pathology in inclusion body myopathy and Paget disease
of bone, including both intranuclear inclusions and dystrophic neurites. Similar
to FTLD-U, phosphorylated TDP-43 was detected only in insoluble brain extracts
from affected brain regions. Identification of TDP-43, but not VCP, within
ubiquitin-positive inclusions supports the hypothesis that VCP gene mutations
lead to a dominant negative loss or alteration of VCP function culminating in
impaired degradation of TDP-43. TDP-43 is a common pathologic substrate linking
a
variety of distinct patterns of FTLD-U pathology caused by different genetic
alterations.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17279000 [PubMed - indexed for MEDLINE]
50: Ann Rheum Dis. 2007 Oct;66(10):1276-83. Epub 2007 Feb 2.
Limited effects of high-dose intravenous immunoglobulin (IVIG) treatment on
molecular expression in muscle tissue of patients with inflammatory myopathies.
Helmers SB, Dastmalchi M, Alexanderson H, Nennesmo I, Esbjörnsson M, Lindvall
B,
Lundberg IE.
Rheumatology Unit, Department of Medicine, Karolinska University Hospital,
Solna,
Karolinska Institutet, Stockholm, Sweden. Sevim.Barbasso@ki.se
OBJECTIVES: The study was conducted with the aim of achieving an improved
understanding of the molecular mechanisms of high-dose intravenous immunoglobulin
(IVIG) in inflammatory myopathies by investigating the effects on muscle function
and immunological molecules in skeletal muscle of polymyositis (PM),
dermatomyositis (DM) and inclusion body myositis (IBM) patients. METHODS:
Thirteen treatment-resistant patients, 6 PM, 4 DM, 2 IBM and 1 juvenile DM,
were
treated with 2 g/kg of IVIG, three times at monthly intervals. Functional Index
in Myositis and serum creatinine kinase (CK) levels were determined, and muscle
biopsies were performed before treatment and after the third IVIG infusion.
Immunological molecules were also studied in biopsies taken 24-48 h after the
first infusion. RESULTS: Improved muscle function was observed in three patients
(1 PM, 1 DM and 1 IBM) and CK levels decreased in five. T cells, macrophages,
major histocompatibility complex (MHC) class I antigen on muscle fibres,
intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1
(VCAM-1) expression and membranolytic attack complex (MAC) deposits on
capillaries were present to an equal degree in biopsies before and after IVIG
treatment. No correlation between the clinical response and molecular changes
was
found. CONCLUSIONS: The clinical effects of high-dose IVIG on muscle function
in
patients with refractory inflammatory active myositis did not correspond to
effects on any of the investigated molecules in our study. T cells, macrophages,
phenotypical changes in muscle fibres and endothelial cell activation were still
present after treatment. These observations question a role for IVIG as an
immune-modulating therapy in patients with inflammatory myopathies.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17277004 [PubMed - indexed for MEDLINE]
51: J Physiol. 2007 Mar 15;579(Pt 3):671-7. Epub 2007 Feb 1.
Pathogenic point mutations in a transmembrane domain of the epsilon subunit
increase the Ca2+ permeability of the human endplate ACh receptor.
Di Castro A, Martinello K, Grassi F, Eusebi F, Engel AG.
Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia
Umana
e Farmacologia, Università La Sapienza P.le A. Moro 5; I-00185 Roma,
Italy.
The epsilon subunit of the human endplate ACh receptor (AChR) is a key
determinant of the large fraction of the ACh-evoked current carried by Ca2+
ions
(P(f)). Consequently, missense mutations in the epsilon subunit are potential
targets for altering the P(f) of human AChR. In this paper we investigate the
effects of two pathogenic point mutations in the M2 transmembrane segment AChR
epsilon subunit, epsilonT264P and epsilonV259F, that cause slow-channel syndromes
(SCS). When expressed in GH4C1 cells, the mutant receptors subunits raise Ca2+
permeability of the receptors approximately 1.5 and approximately 2-fold above
that of wild-type, to attain P(f) values of 11.8% (epsilonT264P) and 15.4%
(epsilonV259F). The latter value exceeds most P(f) values reported to date for
ligand-gated ion channels. Consistent with these findings, the biionic Ca2+
permeability ratio (P(Ca)/P(Cs)) of the mutant AChRs is also increased. Upon
repetitive stimulation with ACh, the mutant receptors show an enhanced current
run-down compared with wild-type, leading to a strong reduction of their
function. We propose that the enhanced Ca2+ permeability of the mutant receptors
overrides the protective effect of desensitization and, together with the
prolonged opening events of the AChR channel, is an important determinant of
the
excitotoxic endplate damage in the SCS.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17272341 [PubMed - indexed for MEDLINE]
52: Exp Neurol. 2007 Apr;204(2):610-8. Epub 2006 Dec 23.
Endoplasmic reticulum stress induces myostatin precursor protein and NF-kappaB
in
cultured human muscle fibers: relevance to inclusion body myositis.
Nogalska A, Wojcik S, Engel WK, McFerrin J, Askanas V.
Department of Neurology, USC Neuromuscular Center, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, 637 S. Lucas Avenue,
Los Angeles, CA 90017, USA.
Sporadic-inclusion body myositis (s-IBM) is the most common progressive muscle
disease of older persons. It leads to pronounced muscle fiber atrophy and
weakness, and there is no successful treatment. We have previously shown that
myostatin precursor protein (MstnPP) and myostatin (Mstn) dimer are increased
in
biopsied s-IBM muscle fibers, and proposed that MstnPP/Mstn increase may
contribute to muscle fiber atrophy and weakness in s-IBM patients. Mstn is known
to be a negative regulator of muscle fiber mass. It is synthesized as MstnPP,
which undergoes posttranslational processing in the muscle fiber to produce
mature, active Mstn. To explore possible mechanisms involved in Mstn
abnormalities in s-IBM, in the present study we utilized primary cultures of
normal human muscle fibers and experimentally modified the intracellular
micro-environment to induce endoplasmic-reticulum (ER)-stress, thereby mimicking
an important aspect of the s-IBM muscle fiber milieu. ER stress was induced
by
treating well-differentiated cultured muscle fibers with either tunicamycin
or
thapsigargin, both well-established ER stress inducers. Our results indicate
for
the first time that the ER stress significantly increased MstnPP mRNA and
protein. The results also suggest that in our system ER stress activates
NF-kappaB, and we suggest that MstnPP increase occurred through the
ER-stress-activated NF-kappaB. We therefore propose a novel mechanism leading
to
the Mstn increase in s-IBM. Accordingly, interfering with pathways inducing
ER
stress, NF-kappaB activation or its action on the MstnPP gene promoter might
prevent Mstn increase and provide a new therapeutic approach for s-IBM and,
possibly, for muscle atrophy in other neuromuscular diseases.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17261282 [PubMed - indexed for MEDLINE]
53: BMC Neurol. 2007 Jan 29;7:3.
Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study.
Sparks S, Rakocevic G, Joe G, Manoli I, Shrader J, Harris-Love M, Sonies B,
Ciccone C, Dorward H, Krasnewich D, Huizing M, Dalakas MC, Gahl WA.
Medical Genetics Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, MD, USA. ssparks@mail.nih.gov
<ssparks@mail.nih.gov>
BACKGROUND: Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive,
adult onset, non-inflammatory neuromuscular disorder with no effective treatment.
The causative gene, GNE, codes for UDP-N-acetylglucosamine
2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions
in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins,
such as alpha-dystroglycan and neural cell adhesion molecule (NCAM), has been
reported in HIBM. METHODS: We treated 4 HIBM patients with intravenous immune
globulin (IVIG), in order to provide sialic acid, because IgG contains 8 micromol
of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive
days followed by 3 doses of 400 mg/kg at weekly intervals. RESULTS: For all
four
patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2
kg
(+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study.
Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly
after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite
improvement for 8 other muscle groups was 5% after the initial loading and 19%
by
the end of the study. Esophageal motility and lingual strength improved in the
patients with abnormal barium swallows. Objective measures of functional
improvement gave variable results, but the patients experienced improvements
in
daily activities that they considered clinically significant. Immunohistochemical
staining and immunoblotting of muscle biopsies for alpha-dystroglycan and NCAM
did not provide consistent evidence for increased sialylation after IVIG
treatment. Side effects were limited to transient headaches and vomiting.
CONCLUSION: The mild benefits in muscle strength experienced by HIBM patients
after IVIG treatment may be related to the provision of sialic acid supplied
by
IVIG. Other sources of sialic acid are being explored as treatment options for
HIBM.
Publication Types:
Case Reports
Research Support, N.I.H., Intramural
PMID: 17261181 [PubMed - indexed for MEDLINE]
54: Neuromuscul Disord. 2007 Feb;17(2):186-93. Epub 2007 Jan 23.
Distribution of glucocorticoid receptor alpha and beta subtypes in the idiopathic
inflammatory myopathies.
De Bleecker JL, De Paepe B, Vervaet VL, Arys B, Creus KK, Werbrouck BF, Martin
JJ.
Department of Neurology, Ghent University Hospital, De Pintelaan 185, B-9000
Gent, Belgium. jan.debleecker@Ugent.be
In contrast with dermatomyositis and polymyositis, inclusion body myositis
is
unresponsive to glucocorticoid treatment. Glucocorticoid action is mediated
through an active glucocorticoid receptor-alpha and negatively regulated by
another glucocorticoid receptor isoform. In several autoimmune diseases
glucocorticoid receptor-beta up-regulation is involved in glucocorticoid
resistance. We studied glucocorticoid receptor distribution in normal and
inflammatory myopathy muscle and investigated whether differences in
glucocorticoid receptor-alpha and glucocorticoid receptor-beta protein expression
are involved in the differential glucocorticoid sensitivity in inclusion body
myositis versus polymyositis. Multistep immunofluorescence and Western blotting
on fractionated cytoplasmic or nuclear muscle samples were used. Glucocorticoid
receptor-alpha was the predominant receptor subtype in muscle and occurred
abundantly in myonuclei of control and diseased muscle alike. Glucocorticoid
receptor-beta was constitutively expressed on a subset of endothelial cells.
No
differences between dermatomyositis and the other idiopathic inflammatory
myopathies were observed. Increased nuclear glucocorticoid receptor that has
dissociated from heat shock protein 90 was found in glucocorticoid treated
subjects. Glucocorticoid receptor-alpha and -beta isoform levels were unaltered
in muscle tissues from control subjects that had received glucocorticoid
treatment prior to biopsy. No differences in relative glucocorticoid
receptor-alpha and glucocorticoid receptor-beta protein expression were seen
in
inclusion body myositis versus polymyositis specimens. Our study indicates that
the different glucocorticoid sensitivity in the idiopathic inflammatory
myopathies is not related to up- or down-regulation of a given glucocorticoid
receptor isoform at the protein level.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17251024 [PubMed - indexed for MEDLINE]
55: J Immunol. 2007 Feb 1;178(3):1523-33.
BTNL2, a butyrophilin/B7-like molecule, is a negative costimulatory molecule
modulated in intestinal inflammation.
Arnett HA, Escobar SS, Gonzalez-Suarez E, Budelsky AL, Steffen LA, Boiani N,
Zhang M, Siu G, Brewer AW, Viney JL.
Inflammation, Amgen, Seattle, WA 98119, USA.
Butyrophilin-like 2 (BTNL2) is a butyrophilin family member with homology to
the
B7 costimulatory molecules, polymorphisms of which have been recently associated
through genetic analyses to sporadic inclusion body myositis and sarcoidosis.
We
have characterized the full structure, expression, and function of BTNL2.
Structural analysis of BTNL2 shows a molecule with an extracellular region
containing two sets of two Ig domains, a transmembrane region, and a previously
unreported cytoplasmic tail. Unlike most other butyrophilin members, BTNL2 lacks
the prototypical B30.2 ring domain. TaqMan and Northern blot analysis indicate
BTNL2 is predominantly expressed in digestive tract tissues, in particular small
intestine and Peyer's patches. Immunohistochemistry with BTNL2-specific Abs
further localizes BTNL2 to epithelial and dendritic cells within these tissues.
Despite its homology to the B7 family, BTNL2 does not bind any of the known
B7
family receptors such as CD28, CTLA-4, PD-1, ICOS, or B and T lymphocyte
attenuator. Because of its localization in the gut and potential role in the
immune system, BTNL2 expression was analyzed in a mouse model of inflammatory
bowel disease. BTNL2 is overexpressed during both the asymptomatic and
symptomatic phase of the Mdr1a knockout model of spontaneous colitis. In
functional assays, soluble BTNL2-Fc protein inhibits the proliferation of murine
CD4(+) T cells from the spleen, mesenteric lymph node, and Peyer's patch. In
addition, BTNL2-Fc reduces proliferation and cytokine production from T cells
activated by anti-CD3 and B7-related protein 1. These data suggest a role for
BTNL2 as a negative costimulatory molecule with implications for inflammatory
disease.
PMID: 17237401 [PubMed - indexed for MEDLINE]
56: Drug News Perspect. 2006 Nov;19(9):549-57.
Potential therapeutic targets for idiopathic inflammatory myopathies.
De Bleecker JL, Creus KK, De Paepe B.
Department of Neurology, Ghent University Hospital, Ghent, Belgium.
jan.debleecker@Ugent.be
The inflammatory myopathies essentially comprise three diseases with different
immunopathologic features. Dermatomyositis (DM) is a complement-mediated
microangiopathy. The immune response in polymyositis (PM) and sporadic inclusion
body myositis (IBM) is a CD8+ T-cell-mediated cellular reaction against an
unknown muscle fiber antigen. The multiple immune factors that guide inflammatory
cell diapedesis and trafficking have been elucidated over the past two decades.
Many of these molecules can now be targeted by monoclonal antibodies and other
pharmacologic approaches. Randomized controlled trials are being started on
a
number of new agents to find out whether more specific immune interventions
than
the currently used glucocorticosteroids can treat DM and PM patients with fewer
side effects, and may represent a first treatment modality for IBM, an entity
unresponsive to all currently available pharmacological treatments. Copyright
2006 Prous Science. All rights reserved.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17220960 [PubMed - indexed for MEDLINE]
57: Neurobiol Dis. 2007 Mar;25(3):665-74. Epub 2007 Jan 3.
The cell-specific expression of metalloproteinase-disintegrins (ADAMs) in
inflammatory myopathies.
Dehmel T, Janke A, Hartung HP, Goebel HH, Wiendl H, Kieseier BC.
Department of Neurology, Heinrich-Heine University, Moorenstrasse 5, 40225
Duesseldorf, Germany.
Inflammatory cell invasion and cytokine activation are important steps in the
pathogenesis of immune-mediated diseases of muscle.
Metalloproteinase-disintegrins (ADAMs) are considered to play a critical role
in
leukocyte migration by promoting cellular adhesion, cleavage of molecules of
the
extracellular matrix and shedding of membrane bound cytokines. Here, we report
the expression patterns of ADAM8, ADAM9, ADAM10, ADAM12, ADAM17 and ADAM19 in
cultured human myoblasts and peripheral blood mononuclear cells (PBMCs) in vitro,
as well as in biopsies from patients suffering from polymyositis (PM),
dermatomyositis (DM), inclusion body myositis (IBM) and non-inflammatory
controls. We observed an in vitro downregulation of the RNAs of ADAM10, ADAM17
and ADAM19 in myoblasts after stimulation with various pro- and anti-inflammatory
mediators, whereas in PBMCs an RNA upregulation of ADAM9, ADAM10, ADAM17 and
ADAM19 was detectable under identical conditions. In human muscle biopsies,
invading CD3+ T lymphocytes expressed ADAM17 and ADAM19, whereas macrophages
co-localized to ADAM8, as detected by immunohistochemistry. Transfection of
PBMCs
with ADAM19 single interfering RNA and incubation with a metalloproteinase
inhibitor suggest proteolytic activity of ADAM19 and involvement in the shedding
of tumor necrosis factor-alpha. No differences in the cellular expression
profiles between PM, DM and IBM were found, whereas the sections from
non-inflammatory controls did not reveal any positive immunoreactivity for ADAMs,
except for ADAM10, which is localized exclusively to muscle fibres. Our results
suggest that certain ADAMs are expressed by specific cell populations during
the
genesis of immune-mediated diseases of human muscle.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17207628 [PubMed - indexed for MEDLINE]
58: Arthritis Rheum. 2007 Jan;56(1):372-83.
Restricted T cell receptor BV gene usage in the lungs and muscles of patients
with idiopathic inflammatory myopathies.
Englund P, Wahlström J, Fathi M, Rasmussen E, Grunewald J, Tornling G,
Lundberg
IE.
Karolinska University Hospital at Solna, and Karolinska Institutet, Stockholm,
Sweden.
OBJECTIVE: To investigate T cell receptor (TCR) expression in 3 different
compartments that could be involved in patients with myositis: muscle, lung,
and
peripheral blood. METHODS: Nine patients with polymyositis (PM), dermatomyositis,
or inclusion body myositis underwent bronchoscopy and bronchoalveolar lavage
(BAL) as well as muscle biopsy and blood sampling. A panel of 19 monoclonal
antibodies specific for TCR V(beta) (BV) and V(alpha) (AV) were used to
characterize the TCR profile in CD4(+) and CD8(+) T cell populations in BAL
fluid
and peripheral blood by flow cytometry. Muscle biopsy tissues were analyzed
by
immunohistochemistry. Patients were also typed for HLA-DRB1 and DRB3 alleles.
RESULTS: A total of 17 T cell expansions were detected in BAL fluid, 6 in the
CD4(+) T cell population and 11 in the CD8(+) T cell population. Four T cell
expansions were detected in peripheral blood. A selective TCR V usage was found
in muscle. Two PM patients, both of whom had BAL fluid BV3(+) T cell expansions
in the CD4 population and in whom BV3 was also a prominent TCR V segment in
muscle tissue, shared the HLA-DRB1*03 allele. These 2 patients were the only
ones
who were positive for anti-Jo-1 antibody. CONCLUSION: We found a restricted
accumulation of T lymphocytes expressing selected TCR V-gene segments in the
target organ compartments (i.e., lung and muscle). The occurrence of shared
TCR
gene segment usage in muscle and lungs could suggest common target antigens
in
these organs.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17195241 [PubMed - indexed for MEDLINE]
59: J Immunol. 2007 Jan 1;178(1):547-56.
A local antigen-driven humoral response is present in the inflammatory
myopathies.
Bradshaw EM, Orihuela A, McArdel SL, Salajegheh M, Amato AA, Hafler DA, Greenberg
SA, O'Connor KC.
Department of Neurology, Laboratory of Molecular Immunology, Center for
Neurologic Diseases and Brigham and Women's Hospital, Harvard Medical School,
Boston, MA 02115, USA.
The inflammatory myopathies are putative autoimmune disorders characterized
by
muscle weakness and the presence of intramuscular inflammatory infiltrates.
Although inclusion body myositis and polymyositis have been characterized as
cytotoxic CD8(+) T cell-mediated diseases, we recently demonstrated high
frequencies of CD138(+) plasma cells in the inflamed muscle tissue of patients
with these diseases. To gain a deeper understanding of the role these B cell
family members play in the disease pathology, we examined the molecular
characteristics of the H chain portion of the Ag receptor. Biopsies of muscle
tissue were sectioned and tissue regions and individual cells were isolated
through laser capture microdissection. Ig H chain gene transcripts isolated
from
the sections, regions, and cells were used to determine the variable region
gene
sequences. Analysis of these sequences revealed clear evidence of affinity
maturation in that significant somatic mutation, isotype switching, receptor
revision, codon insertion/deletion, and oligoclonal expansion had occurred within
the B and plasma cell populations. Moreover, analysis of tissue regions isolated
by laser capture microdissection revealed both clonal expansion and variation,
suggesting that local B cell maturation occurs within muscle. In contrast,
sequences from control muscle tissues and peripheral blood revealed none of
these
characteristics found in inflammatory myopathy muscle tissue. Collectively,
these
data demonstrate that Ag drives a B cell Ag-specific response in muscle in
patients with dermatomyositis, inclusion body myositis, and polymyositis. These
findings highlight the need for a revision of the current paradigm of exclusively
T cell-mediated intramuscular Ag-specific autoimmunity in inclusion body myositis
and polymyositis.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17182595 [PubMed - indexed for MEDLINE]
60: Muscle Nerve. 2007 Apr;35(4):443-50.
Myopathy associated with gluten sensitivity.
Hadjivassiliou M, Chattopadhyay AK, Grünewald RA, Jarratt JA, Kandler
RH, Rao DG,
Sanders DS, Wharton SB, Davies-Jones GA.
Department of Neurology, The Royal Hallamshire Hospital, Glossop Road, Sheffield
S10 2JF, UK. m.hadjivassiliou@sheffield.ac.uk
Ataxia and peripheral neuropathy are the most common neurological manifestations
of gluten sensitivity. Myopathy is a less common and poorly characterized
additional neurological manifestation of gluten sensitivity. We present our
experience with 13 patients who presented with symptoms and signs suggestive
of a
myopathy and in whom investigation led to the diagnosis of gluten sensitivity.
Three of these patients had a neuropathy with or without ataxia in addition
to
the myopathy. The mean age at onset of the myopathic symptoms was 54 years.
Ten
patients had neurophysiological evidence of myopathy. Inflammatory myopathy
was
the most common finding on neuropathological examination. One patient had
basophilic rimmed vacuoles suggestive of inclusion-body myositis. Six patients
received immunosuppressive treatment in addition to starting on a gluten-free
diet; five improved and one remained unchanged. Among seven patients not on
immunosuppressive treatment, four showed clinical improvement of the myopathy
with a gluten-free diet. The improvement was also associated with reduction
or
normalization of serum creatine kinase level. The myopathy progressed in one
patient who refused the gluten-free diet. Myopathy may be another manifestation
of gluten sensitivity and is likely to have an immune-mediated pathogenesis.
A
gluten-free diet may be a useful therapeutic intervention.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17143894 [PubMed - indexed for MEDLINE]
61: Muscle Nerve. 2007 Feb;35(2):266-7.
Synaptic dysfunction does not contribute to muscle weakness in inclusion-body
myositis.
Badrising UA, Verschuuren JJ, Wintzen AR, van Dijk JG.
Publication Types:
Comparative Study
Letter
PMID: 17143892 [PubMed - indexed for MEDLINE]
62: Clin Rheumatol. 2007 Jul;26(7):1119-22. Epub 2006 Nov 22.
99mTechnetium pyrophosphate scintigraphy in the detection of skeletal muscle
disease.
Walker UA, Garve K, Brink I, Miehle N, Peter HH, Kelly T.
Department of Rheumatology and Clinical Immunology, Albert-Ludwigs University
Medical School, Hugstetterstr. 55, 79106 Freiburg, Germany.
ulrich.walker@klinikum.uni-freiburg.de
We aimed to assess the specificity and sensitivity of (99m)technetium
pyrophosphate muscle scintigraphy in the diagnostic workup of patients with
suspected myopathy. We reviewed the charts of 166 patients; 52% of the subjects
had myalgias, 36% had muscle weakness, 45% had an elevated serum creatine kinase
(CK), and 49% had an increased C reactive protein (CRP). Scintigraphy was
positive in 34 patients (20%). The test was more sensitive in the presence of
muscle weakness, elevated CK, or increased CRP. The presence of myalgias did
not
influence the odds. Sensitivity was 60% in patients with the final diagnosis
of
polymyositis, dermatomyositis, or inclusion body myositis, and 70% in
noninflammatory myopathies. Eight percent had false positive scintigrams. In
individuals with biopsy-proven myopathy (51 subjects), the diagnostic sensitivity
was 43%, and its specificity was 60%. Low positive and high negative likelihood
ratios (5.0 and 0.65, respectively) document an only limited diagnostic
efficiency of (99m)Tc-PYP scintigraphy in the evaluation of inflammatory and
noninflammatory myopathies and suggest that the test is not helpful in the
routine diagnostic workup of muscle complaints, even after a priori selection
of
patients for CK plus CRP abnormalities.
PMID: 17119862 [PubMed - indexed for MEDLINE]
63: Joint Bone Spine. 2006 Dec;73(6):646-54. Epub 2006 Oct 10.
Contribution of autoantibodies to the diagnosis and nosology of inflammatory
muscle disease.
Sordet C, Goetz J, Sibilia J.
Rheumatology Department and Immunology Laboratory, Strasbourg Teaching Hospital,
Louis Pasteur University, EA 3432 Strasbourg, France.
The myositides are systemic autoimmune conditions of which the most important
are
polymyositis, dermatomyositis, and inclusion body myositis. In addition to the
classic clinical diagnostic criteria, myositis-specific autoantibodies were
identified about 15 years ago. Among the dozen or so myositis-specific
autoantibodies reported to date, the most characteristic are directed against
cytoplasmic antigens, such as tRNA synthetase (Jo-1 or PL-1, PL-7, PL-12, EJ,
OJ,
JS, and KS), signal-recognition particle (SRP), Mas, KJ, Fer (eEF1), and Wa.
Antibodies to nuclear antigens include anti-Mi-2, anti-PMS (PMS1, and PMS2),
and
related antibodies (MLH1, DNA protein kinase catalytic subunit (DNA PKCS)...),
and anti-56 kDa. Myositis-associated antibodies are not specific but may be
found
in patients with myositis. They are directed to nuclear or nucleolar antigens
such as PM-Scl, Ku, RNP (U1-RNP and U2-RNP, U4/U6-RNP, and U5-RNP), Ro 52 kDa
and, more rarely, Ro 60 kDa and La. Myositis-specific antibodies have proved
useful on two fronts. They have improved the diagnosis of myositis by leading
to
the identification of characteristic clinical patterns, such as anti-synthetase
syndrome. The place of autoantibodies alongside classic clinical and laboratory
criteria remains to be determined, however. First, standardized assays will
have
to be developed to replace current detection methods, which use widely variable
techniques and antigen preparations. Myositis-specific antibodies have also
shed
light on the pathogenesis of myositis. For instance, the development of
antibodies to tRNA synthetases constitutes an original autoimmunity model that
shows how muscle damage, probably of a nonspecific nature, can lead to the
production of autoantibodies that perpetuate and aggravate the muscle lesions.
Publication Types:
Review
PMID: 17110150 [PubMed - indexed for MEDLINE]
64: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16995-7000. Epub 2006 Oct 31.
MyoD expression restores defective myogenic differentiation of human
mesoangioblasts from inclusion-body myositis muscle.
Morosetti R, Mirabella M, Gliubizzi C, Broccolini A, De Angelis L, Tagliafico
E,
Sampaolesi M, Gidaro T, Papacci M, Roncaglia E, Rutella S, Ferrari S, Tonali
PA,
Ricci E, Cossu G.
Department of Neurosciences and Interdisciplinary Laboratory for Stem Cell
Research and Cellular Therapy, Catholic University, Largo A. Gemelli 8, 00168
Rome, Italy.
Inflammatory myopathies (IM) are acquired diseases of skeletal muscle comprising
dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM).
Immunosuppressive therapies, usually beneficial for DM and PM, are poorly
effective in IBM. We report the isolation and characterization of
mesoangioblasts, vessel-associated stem cells, from diagnostic muscle biopsies
of
IM. The number of cells isolated, proliferation rate and lifespan, markers
expression, and ability to differentiate into smooth muscle do not differ among
normal and IM mesoangioblasts. At variance with normal, DM and PM
mesoangioblasts, cells isolated from IBM, fail to differentiate into skeletal
myotubes. These data correlate with lack in connective tissue of IBM muscle
of
alkaline phosphatase (ALP)-positive cells, conversely dramatically increased
in
PM and DM. A myogenic inhibitory basic helix-loop-helix factor B3 is highly
expressed in IBM mesoangioblasts. Indeed, silencing this gene or overexpressing
MyoD rescues the myogenic defect of IBM mesoangioblasts, opening novel cell-based
therapeutic strategies for this crippling disorder.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17077152 [PubMed - indexed for MEDLINE]
65: Am J Clin Pathol. 2006 Dec;126(6):843-8.
Diagnostic yield associated with multiple simultaneous skeletal muscle biopsies.
Prayson RA.
Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, OH
44195, USA.
Certain skeletal muscle disorders, such as inflammatory myopathies, may show
regional variability, prompting consideration of simultaneous biopsy of more
than
1 muscle to increase the likelihood of diagnosis. There are few data in the
literature to support this approach. This study is a retrospective 8-year review
of 99 cases (52 men; mean age, 61.8 years) who had multiple muscles biopsied
simultaneously. The most common clinical symptoms prompting biopsy included
weakness in 83 cases and myalgia in 15. The most common diagnoses were as
follows: neurogenic atrophy, 48; inflammatory myopathy, excluding inclusion
body
myositis, 29; and type II muscle fiber atrophy, 24. Diagnoses were the same
in
both biopsied muscles in 54 cases (55%). In 17 cases, a diagnosis was made from
only 1 biopsy. Of 29 inflammatory myopathies and vasculitis (excluding inclusion
body myositis), a diagnosis could be made from only 1 of the 2 biopsies in 10
cases (34%). In a significant subset of cases, a potentially treatable
inflammatory myopathic condition might have been missed if only 1 site had been
biopsied, justifying biopsy of 2 sites in suspected cases of inflammatory
myopathy.
PMID: 17074688 [PubMed - indexed for MEDLINE]
66: Neuromuscul Disord. 2006 Dec;16(12):839-44. Epub 2006 Oct 23.
AbetaPP-overexpression and proteasome inhibition increase alphaB-crystallin
in
cultured human muscle: relevance to inclusion-body myositis.
Wojcik S, Engel WK, McFerrin J, Paciello O, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA
90017-1912, USA.
Amyloid-beta precursor protein (AbetaPP) and its fragment amyloid-beta (Abeta)
are increased in s-IBM muscle fibers and appear to play an important role in
the
pathogenic cascade. alphaB-Crystallin (alphaBC) was shown immunohistochemically
to be accumulated in s-IBM muscle fibers, but the stressor(s) influencing alphaBC
accumulation was not identified. We now demonstrate, using our experimental
IBM
model based on genetic overexpression of AbetaPP into cultured normal human
muscle fibers, that: (1) AbetaPP overexpression increased alphaBC 3.7-fold
(p=0.025); (2) additional inhibition of proteasome with epoxomicin increased
alphaBC 7-fold (p=0.002); and (3) alphaBC physically associated with AbetaPP
and
Abeta oligomers. We also show that in biopsied s-IBM muscle fibers, alphaBC
was
similarly increased 3-fold (p=0.025) and physically associated with AbetaPP
and
Abeta oligomers. We propose that increased AbetaPP is a stressor increasing
alphaBC expression in s-IBM muscle fibers. Determining the consequences of
alphaBC association with Abeta oligomers could have clinical therapeutic
relevance.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17056255 [PubMed - indexed for MEDLINE]
67: Biochem Soc Trans. 2006 Nov;34(Pt 5):738-42.
Molecular misreading: the occurrence of frameshift proteins in different
diseases.
van Leeuwen FW, Kros JM, Kamphorst W, van Schravendijk C, de Vos RA.
Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam,
The
Netherlands. f.van.leeuwen@nin.knaw.nl
Neuronal homoeostasis requires a constant balance between biosynthetic and
catabolic processes. Eukaryotic cells primarily use two distinct mechanisms
for
degradation: the proteasome and autophagy of aggregates by the lysosomes. We
focused on the UPS (ubiquitin-proteasome system). As a result of molecular
misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates
in the neuritic plaques and neurofibrillary tangles in all patients with AD
(Alzheimer's disease) and in the neuronal and glial hallmarks of other
tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1
is
not present in synucleinopathies such as Parkinson's disease. We showed that
UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is
also
present in non-neurological cells, hepatocytes of the diseased liver and in
muscles during inclusion body myositis. Other frequently occurring (age-related)
diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently
under investigation. These findings point to the importance of the UPS in
diseases and open new avenues for target identification of the main players
of
the UPS. Treatment of these diseases with tools (e.g. viral RNA interference
constructs) to intervene with specific targets is the next step.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 17052186 [PubMed - indexed for MEDLINE]
68: Acta Myol. 2006 Jun;25(1):13-22.
Parkin and its association with alpha-synuclein and AbetaPP in inclusion-body
myositis and AbetaPP-overexpressing cultured human muscle fibers.
Paciello O, Wójcik S, Engel WK, McFerrin J, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles
90017-1912, USA.
Parkin, an E3-ubiquitin ligase in the ubiquitin-proteasome system, facilitates
degradation of alpha-synuclein and other proteins. Since ubiquitinated
multiprotein-aggregates containing amyloid-beta (Abeta), alpha-synuclein, and
other proteins, are characteristic of sporadic inclusion-body myositis (s-IBM)
muscle fibers, we asked whether parkin might have a role in s-IBM pathogenesis.
We studied the association of parkin with alpha-synuclein and Abeta-precursor
protein (AbetaPP) in s-IBM muscle biopsies and in our IBM model based on
overexpression of AbetaPP into cultured human muscle fibers. We report the
following in s-IBM muscle fibers: a) parkin was increased 2.7 fold and
accumulated in aggregates also containing Abeta and alpha-synuclein; b)
alpha-synuclein was increased 6.3 fold; c) parkin physically associated with
alpha-synuclein and AbetaPP; d) alpha-synuclein and AbetaPP were ubiquitinated.
In the IBM model: a) parkin was increased 2.7 fold, b) it associated with
alpha-synuclein and AbetaPP. CONCLUSION: 1. This is the first demonstration
that
in a human muscle disease alpha-synuclein associates with parkin, and might
be
ubiquitinated by it. 2. The small increase of parkin relative to the much larger
increase of alpha-synuclein might be insufficient to secure complete
ubiquitination and consequent degradation of alpha-syn. 3. AbetaPP might be
a
novel substrate of parkin.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 17039976 [PubMed - indexed for MEDLINE]
69: Hum Pathol. 2006 Oct;37(10):1367-8; author reply 1368.
Comment on:
Hum Pathol. 2005 Aug;36(8):917-21.
Is myocardial damage truly absent in inclusion body myositis with elevated
troponin T level?
Finsterer J, Stöllberger C.
Publication Types:
Comment
Letter
PMID: 16996378 [PubMed - indexed for MEDLINE]
70: Brain. 2007 Feb;130(Pt 2):381-93. Epub 2006 Sep 19.
Pathological consequences of VCP mutations on human striated muscle.
Hübbers CU, Clemen CS, Kesper K, Böddrich A, Hofmann A, Kämäräinen
O, Tolksdorf
K, Stumpf M, Reichelt J, Roth U, Krause S, Watts G, Kimonis V, Wattjes MP,
Reimann J, Thal DR, Biermann K, Evert BO, Lochmüller H, Wanker EE, Schoser
BG,
Noegel AA, Schröder R.
Institute of Biochemistry I, University of Cologne, Cologne, Germany.
Mutations in the valosin-containing protein (VCP, p97) gene on chromosome
9p13-p12 cause a late-onset form of autosomal dominant inclusion body myopathy
associated with Paget disease of the bone and frontotemporal dementia (IBMPFD).
We report on the pathological consequences of three heterozygous VCP (R93C,
R155H, R155C) mutations on human striated muscle. IBMPFD skeletal muscle
pathology is characterized by degenerative changes and filamentous VCP- and
ubiquitin-positive cytoplasmic and nuclear protein aggregates. Furthermore,
this
is the first report demonstrating that mutant VCP leads to a novel form of
dilatative cardiomyopathy with inclusion bodies. In contrast to post-mitotic
striated muscle cells and neurons of IBMPFD patients, evidence of protein
aggregate pathology was not detected in primary IBMPFD myoblasts or in transient
and stable transfected cells using wild-type-VCP and R93C-, R155H-, R155C-VCP
mutants. Glutathione S-transferase pull-down experiments showed that all three
VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3. Structural
analysis demonstrated that R93 and R155 are both surface-accessible residues
located in the centre of cavities that may enable ligand-binding. Mutations
at
R93 and R155 are predicted to induce changes in the tertiary structure of the
VCP
protein. The search for putative ligands to the R93 and R155 cavities resulted
in
the identification of cyclic sugar compounds with high binding scores. The latter
findings provide a novel link to VCP carbohydrate interactions in the complex
pathology of IBMPFD.
Publication Types:
Case Reports
PMID: 16984901 [PubMed - indexed for MEDLINE]
71: J Neurol Neurosurg Psychiatry. 2006 Oct;77(10):1187-90.
Comment in:
J Neurol Neurosurg Psychiatry. 2006 Oct;77(10):1104-5.
Expression of granulysin in polymyositis and inclusion-body myositis.
Ikezoe K, Ohshima S, Osoegawa M, Tanaka M, Ogawa K, Nagata K, Kira JI.
Department of Neurology, Neurological Institute, Graduate School of Medical
Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582,
Japan.
BACKGROUND: Granulysin, a recently defined cytolytic molecule, is expressed
in
cytotoxic T cells and natural killer cells in a similar way to perforin, which
is
reported to have a major role in the pathogenesis of polymyositis and
inclusion-body myositis (IBM). OBJECTIVE: To clarify the role of granulysin
in
polymyositis and IBM. METHODS: The expression of granulysin and perforin was
examined by double staining with CD8, CD4 and CD56 in endomysial infiltrating
cells and autoinvasive cells in muscle biopsy specimens of 17 patients with
polymyositis (6 steroid resistant and 11 steroid responsive) and of 7 patients
with IBM. RESULTS: Similar to perforin, granulysin was expressed in CD8, CD4
or
CD56 cells in patients with polymyositis and IBM. The ratio of cells double
positive for granulysin and CD8 to all CD8 cells at endomysial sites was notably
higher in steroid-resistant polymyositis than in steroid-responsive polymyositis
and IBM. CONCLUSION: Granulysin expression in CD8 cells seems to be correlated
with steroid resistance in polymyositis.
PMID: 16980658 [PubMed - indexed for MEDLINE]
72: Muscle Nerve. 2007 Jan;35(1):17-23.
Myeloid dendritic cells in inclusion-body myositis and polymyositis.
Greenberg SA, Pinkus GS, Amato AA, Pinkus JL.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's
Hospital, 75 Francis Street, and Harvard Medical School, Boston, Massachusetts
02115, USA. sgreenberg@partners.org
Dendritic cells (DCs), immune system cells central to the development of
immunity, have not previously been reported in muscle in inclusion-body myositis
(IBM). We performed immunohistochemical studies on muscle biopsy specimens from
50 patients using monoclonal antibodies that distinguish two classes of DCs,
myeloid DC and plasmacytoid DC. In 17 of 20 IBM and 9 of 10 polymyositis (PM)
specimens, myeloid DCs were present in substantial numbers, frequently surrounded
and sometimes invading otherwise intact myofibers, and were part of dense
collections of cells that included T cells. Dermatomyositis muscle had more
plasmacytoid DCs than myeloid DCs, whereas IBM and PM had greater numbers of
myeloid DCs. The stellate morphology of myeloid DCs in dense collections of
cells
that included T cells suggests local intramuscular antigen presentation in IBM
and PM.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16969836 [PubMed - indexed for MEDLINE]
73: Muscle Nerve. 2007 Jan;35(1):49-54.
Celiac disease and antibodies associated with celiac disease in patients with
inflammatory myopathy.
Selva-O'Callaghan A, Casellas F, de Torres I, Palou E, Grau-Junyent JM,
Vilardell-Tarrés M.
Internal Medicine Department, Vall D'Hebron General Hospital, Universitat
Autonoma Barcelona, C/Siracusa No. 12 Bis A, Barcelona, Spain. aselva@vhebron.net
Celiac disease is usually associated with autoimmune disorders and has
occasionally been reported in patients with inflammatory myopathies. Our aim
was
to determine the presence of celiac disease and antibodies associated with celiac
disease in patients with inflammatory myopathies and to investigate their
relationship. Serum antigliadin, anti-tissue transglutaminase, and antiendomysial
antibodies were determined in 51 patients with inflammatory myopathies. HLA-DQ2
and -DQ8 alleles were studied to assess their complementary diagnostic value.
Jejunal biopsy was performed in patients with moderate to high levels of
antigliadin antibodies. Patients with jejunal histology consistent with celiac
disease initiated a gluten-free diet. Seventeen patients (31%) were positive
for
antigliadin antibodies, which were significantly more frequent in patients with
inclusion-body myositis than dermatomyositis (P < 0.001). Positive status
to
HLA-DQ2 and/or -DQ8 did not differ between antigliadin-positive (75% and 12.5%)
or -negative (60% and 15%) patients. Three of five jejunal biopsies were
diagnostic for celiac disease with histological normalization after a gluten-free
diet. Thus, celiac disease is more prevalent in patients with inflammatory
myopathies than in the general population. Positive status to HLA-DQ2 allele,
which is known to be more frequent in patients with inflammatory myopathies,
could explain the high prevalence of antigliadin antibodies in this population.
The diagnostic value of HLA-DQ2 or -DQ8 haplotypes to detect celiac disease
in
patients with inflammatory myopathy is limited.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16967485 [PubMed - indexed for MEDLINE]
74: Phys Med Biol. 2006 Sep 21;51(18):4719-33. Epub 2006 Sep 4.
Mean time-of-flight of photons in transillumination measurements of optically
anisotropic tissue with an inclusion.
Dudko OK, Weiss GH, Chernomordik V.
Mathematical and Statistical Computing Laboratory, Division of Computational
Bioscience, Center for Information Technology, National Institutes of Health,
Bethesda, MD 20892, USA.
We study the effect of optical anisotropy on the mean time-of-flight of photons
in a slab of turbid medium containing an inclusion whose optical properties
differ from those of the bulk. For this analysis the difference in the mean
time
for a photon introduced into the slab to reach a specified target point with
and
without the inclusion is calculated. This difference is defined to be a measure
of the contrast. The theoretical model is based on a continuous-time random
walk
on a lattice, which can be solved exactly and furnishes an exact expression
for
the contrast. Qualitative and quantitative characteristics of the contrast are
analysed as functions of the geometric configuration of the system components
(locations of the source, the inclusion and the detector), parameters that
specify the optical anisotropy of the medium, and either the scattering
properties of the inclusion or the lifetime of the small fluorophore in the
case
of the time-resolved fluorescence experimental configuration.
Publication Types:
Research Support, N.I.H., Intramural
PMID: 16953052 [PubMed - indexed for MEDLINE]
75: FASEB J. 2006 Oct;20(12):2165-7. Epub 2006 Aug 29.
Transgenic expression of beta-APP in fast-twitch skeletal muscle leads to calcium
dyshomeostasis and IBM-like pathology.
Moussa CE, Fu Q, Kumar P, Shtifman A, Lopez JR, Allen PD, LaFerla F, Weinberg
D,
Magrane J, Aprahamian T, Walsh K, Rosen KM, Querfurth HW.
Department of Neurology, Caritas St. Elizabeth's Medical Center of Boston,
Tufts
University School of Medicine, 736 Cambridge St., Boston, MA, USA.
Intracellular deposition of the beta-amyloid (Abeta) peptide is an increasingly
recognized pathological hallmark associated with neurodegeneration and muscle
wasting in Alzheimer's disease (AD) and inclusion body myositis (IBM),
respectively. Previous reports have implicated dysregulation of beta-amyloid
precursor protein (betaAPP) expression in IBM. Accumulation of full-length
betaAPP, its various proteolytic derivatives including Abeta, and phospho-tau
into vacuolated inclusions is an early pathogenic event. We previously reported
on a statistical tendency favoring fast twitch fiber involvement in IBM,
reminiscent of the tissue specific patterns of misfolded protein deposition
seen
in neurodegenerative diseases. To test this principle, we generated an animal
model in which human wild-type (WT) betaAPP expression was limited to postnatal
type II skeletal muscle. Hemizygous transgenic mice harboring increased levels
of
holo betaAPP751 and Abeta in skeletal muscle fibers became significantly weaker
with age compared with nontransgenic littermates and exhibited typical myopathic
features. A subpopulation of dissociated muscle fibers from transgenic mice
exhibited a 2-fold increase in resting calcium and membrane depolarization
compared with nontransgenic littermates. Taken together, these data indicate
that
overexpression of human betaAPP in fast twitch skeletal muscle of transgenic
mice
is sufficient for the development of some features characteristic of IBM,
including abnormal tau histochemistry. The increase in resting calcium and
depolarization are novel findings, suggesting both a mechanism for the weakness
and an avenue for therapeutic intervention in IBM.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16940437 [PubMed - indexed for MEDLINE]
76: Neuromuscul Disord. 2006 Nov;16(11):754-8. Epub 2006 Aug 28.
Familial inclusion body myositis in a mother and son with different ancestral
MHC
haplotypes.
Mastaglia F, Price P, Walters S, Fabian V, Miller J, Zilko P.
Centre for Neuromuscular and Neurological Disorders, University of Western
Australia, 4th Floor, A Block, Queen Elizabeth II Medical Centre, Nedlands WA
6009, Australia. flmast@cyllene.uwa.edu.au
An Ashkenazi Jewish family in which the mother and a son both have inclusion
body
myositis (IBM) is reported. The condition developed at an earlier age and was
more rapidly progressive and less responsive to treatment in the son than in
the
mother or other IBM patients in our clinic. Genetic analysis showed that the
mother carried alleles of the 8.1 MHC ancestral haplotype (AH; HLA-B8,
DRB1*0301), which is found in 85% of IBM patients in Western Australia. The
son
did not inherit this haplotype, but carried alleles characteristic of the 52.1AH
(HLA-B5, DRB1*1502) of paternal origin. The findings indicate that in this family
either the 8.1AH or 52.1AH may carry susceptibility for IBM and that the 52.1AH
is associated with a more severe and treatment-resistant form of the disease.
Publication Types:
Case Reports
PMID: 16934978 [PubMed - indexed for MEDLINE]
77: Nat Clin Pract Rheumatol. 2006 May;2(5):270-7.
Mechanisms of disease: genetics of Paget's disease of bone and related disorders.
Daroszewska A, Ralston SH.
University of Edinburgh, UK.
Paget's disease of bone (PDB) is a common disorder in which focal abnormalities
of increased bone turnover lead to complications such as bone pain, deformity,
pathological fractures, and deafness. PDB has a strong genetic component and
several susceptibility loci for the disease have been identified by genome-wide
scans. Mutations that predispose individuals to PDB and related disorders have
been identified in four genes. The rare PDB-like syndromes of familial expansile
osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia
are caused by insertion mutations in TNFRSF11A, which encodes receptor activator
of nuclear factor (NF)kappaB (RANK)-a critical regulator of osteoclast function.
Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy
receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms
in this gene seem to increase the risk for classical PDB. Mutations of the
sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in
the
NFkappaB pathway, are a common cause of classical PDB. The rare syndrome of
hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused
by mutations in the valosin-containing protein (VCP) gene. This gene encodes
VCP,
which has a role in targeting the inhibitor of NFkappaB for degradation by the
proteasome. Several additional genes for PDB remain to be discovered, and it
seems likely that they will also involve the RANK-NFkappaB signaling pathway
or
components of the proteasomal processing of this pathway, underscoring the
critical importance of this signaling pathway in bone metabolism and bone
disease.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16932700 [PubMed - indexed for MEDLINE]
78: Nat Clin Pract Rheumatol. 2006 Apr;2(4):219-27.
Erratum in:
Nat Clin Pract Rheumatol. 2006 Jul;2(7):398.
Mechanisms of disease: signaling pathways and immunobiology of inflammatory
myopathies.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
The signaling pathways involved in the immunobiology of polymyositis,
dermatomyositis, and inclusion-body myositis are outlined in this Review, which
is based on research performed during the past 10 years. In dermatomyositis,
the
complement cascade is activated and the expression of cytokines and chemokines
is
upregulated. In polymyositis and inclusion-body myositis, autoinvasive CD8+
T
cells are clonally expanded. This T-cell subset possesses conserved amino-acid
sequences in complementarity-determining region 3 of the T-cell receptor and,
via
the perforin pathway, exerts a myotoxic effect on muscle fibers that express
major histocompatibility complex (MHC) class I molecules. In all inflammatory
myopathies, molecules associated with T-cell transmigration and cytokine
signaling, as well as chemokines and their receptors, are strongly expressed
by
endothelial and inflammatory cells. Early in the pathogenesis of polymyositis
and
inclusion-body myositis, expression of MHC class I molecules on muscle fibers
is
upregulated, even in the absence of autoinvasive CD8+ T cells. Emerging data
indicate that such continuous upregulation of the expression of MHC class I
molecules on muscle fibers leads to an endoplasmic reticulum stress response,
intracellular accumulation of misfolded glycoproteins, and activation of nuclear
factor kappaB pathways, which can further stimulate formation of MHC class I-CD8
complexes, resulting in a self-sustaining inflammatory response. Advances in
our
understanding of the signaling pathways involved in the pathogenesis of these
inflammatory myopathies are expected to result in the identification of novel
therapeutic targets for these diseases.
Publication Types:
Research Support, N.I.H., Intramural
Review
PMID: 16932688 [PubMed - indexed for MEDLINE]
79: Nat Clin Pract Neurol. 2006 Aug;2(8):437-47.
Sporadic inclusion body myositis--diagnosis, pathogenesis and therapeutic
strategies.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical
phenotype of slow-onset weakness and atrophy, affecting proximal and distal
limb
muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized
by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated
fibers, vacuolar degeneration, and accumulation of amyloid-related proteins.
The
cause of sIBM is unclear, but two processes-one autoimmune and the other
degenerative-appear to occur in parallel. In contrast to dystrophies, in sIBM
the
autoinvasive CD8(+) T cells are cytotoxic and antigen-driven, invading muscle
fibers expressing major histocompatibility complex class I antigen and
costimulatory molecules. The concurrent degenerative features include
vacuolization, filamentous inclusions and intracellular accumulations of
amyloid-beta-related molecules. Although viruses have not been amplified from
the
muscle fibers, at least 12 cases of sIBM have been seen in association with
retroviral infections, indicating that a chronic persistent viral infection
might
be a potential triggering factor. Emerging data imply that continuous
upregulation of cytokines and major histocompatibility complex class I on the
muscle fibers causes an endoplasmic reticulum stress response, resulting in
intracellular accumulation of misfolded glycoproteins and activation of the
transcription factor NFkappaB, leading to further cytokine activation. In spite
of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to
immunotherapies. New therapies using monoclonal antibodies against lymphocyte
signaling pathways might prove helpful in arresting disease progression.
Publication Types:
Research Support, N.I.H., Intramural
Review
PMID: 16932602 [PubMed - indexed for MEDLINE]
80: Neurology. 2006 Aug 22;67(4):560-1.
Comment on:
Neurology. 2006 Aug 22;67(4):644-51.
Frontotemporal dementia: the post-tau era.
Ghetti B, Goebel HH.
Publication Types:
Comment
Editorial
PMID: 16924003 [PubMed - indexed for MEDLINE]
81: Neuromuscul Disord. 2006 Aug;16(8):495-7. Epub 2006 Aug 22.
Raised troponin T in inclusion body myositis is common and serum levels are
persistent over time.
Lindberg C, Klintberg L, Oldfors A.
Neuromuscular Centre, Department of Neurology, Sahlgrenska University Hospital,
Sweden. christopher.lindberg@vgregion.se
Cardiac Troponin T (cTnT), creatine kinase (CK) and creatine kinase isoenzyme
MB
(CKMB) were measured in 42 consecutive patients with sporadic inclusion body
myositis (s-IBM). 26 patients (62%) had a cTnT level >0.05 microg/L, the
cut off
used in the diagnosis of myocardial infarction. The cTnT levels correlated
somewhat more closely to CKMB (rho=0.83, p<0.0001) than to CK (rho=0.60,
p<0.0001). Patients on immunosuppressive treatment had lower cTnT levels
than
untreated, while there were no significant differences according to age, disease
duration or gender. Repeated samples in 26 patients showed that the cTnT levels
were essentially unchanged over time up to 17 months. None of the patients had
signs of myocardial damage or renal failure at time of sampling. It may be of
value to analyse cTnT at some occasion(s) in s-IBM patients.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16920359 [PubMed - indexed for MEDLINE]
82: Curr Rheumatol Rep. 2006 Jun;8(3):178-87.
Differential diagnosis of idiopathic inflammatory myopathies.
Baer AN.
Department of Medicine, Division of Allergy, Immunology, and Rheumatology,
School
of Medicine and Biomedical Sciences, State University of New York at Buffalo,
Erie County Medical Center, 462 Grider Street, Buffalo, NY 14215, USA.
alanbaer@buffalo.edu
Symmetric proximal muscle weakness has many potential etiologies. An onset
over
weeks to months and elevated serum levels of muscle enzymes point to the
diagnosis of an idiopathic inflammatory myopathy, including dermatomyositis,
polymyositis, and inclusion body myositis. However, there is a broad differential
diagnosis, including certain muscular dystrophies, metabolic myopathies, drug-
or
toxin-induced myotoxicity, neuropathies, and infectious myositides. The
differentiation is critical for defining appropriate treatment. In addition,
an
alternative diagnosis may explain the lack of response to immunosuppressive
treatment for some patients with polymyositis. Careful clinical evaluation and
choice of available diagnostic tests are required to establish the correct
diagnosis.
Publication Types:
Review
PMID: 16901075 [PubMed - indexed for MEDLINE]
83: J Neuropathol Exp Neurol. 2006 Aug;65(8):826-33.
Proteomic analysis of inclusion body myositis.
Li J, Yin C, Okamoto H, Jaffe H, Oldfield EH, Zhuang Z, Vortmeyer AO, Rushing EJ.
Surgical Neurology Branch, National Institutes of Neurological Disorders and
Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
Sporadic inclusion body myositis (IBM) is the most frequently acquired
inflammatory myopathy of late adult life, yet its diagnostic criteria and
pathogenesis remain poorly defined. Because effective treatment is lacking,
research efforts have intensified to identify specific markers for this
debilitating disorder. In this study, proteomic analysis of 4 cases of sporadic
IBM was compared with 5 cases of inflammatory myopathy without clinicopathologic
features of IBM to distinguish the IBM-specific proteome. Proteins were separated
by 2-dimensional polyacrylamide gel electrophoresis and profiled by mass
spectrometric sequencing. Expression of most proteins remained unchanged;
however, 16 proteins were upregulated and 6 proteins were downregulated in IBM
compared with cases of non-IBM inflammatory myopathy. These IBM-specific proteins
included apolipoprotein A-I, amyloid beta precursor protein, and transthyretin,
which have been associated with amyloidosis; superoxide dismutase, enolase,
and
various molecular chaperones indicate perturbations in detoxification, energy
metabolism, and protein folding, respectively. The IBM-downregulated proteins
mainly serve as carriers for muscle contraction and other normal muscle
functions. We further applied Western blot and immunohistochemistry to verify
the
proteomic findings. This study validates proteomics as a powerful tool in the
study of muscle disease and indicates a unique pattern of protein expression
in
IBM.
Publication Types:
Comparative Study
PMID: 16896316 [PubMed - indexed for MEDLINE]
84: J Rheumatol. 2006 Aug;33(8):1623-30.
Platelet-endothelial cell adhesion molecule-1 and CD146: soluble levels and
in
situ expression of cellular adhesion molecules implicated in the cohesion of
endothelial cells in idiopathic inflammatory myopathies.
Figarella-Branger D, Schleinitz N, Boutière-Albanèse B, Camoin
L, Bardin N, Guis
S, Pouget J, Cognet C, Pellissier JF, Dignat-George F.
Laboratoire de Biopathologie de l'Adhésion et de la Signalisation, EA
3281,
Faculté de Médecine Timone, Université de la Méditerranée,
Marseille, France.
Dominique.Figarella-Branger@medecine.univ-mrs.fr
OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a heterogeneous group
of
diseases characterized by chronic inflammation of muscles. We investigated the
role of cellular adhesion molecules implicated in the cohesion of endothelial
cells in IIM. METHODS: In 22 patients with IIM we investigated plasma
concentrations of soluble junctional adhesion molecules [platelet-endothelial
cell adhesion molecule (sPECAM-1) and sCD146] and cellular adhesion molecules
[sP-selectin, sE-selectin, intercellular adhesion molecule (sICAM-1), and
vascular cell adhesion molecule (sVCAM-1)] implicated in leukocyte/endothelial
cell interactions. Results were compared to a control group. Muscle biopsy
samples from 8 out of 22 IIM patients were studied by immunohistochemistry for
tissue expression of these molecules and compared to normal muscle samples.
PECAM-1 and CD146 expression was also studied using immunoblots from muscle
biopsies from 5 patients and 2 controls. RESULTS: We observed distinct patterns
of soluble levels and in situ expression between dermatomyositis (DM),
polymyositis (PM), and sporadic inclusion body myositis (s-IBM). PM samples
showed significantly increased levels of sCD146, sPECAM-1, and s-ICAM1 and
increased expression of CD146, CD31, and ICAM-1 in endothelial cells, whereas
CD146 and ICAM-1 were also recorded in some muscle fibers. In DM, sE-selectin,
sP-selectin, and sPECAM-1 were significantly increased, with abnormal expression
of ICAM-1 in endothelial cells and perifascicular muscle fibers. In the small
group of s-IBM samples, results were similar to PM, but the only significant
increase was the level of sPECAM-1. Immunoblots confirmed increased expression
of
PECAM-1 and CD146 in all IIM muscles in comparison to controls, with the highest
expression in PM and IBM samples. CONCLUSION: We observed abnormal increases
of
soluble levels of adhesion molecules implicated in endothelial cell junctions
in
PM (sCD146, sPECAM-1) and to a lesser extent in DM and s-IBM (sPECAM-1). We
conclude that the distinctly different profiles between PM/s-IBM and DM reflect
differences in the pathophysiological background of these diseases.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16881117 [PubMed - indexed for MEDLINE]
85: Clin Neuropathol. 2006 Jul-Aug;25(4):172-9.
Pediatric macrophagic myofasciitis associated with motor delay.
Gruis KL, Teener JW, Blaivas M.
Department of Neurology, University of Michigan Health System, Ann Arbor, MI,
USA. kgruis@umich.edu
BACKGROUND: Macrophagic myofasciitis (MMF) is a rare inflammatory myopathy
characterized by accumulation of perifascicular macrophages without muscle fiber
necrosis. Few sporadic pediatric cases have been described, and MMF is recognized
as a possible reaction to intramuscular injections of aluminum-containing
vaccines. The association of MMF and motor delay is unclear in the pediatric
population. We report the clinical evaluation and follow-up of 4 young children
with MMF and review of 4 cases previously reported of sporadic, pediatric MMF
to
better determine the possible association of sporadic MMF in children presenting
with motor delay. PATIENTS AND METHODS: Described our 4 case reports in which
we
observed children presenting for evaluation of motor delay with unrevealing
clinical and laboratory evaluations for common causes of motor delay and
histopathological evaluations consistent with macrophagic myofasciitis. Muscle
data was obtained by quadriceps muscle biopsy. RESULTS: Clinical presentations
were similar in all children and were characterized by motor delay, hypotonia,
and failure to thrive with an unrevealing evaluation for central nervous system
disease, congenital, and mitochondrial myopathies. CONCLUSIONS: Our cases and
those previously reported in the literature demonstrate MMF should be considered
in the evaluation of children with failure to thrive, hypotonia, and muscle
weakness, as clinical outcome appears to be favorable.
Publication Types:
Case Reports
Review
PMID: 16866298 [PubMed - indexed for MEDLINE]
86: Acta Neuropathol. 2006 Sep;112(3):325-32. Epub 2006 Jul 22.
The inflammatory reaction pattern distinguishes primary dysferlinopathies from
idiopathic inflammatory myopathies: an important role for the membrane attack
complex.
Brunn A, Schröder R, Deckert M.
Department of Neuropathology, University of Cologne, Kerpener Strasse 62, 50924
Köln, Germany. anna.brunn@uni-koeln.de
Degenerative muscle changes in dysferlinopathies are often accompanied by
inflammatory infiltrates and may even mimic primary idiopathic inflammatory
myopathies. In the present study, the inflammatory reaction pattern with respect
to the cellular composition of the infiltrates and the expression of potent
cytokines was characterized in dysferlinopathies and in idiopathic inflammatory
myopathies. Cellular infiltrates in dysferlinopathies mainly consisted of
CD4+CD25- T cells and macrophages. We noted a prominent expression of
interferon-gamma which may contribute to the marked upregulation of MHC class
I
antigen observed on the vast majority of muscle fibres. Furthermore, membrane
attack complex positive deposits were found on intact as well as necrotic muscle
fibres. Collectively, our study indicates that the inflammatory reaction pattern
in dysferlinopathies is distinct from the one in idiopathic inflammatory
myopathies. In particular, membrane attack complex deposits and a
pro-inflammatory milieu in the absence of interleukin-10 expression may
contribute to progressive muscle damage in dysferlinopathies.
PMID: 16862423 [PubMed - indexed for MEDLINE]
87: Muscle Nerve. 2006 Oct;34(4):444-50.
Elevated levels of amyloid precursor protein in muscle of patients with
amyotrophic lateral sclerosis and a mouse model of the disease.
Koistinen H, Prinjha R, Soden P, Harper A, Banner SJ, Pradat PF, Loeffler JP,
Dingwall C.
Neurodegeneration Research Department, GlaxoSmithKline Research & Development
Ltd., New Frontiers Science Park, Third Avenue, Harlow, Essex, UK.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease
defined by motor neuron loss. Transgenic mouse models show features that closely
mimic those seen in the clinical situation, reflected in the molecular changes
observed in mouse models and in tissues from patients. We report a dramatic
increase in the expression of amyloid precursor protein (APP) in the hindlimb
muscles, but not the spinal cord of the G93A transgenic mouse model,
significantly before the appearance of clinical abnormalities. APP levels were
unchanged in nontransgenic mice and in mice overexpressing human wild-type
Cu/Zn-dependent superoxide dismutase 1 (SOD1). Preliminary results indicate
a
similar change in APP expression in human deltoid muscle samples from ALS
patients compared with age-matched controls. The inhibitory role of APP in
innervation at the neuromuscular junction and increased expression in
inclusion-body myositis suggest that presymptomatic upregulation of APP may
be
consistent with a potential role for APP in ALS pathology.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16856153 [PubMed - indexed for MEDLINE]
88: Muscle Nerve. 2006 Oct;34(4):406-16.
Nuclear membrane proteins are present within rimmed vacuoles in inclusion-body
myositis.
Greenberg SA, Pinkus JL, Amato AA.
Department of Neurology, Division of Neuromuscular Disease, Brigham and Women's
Hospital, Boston, Massachusetts 02115, USA. sagreenberg@partners.org
The rimmed vacuoles within muscle in inclusion-body myositis (IBM) are structures
of uncertain origin. Two hypotheses have been proposed for their formation:
that
they develop as a consequence of abnormal lysosomal function or in association
with the breakdown of myonuclei. We tested the latter hypothesis by studying
muscle samples from 14 patients with IBM and 18 controls using
immunohistochemistry for nuclear membrane proteins, examining semithin sections,
and performing electron microscopy. We found that in IBM muscle vacuoles were
immunoreactive for the inner nuclear membrane proteins emerin and lamin A/C.
Myonuclei with fragmented or focally absent nuclear membranes were present in
immunohistochemical and electron microscopy studies. The association of nuclear
membrane proteins with rimmed vacuoles confirms the hypotheses that rimmed
vacuoles in IBM form in association with myonuclear pathology and that IBM
differs from other inflammatory myopathies in that abnormalities of myonuclei
are
more prominent.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16823856 [PubMed - indexed for MEDLINE]
89: Neurology. 2006 Jun 27;66(12):1959; author reply 1959.
Comment on:
Neurology. 2006 Jan 24;66(2 Suppl 1):S110-3.
Treatment and prevention of the amyloidoses: can the lessons learned be applied
to sporadic inclusion-body myositis?
Konstantopoulos K, Vaiopoulos G, Mailis A.
Publication Types:
Comment
Letter
PMID: 16801679 [PubMed - indexed for MEDLINE]
90: Neurology. 2006 Aug 22;67(4):644-51. Epub 2006 Jun 21.
Comment in:
Neurology. 2006 Aug 22;67(4):560-1.
Valosin-containing protein gene mutations: clinical and neuropathologic features.
Guyant-Maréchal L, Laquerrière A, Duyckaerts C, Dumanchin C,
Bou J, Dugny F, Le
Ber I, Frébourg T, Hannequin D, Campion D.
Department of Neurology, Rouen University Hospital, France.
BACKGROUND: Hereditary inclusion body myopathy (IBMPFD) with Paget disease
of
bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder
with
autosomal dominant inheritance. Recently, missense mutations in the gene encoding
valosin-containing protein (VCP) have been found in individuals with IBMPFD.
VCP/P97, which exerts a variety of cellular functions, plays a key role in the
ubiquitin-proteasome dependent degradation of cytosolic proteins and in the
retrotranslocation of misfolded proteins from the endoplasmic reticulum into
the
cytoplasm. METHODS: The authors describe the clinical features of two kindreds
in
which VCP R93C and R155C missense mutations segregate and perform a
histopathologic examination of brain, muscle, bone, and liver of three subjects
harboring the R155C mutation. RESULTS: Frontotemporal dementia was present in
100% of affected subjects in Family F1 and 70% in Family F2, as compared with
an
average of 30% in previously described IBMPFD families. In contrast, PDB was
a
more inconstant clinical feature. Biochemical and histopathologic data are
consistent with the hypothesis that VCP R155C mutation disrupts normal VCP
function, leading to diffuse accumulation of ubiquitinated proteins within the
cells. CONCLUSIONS: VCP mutations are present in two families in which FTD is
the
most prominent symptom. The histopathologic study performed in patients harboring
the R155C mutation supports the hypothesis that this mutation disrupts normal
VCP
function, leading to diffuse accumulation of ubiquitinated proteins within the
cells. IBMPFD belongs to a class of genetic diseases associated with an
alteration of the ubiquitin-proteasome system.
PMID: 16790606 [PubMed - indexed for MEDLINE]
91: Acta Neuropathol. 2006 Aug;112(2):185-93. Epub 2006 Jun 21.
Rimmed vacuoles with beta-amyloid and tau protein deposits in the muscle of
children with hereditary myopathy.
Fidzianska A, Glinka Z.
Neuromuscular Unit MRC, Polish Academy of Science, Pawinskiego 5, 02-106, Warsaw,
Poland. neurmyol@cmdik.pan.pl
We investigated whether beta-amyloid and tau protein are involved in the
formation of inclusion body myositis (IBM)-like inclusions found in children
with
rimmed vacuoles and congenitally affected muscles. We immunostained muscle biopsy
specimens from four children and one 18-year-old boy with congenital myopathy
containing rimmed vacuoles and IBM-like inclusions with antibodies against
beta-amyloid, tau protein and ubiquitin. Focal accumulations of both beta-amyloid
and phosphorylated tau coexisted with tubulofilamentous structures in all cases.
Our studies demonstrate for the first time that the full morphological phenotype
of IBM including beta-amyloid and tau protein deposits may also develop in
children, and that congenital, probably genetic, muscle defects may lead to
abnormal protein aggregation in IBM-like inclusions.
Publication Types:
Case Reports
Research Support, Non-U.S. Gov't
PMID: 16788822 [PubMed - indexed for MEDLINE]
92: J Neuropathol Exp Neurol. 2006 Jun;65(6):571-81.
Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing
protein gene mutations.
Forman MS, Mackenzie IR, Cairns NJ, Swanson E, Boyer PJ, Drachman DA, Jhaveri
BS,
Karlawish JH, Pestronk A, Smith TW, Tu PH, Watts GD, Markesbery WR, Smith CD,
Kimonis VE.
Department of Pathology, University of Pennsylvania School of Medicine,
Philadelphia, 19104, USA. formanm@mail.med.upenn.edu
Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease
of
bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in
the
valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene
superfamily. The neuropathology associated with sporadic FTD is heterogeneous
and
includes tauopathies and frontotemporal lobar degeneration with
ubiquitin-positive inclusions (FTLD-U). However, there is limited information
on
the neuropathology in IBMPFD. We performed a detailed, systematic analysis of
the
neuropathologic changes in 8 patients with VCP mutations. A novel pattern of
ubiquitin pathology was identified in IBMPFD that was distinct from sporadic
and
familial FTLD-U without VCP gene mutations. This was characterized by
ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites.
In
contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The
ubiquitin pathology was abundant in the neocortex, less robust in limbic and
subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were
detected with antibodies to VCP and there was no biochemical alteration in the
VCP protein. VCP is associated with a variety of cellular activities, including
regulation of the ubiquitin-proteasome system. Our findings are consistent with
the hypothesis that the pathology associated with VCP gene mutations is the
result of impairment of ubiquitin-based degradation pathways.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16783167 [PubMed - indexed for MEDLINE]
93: Eur Neurol. 2006;55(4):204-8. Epub 2006 Jun 13.
Serum levels of matrix metalloproteinases-2 and -9 and their tissue inhibitors
in
inflammatory neuromuscular disorders.
Hurnaus S, Mueller-Felber W, Pongratz D, Schoser BG.
Friedrich Baur Institute, Department of Neurology, Ludwig Maximilian University
Munich, Munich, Germany.
We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue
inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG)
therapy in 33 patients with chronic immune-mediated neuropathies and myopathies
and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9
and
TIMP-1 serum levels higher in all patients compared to age-matched controls.
Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels
increased, while MMP-9 serum levels decreased, indicating tissue repair. After
60
days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and
TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage.
Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended
to change MMP/TIMP levels in a way that paralleled clinical improvement and
relapse. In sum, during a distinct time period, IVIG therapy seems to be able
to
modulate MMP-mediated tissue repair.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16772717 [PubMed - indexed for MEDLINE]
94: Eur Neurol. 2006;55(4):183-8. Epub 2006 Jun 13.
Needle electromyographic findings in 98 patients with myositis.
Blijham PJ, Hengstman GJ, Hama-Amin AD, van Engelen BG, Zwarts MJ.
Department of Clinical Neurophysiology, Institute of Neurology, Institute of
Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
BACKGROUND/AIMS: Little is known about the distribution of electromyographic
(EMG) abnormalities in myositis even though this is relevant in daily practice.
METHODS: A retrospective semiquantitative analysis of needle EMG findings was
performed in a group of 98 patients with myositis. The frequency, type, and
distribution of abnormalities were studied. The influence of the use of
corticosteroids and the stage of the disease were evaluated. RESULTS: In most
patients, a myopathic pattern with spontaneous activity was found, although
several clinically relevant exceptions were noted. Long-duration motor unit
potentials were found in all three diagnostic groups and were not associated
with
disease duration. In the lower extremity a distal to proximal gradient was
present, adding to the diagnostic confusion with neurogenic diseases, and
spontaneous activity was absent in a relatively large group although none of
the
patients in the acute stage of the disease had a normal EMG. The use of
corticosteroids reduced the number of abnormal findings in dermatomyositis and
polymyositis, but not in inclusion body myositis. CONCLUSION: A myopathic pattern
with spontaneous activity was most frequently found, although several clinically
relevant exceptions were noted. These results illustrate the spectrum of EMG
findings in myositis, and may aid the clinician in the interpretation of the
EMG
in these patients.
PMID: 16772711 [PubMed - indexed for MEDLINE]
95: Autoimmunity. 2006 May;39(3):161-70.
Update on idiopathic inflammatory myopathies.
Briani C, Doria A, Sarzi-Puttini P, Dalakas MC.
University of Padova, Department of Neurosciences, Padova, Italy.
chiara.briani@unipd.it
The inflammatory myopathies are a group of acquired diseases, characterized
by an
inflammatory infiltrate of the skeletal muscle. On the basis of clinical,
immuno-pathological and demographic features, three major diseases can be
identified: dermatomyositis (DM); polymyositis (PM); and inclusion body myositis
(IBM). New diagnostic criteria have recently been introduced, which are crucial
for discriminating between the three different subsets of inflammatory myopathies
and for excluding other disorders. DM is a complement-mediated microangiopathy
affecting skin and muscle. PM and IBM are T cell-mediated disorders, where
CD8-positive cytotoxic T cells invade muscle fibres expressing MHC class I
antigens, thus leading to fibre necrosis. In IBM, vacuolar formation with amyloid
deposits are also present. This article summarizes the main clinical, laboratory,
electrophysiological, immunological and histologic features as well as the
therapeutic options of the inflammatory myopathies.
Publication Types:
Review
PMID: 16769649 [PubMed - indexed for MEDLINE]
96: Mol Genet Metab. 2006 Aug;88(4):389-90. Epub 2006 Jun 9.
Normal sialylation of serum N-linked and O-GalNAc-linked glycans in hereditary
inclusion-body myopathy.
Savelkoul PJ, Manoli I, Sparks SE, Ciccone C, Gahl WA, Krasnewich DM, Huizing M.
Publication Types:
Letter
PMID: 16762577 [PubMed - indexed for MEDLINE]
97: Clin Rheumatol. 2007 Jul;26(7):1186-8. Epub 2006 May 31.
Treatment of early and refractory dermatomyositis with infliximab: a report
of
two cases.
Dold S, Justiniano ME, Marquez J, Espinoza LR.
Section of Rheumatology, Department of Medicine, Louisiana State University
School of Medicine, LSU Medical Center, 1542 Tulane Avenue, New Orleans, LA
70112, USA.
The idiopathic inflammatory myopathies embody the largest group of acquired
and
potentially treatable causes of skeletal muscle weakness. The three major groups
of this disorder are polymyositis (PM), dermatomyositis (DM), and inclusion
body
myositis. Corticosteroids continue to be the mainstay of initial treatment in
the
majority of cases of PM/DM. The treatment of refractory disease can be
challenging despite the utilization of the medications currently available.
We
report two patients with refractory DM who were treated with infliximab. We
describe their presentation, clinical course, treatment, and outcomes.
Publication Types:
Case Reports
PMID: 16736125 [PubMed - indexed for MEDLINE]
98: Am J Pathol. 2006 Jun;168(6):1986-97.
Genetically augmenting Abeta42 levels in skeletal muscle exacerbates inclusion
body myositis-like pathology and motor deficits in transgenic mice.
Kitazawa M, Green KN, Caccamo A, LaFerla FM.
Department of Neurobiology and Behavior, 1109 Gillespie Neuroscience Facility,
University of California, Irvine, Irvine, CA 92697-4545, USA.
The pathogenic basis of inclusion body myositis (IBM), the leading muscle
degenerative disease afflicting the elderly, is unknown, although the
histopathological features are remarkably similar to those observed in
Alzheimer's disease. One leading hypothesis is that the buildup of amyloid-beta
(Abeta) peptide within selective skeletal muscle fibers contributes to the
degenerative phenotype. Abeta is a small peptide derived via endoproteolysis
of
the amyloid precursor protein (APP). To determine the pathogenic effect of
augmenting Abeta42 levels in skeletal muscle, we used a genetic approach to
replace the endogenous wild-type presenilin-1 (PS1) allele with the PS1(M146V)
allele in MCK-APP mice. Although APP transgene expression was unaltered, Abeta
levels, particularly Abeta42, were elevated in skeletal muscle of the double
transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated
phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater
activation of GSK-3beta and cdk5 were observed. Other IBM-like pathological
features, such as inclusion bodies and inflammatory infiltrates, were more severe
and prominent in the MCK-APP/PS1 mice. Motor coordination and balance were more
adversely affected and manifested at an earlier age in the MCK-APP/PS1 mice.
The
data presented here provide experimental evidence that Abeta42 plays a proximal
and critical role in the muscle degenerative process.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 16723713 [PubMed - indexed for MEDLINE]
99: Neuromuscul Disord. 2006 Jun;16(6):361-7. Epub 2006 May 8.
Different early pathogenesis in myotilinopathy compared to primary desminopathy.
Fischer D, Clemen CS, Olivé M, Ferrer I, Goudeau B, Roth U, Badorf P,
Wattjes MP,
Lutterbey G, Kral T, van der Ven PF, Fürst DO, Vicart P, Goldfarb LG, Moza
M,
Carpen O, Reichelt J, Schröder R.
Muskellabor, Department of Neurology, University of Bonn, Bonn, Germany.
dirk.fischer@ukb.uni-bonn.de
Mutations in the human myotilin gene may cause limb-girdle muscular dystrophy
1A
and myofibrillar myopathy. Here, we describe a German patient with the clinically
distinct disease phenotype of late adult onset distal anterior leg myopathy
caused by a heterozygous S55F myotilin mutation. In addition to a thorough
morphological and clinical analysis, we performed for the first time a protein
chemical analysis and transient transfections. Morphological analysis revealed
an
inclusion body myopathy with myotilin- and desmin-positive aggregates. The
clinical and pathological phenotype considerably overlaps with late onset distal
anterior leg myopathy of the Markesbery-Griggs type. Interestingly, all three
analyzed myotilin missense mutations (S55F, S60F and S60C) do not lead to gross
changes in the total amount of myotilin or to aberrant posttranslational
modifications in diseased muscle, as observed in a number of muscular
dystrophies. Transiently transfected wild-type and S55F mutant myotilin similarly
colocalised with actin-containing stress fibers in BHK-21 cells. Like the
wild-type protein, mutated myotilin did not disrupt the endogenous desmin
cytoskeleton or lead to pathological protein aggregation in these cells. This
lack of an obvious dominant negative effect sharply contrasts to transfections
with, for instance, the disease-causing A357P desmin mutant. In conclusion our
data indicate that the disorganization of the extrasarcomeric cytoskeleton and
the presence of desmin-positive aggregates are in fact late secondary events
in
the pathogenesis of primary myotilinopathies, rather than directly related.
These
findings suggest that unrelated molecular pathways may result in seemingly
similar disease phenotypes at late disease stages.
Publication Types:
Case Reports
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16684602 [PubMed - indexed for MEDLINE]
100: Neuromuscul Disord. 2006 May;16(5):311-5. Epub 2006 Mar 24.
Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral
haplotype 52.1.
Scott AP, Allcock RJ, Mastaglia F, Nishino I, Nonaka I, Laing N.
School of Surgery and Pathology, M504, UWA, Stirling Highway, Nedlands, WA
6009,
Perth WA, Australia. ascott@cyllene.uwa.edu.au
In Caucasians, sporadic inclusion body myositis has been associated with the
MHC
ancestral haplotypes; HLA-A1, B8, DR3 (8.1AH) and HLA-B35, DR1 (35.2AH). It
is
not known whether these haplotypes carry susceptibility for the disease in other
ethnic groups. We report here the results of HLA-B and -DRB1 typing using a
high-resolution sequence-based technique in a cohort of 31 Japanese patients
with
definite sIBM. Patient allele frequencies were 40.3% for HLA-B*5201 (10.7% in
controls: p<0.001) and 37.1% for HLA-DRB1*1502 (10% in controls: p<0.001).
Both
alleles were found together as part of a conserved haplotype (52.1AH) at a
frequency of 37.1% in patients (8.4% in controls: p<0.001). This is the first
description of a haplotypic MHC association with sporadic inclusion body myositis
in Japanese patients. These findings indicate that different MHC ancestral
haplotypes are associated with sIBM in different ethnic groups and further
emphasize the importance of genetic factors in this condition.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16564169 [PubMed - indexed for MEDLINE]
101: Neuromuscul Disord. 2006 Apr;16(4):223-36. Epub 2006 Mar 15.
Therapeutic targets in patients with inflammatory myopathies: present approaches
and a look to the future.
Dalakas MC.
Neuromuscular Diseases Section, NINDS, NIH, Building 10, Room 4N248, 10 Center
Drive MSC 1382, Bethesda, MD 20892-1382, USA. dalakasm@ninds.nih.gov
Publication Types:
Research Support, N.I.H., Intramural
Review
PMID: 16542836 [PubMed - indexed for MEDLINE]
102: Neurology. 2006 Mar 14;66(5):755-8.
NCAM is hyposialylated in hereditary inclusion body myopathy due to GNE
mutations.
Ricci E, Broccolini A, Gidaro T, Morosetti R, Gliubizzi C, Frusciante R, Di
Lella
GM, Tonali PA, Mirabella M.
Department of Neuroscience, Catholic University, Rome, Italy.
The authors found that the neural cell adhesion molecule (NCAM) is hyposialylated
in hereditary inclusion body myopathy (HIBM) muscle, as suggested by its
decreased molecular weight by Western blot. This abnormality represented the
only
pathologic feature differentiating HIBM due to GNE mutations from other
myopathies with similar clinical and pathologic characteristics. If further
confirmed in larger series of patients, this may be a useful diagnostic marker
of
GNE-related HIBM.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16534119 [PubMed - indexed for MEDLINE]
103: J Biol Chem. 2006 May 5;281(18):12809-16. Epub 2006 Mar 3.
Parkin protects against mitochondrial toxins and beta-amyloid accumulation
in
skeletal muscle cells.
Rosen KM, Veereshwarayya V, Moussa CE, Fu Q, Goldberg MS, Schlossmacher MG,
Shen
J, Querfurth HW.
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University
School of Medicine, Boston, Massachusetts 02135, USA. kenneth_rosen@cchcs.org
Mutations in the ubiquitin ligase-encoding Parkin gene have been implicated
in
the pathogenesis of autosomal recessive Parkinson disease. Outside of the central
nervous system, Parkin is prominently expressed in skeletal muscle. We have
found
accumulations of Parkin protein in skeletal muscle biopsies taken from patients
with inclusion body myositis, a degenerative disorder in which intramyofiber
accumulations of the beta-amyloid peptide are pathognomonic. In comparing primary
cultures of skeletal muscle derived from parkin knock-out and wild-type mice,
we
have found the absence of parkin to result in greater sensitivity to
mitochondrial stressors rotenone and carbonyl cyanide 3-chlorophenylhydrazone,
without any alteration in sensitivity to calcium ionophore or hydrogen peroxide.
Utilizing viral expression constructs coding for the Alzheimer disease and
inclusion body myositis-linked beta-amyloid precursor protein and for its
metabolic byproducts A beta42 and C100, we found that parkin knock-out muscle
cells are also more sensitive to the toxic effects of intracellular A beta.
We
also constructed a lentiviral system to overexpress wild-type Parkin and have
shown that boosting the levels of parkin expression in normal skeletal muscle
cultures provides substantial protection against both mitochondrial toxins and
overexpressed beta-amyloid. Correspondingly, exogenous Parkin significantly
lowered A beta levels. These data support the hypothesis that in myocytes parkin
has dual properties in the maintenance of skeletal muscle mitochondrial
homeostasis and in the regulation of A beta levels.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 16517603 [PubMed - indexed for MEDLINE]
104: Biochemistry. 2006 Mar 7;45(9):2968-77.
Influence of UDP-GlcNAc 2-epimerase/ManNAc kinase mutant proteins on hereditary
inclusion body myopathy.
Penner J, Mantey LR, Elgavish S, Ghaderi D, Cirak S, Berger M, Krause S, Lucka
L,
Voit T, Mitrani-Rosenbaum S, Hinderlich S.
Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Institut
für
Biochemie und Molekularbiologie, Arnimallee 22, 14195 Berlin-Dahlem, Germany.
Hereditary inclusion body myopathy (HIBM), a neuromuscular disorder, is caused
by
mutations in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase
(GNE), the key enzyme of sialic acid biosynthesis. To date, more than 40
different mutations in the GNE gene have been reported to cause the disease.
Ten
of them, representing mutations in both functional domains of GNE, were
recombinantly expressed in insect cells (Sf9). Each of the mutants that was
analyzed displayed a reduction in the two known GNE activities, thus revealing
that mutations may also influence the function of the domain not harboring them.
The extent of reduction strongly differs among the point mutants, ranging from
only 20% reduction found for A631T and A631V to almost 80% reduction of at least
one activity in D378Y and N519S mutants and more than 80% reduction of both
activities of G576E, underlined by structural changes of N519S and G576E, as
observed in CD spectroscopy and gel filtration analysis, respectively. We
therefore generated models of the three-dimensional structures of the epimerase
and the kinase domains of GNE, based on Escherichia coli UDP-N-acetylglucosamine
2-epimerase and glucokinase, respectively, and determined the localization of
the
HIBM mutations within these proteins. Whereas in the kinase domain most of the
mutations are localized inside the enzyme, mutations in the epimerase domain
are
mostly located at the protein surface. Otherwise, the different mutations result
in different enzymatic activities but not in different disease phenotypes and,
therefore, do not suggest a direct role of the enzymatic function of GNE in
the
disease mechanism.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16503651 [PubMed - indexed for MEDLINE]
105: Brain. 2006 Apr;129(Pt 4):986-95. Epub 2006 Feb 2.
Shared blood and muscle CD8+ T-cell expansions in inclusion body myositis.
Dimitri D, Benveniste O, Dubourg O, Maisonobe T, Eymard B, Amoura Z, Jean L,
Tiev
K, Piette JC, Klatzmann D, Herson S, Boyer O.
Service de médecine interne 1, Hôpital Pitié-Salpêtrière, Paris, France.
Inclusion body myositis (IBM) is the most frequent inflammatory myopathy over
the
age of fifty. Pathological findings suggest that two processes may contribute
to
IBM pathogenesis: a primary degenerative process affecting muscle fibre and/or
an
autoimmune process mediated by major histocompatibility complex (MHC)
class-I-restricted cytotoxic CD8+ T cells. Previous studies have demonstrated
that muscle-infiltrating CD8+ T cells in IBM display restricted expression of
T-cell receptor (TCR)-BV families or evidenced oligoclonal T-cell expansions.
This study was performed to investigate whether blood T cells similarly exhibit
clonal expansions due to the recirculation of muscle-infiltrating T cells in
the
periphery. For this, we studied the T-cell repertoire of 17 IBM patients by
complementarity-determining-region (CDR) 3 length distribution (immunoscope)
analysis of TCR-B transcripts. Mean age was 68 years (range 53-88) and mean
duration of the disease was 6.5 years (2-20). Oligoclonal T-cell expansions
were
observed in the blood of IBM patients. The quantitative average perturbation
D
index was significantly increased in IBM patients [D = 13.7% +/- 1.2%, mean
+/-
standard error of measurement (SEM)] as compared with 17 age-matched controls
suffering from connective tissue diseases not associated with T-cell repertoire
perturbation, that is, dermatomyositis (DM) and systemic sclerosis (9.3 +/-
0.6%,
P < 0.005). Nevertheless, there was no correlation between the level of blood
perturbation and muscle inflammation. Sorting experiments showed that these
perturbations were due to oligoclonal expansions of CD8+ T cells. In the three
IBM patients analysed, we could relate the blood expansions to T-cell clones
also
found in muscle. The clonally expanded blood T cells dramatically responded
to
interleukin-2 (IL-2) in vitro, suggesting that they had been primed in vivo,
presumably in response to yet unknown muscle auto-antigens. Together, our results
indicate that clonally expanded muscle-infiltrating CD8+ T cells re-circulate
in
the blood and support the concept of a CD8+ T-cell-mediated autoimmune component
in IBM, similarly to what is observed in polymyositis (PM).
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16455793 [PubMed - indexed for MEDLINE]
106: J Neurochem. 2006 Mar;96(5):1491-9. Epub 2006 Jan 25.
Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in
sporadic inclusion-body myositis and in endoplasmic reticulum stress-induced
cultured human muscle fibers.
Nogalska A, Engel WK, McFerrin J, Kokame K, Komano H, Askanas V.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles,
California 90017-1912, USA.
Herp is a stress-response protein localized in the endoplasmic reticulum (ER)
membrane. Herp was proposed to improve ER-folding, decrease ER protein load,
and
participate in ER-associated degradation (ERAD). Intra-muscle-fiber ubiquitinated
multiprotein-aggregates containing, among other proteins, either amyloid-beta
(Abeta) or phosphorylated tau are characteristic of sporadic inclusion-body
myositis (s-IBM). ER stress and proteasome inhibition appear to play a role
in
s-IBM pathogenesis. We have now studied Herp in s-IBM muscle fibers and in
ER-stress-induced or proteasome-inhibited cultured human muscle fibers. In s-IBM
muscle fibers: (i) Herp was strongly immunoreactive in the form of aggregates,
which co-localized with Abeta, GRP78, and beta2 proteasome subunit; (ii) Herp
mRNA and protein were increased. In ER-stress-induced cultured human muscle
fibers: (i) Herp immunoreactivity was diffusely increased; (ii) Herp mRNA and
protein were increased. In proteasome-inhibited cultured human muscle fibers:
(i)
Herp immunoreactivity was in the form of aggregates; (ii) Herp protein was
increased, but its mRNA was not. Accordingly, in s-IBM muscle fibers: (i)
increase of Herp might be due to both ER-stress and proteasome inhibition; (ii)
co-localization of Herp with Abeta, proteasome, and ER-chaperone GRP78 could
reflect its possible role in processing and degradation of cytotoxic proteins
in
ER.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
PMID: 16441512 [PubMed - indexed for MEDLINE]
107: Neurology. 2006 Jan 24;66(2 Suppl 1):S97-101.
Brain and brawn: parallels in oxidative strength.
Moreira PI, Honda K, Zhu X, Nunomura A, Casadesus G, Smith MA, Perry G.
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106,
USA.
Neuronal oxidative stress occurs early in the progression of Alzheimer disease
(AD), significantly before the development of the pathologic hallmarks,
neurofibrillary tangles, and senile plaques. Study of Down syndrome, cases with
autosomal dominant mutation, and sporadic AD all suggest amyloid-beta deposition
and hyperphosphorylated tau function as compensatory responses and downstream
adaptations to ensure that neuronal cells do not succumb to oxidative damage.
Amyloid-beta and tau hyperphosphorylation also define vulnerable muscle cells
in
sporadic inclusion-body myositis (s-IBM). The role of the structural changes
of
s-IBM, as in AD, remains to be determined but may mark a critical response
yielding a novel balance in oxidant homeostasis.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432155 [PubMed - indexed for MEDLINE]
108: Neurology. 2006 Jan 24;66(2 Suppl 1):S93-6.
Retraction in:
Daroff RB, Griggs RC. Neurology. 2006 Dec 12;67(11):2087.
Preferential degradation of oxidized proteins by the 20S proteasome may be
inhibited in aging and in inflammatory neuromuscular diseases.
Davies KJ, Shringarpure R.
The Ethel Percy Andrus Gerontology Center, Division of Molecular & Computational
Biology, University of Southern California, Los Angeles, CA, USA. Kelvin@usc.edu
Free radicals produced by chronic inflammation cause cumulative damage to
cellular macromolecules and appear to contribute to senescence/aging, age-related
disorders, and neuromuscular degenerative diseases such as inclusion-body
myositis. Proteins are major targets for oxidative damage (in addition to DNA
and
lipids) and the accumulation of oxidized proteins has been reported in many
aging
and disease models. In young and healthy individuals, moderately oxidized soluble
cell proteins are selectively and rapidly degraded by the 20S proteasome. The
mechanism of selective proteolysis appears to depend upon oxidation-induced
protein unfolding, with increasing surface hydrophobicity as (previously
shielded) hydrophobic residues are exposed from the interior. The 20S proteasome
can preferentially bind to and degrade such mildly oxidized, hydrophobic proteins
without a need for ubiquitin targeting or ATP activation. Severely oxidized,
aggregated, and crosslinked proteins, however, are poor substrates for
degradation and actually inhibit the proteasome. During aging, and in many
age-related diseases/disorders, the proteasome is progressively inhibited by
binding to increasing levels of oxidized and cross-linked protein aggregates.
Cellular aging and inflammatory neuromuscular degenerative diseases probably
include both an increase in the generation of reactive oxygen species as well
as
a decline in proteasome activity, resulting in the progressive accumulation
of
oxidatively damaged protein aggregates that eventually contribute to cellular
dysfunction and senescence.
Publication Types:
Research Support, N.I.H., Extramural
Retracted Publication
Review
PMID: 16432154 [PubMed - indexed for MEDLINE]
109: Neurology. 2006 Jan 24;66(2 Suppl 1):S74-8.
Common structure and toxic function of amyloid oligomers implies a common
mechanism of pathogenesis.
Glabe CG, Kayed R.
Department of Molecular Biology and Biochemistry, University of California,
Irvine, CA 92697, USA. cglabe@uci.edu
Recent findings indicate that soluble amyloid oligomers may represent the primary
pathologic species in degenerative diseases. These amyloid oligomers share common
structural features and the ability to permeabilize membranes, suggesting that
they also share a common primary mechanism of pathogenesis. Membrane
permeabilization by amyloid oligomers may initiate a common group of downstream
pathologic processes, including intracellular calcium dyshomeostasis, production
of reactive oxygen species, altered signaling pathways, and mitochondrial
dysfunction that represent key effectors of cellular dysfunction and cell death
in amyloid-associated degenerative disease, such as sporadic inclusion-body
myositis.
Publication Types:
Review
PMID: 16432151 [PubMed - indexed for MEDLINE]
110: Neurology. 2006 Jan 24;66(2 Suppl 1):S65-8.
Inclusion-body myositis and Alzheimer disease: two sides of the same coin,
or
different currencies altogether?
Murphy MP, Golde TE.
Department of Molecular and Cellular Biochemistry, Sanders-Brown Center on
Aging,
University of Kentucky, Lexington, KY 40536, USA. mpmurp3@uky.edu
Publication Types:
Comparative Study
Review
PMID: 16432148 [PubMed - indexed for MEDLINE]
111: Neurology. 2006 Jan 24;66(2 Suppl 1):S59-64.
Immunotherapeutic relief from persistent infections and amyloid disorders.
McGavern DB.
Division of Virology, Department of Neuropharmacology, The Scripps Research
Institute, La Jolla, CA, USA. mcgad@scripps.edu
Persistent infections and amyloid disorders afflict a significant number of
people worldwide. It would appear at first glance that the treatment of these
afflictions should be entirely unrelated; however, in both cases components
of
the adaptive immune system have been harnessed in an attempt to provide some
therapeutic relief. Given that the ability of a pathogen to establish persistence
often depends in part on a shortcoming of the adaptive immune response, it seems
logical to devise immunotherapies with the intention of supplementing (or
replacing) the insufficient immunologic element. A case in point is an
intervention referred as immunocytotherapy, which relies upon the adoptive
transfer of pathogen-specific T lymphocytes into a persistently infected host.
Remarkably, the adoptively transferred T lymphocytes not only have the capacity
to clear the persistent infection, but can also provide the recipient with
protection against subsequent rechallenge (i.e., immunologic memory). Treatment
of amyloid disorders (e.g., Alzheimer disease, sporadic inclusion-body myositis)
with a similar therapeutic approach is complicated by the fact that the aberrant
protein accumulations are self-derived. Focusing the adaptive response on these
aberrant self-proteins has the potential to result in autoimmune pathology.
This
review critically evaluates the importance of immunotherapeutic approaches for
the treatment of persistent infections and amyloid disorders, and attempts to
delineate the interventions that are most likely to succeed in an exceedingly
complex disorder such as sporadic inclusion-body myositis.
Publication Types:
Review
PMID: 16432147 [PubMed - indexed for MEDLINE]
112: Neurology. 2006 Jan 24;66(2 Suppl 1):S56-8.
Controlling autoimmunity in sporadic inclusion-body myositis.
Steinman L.
Department of Neurology and Neurological Sciences, Beckman Center for Molecular
Medicine, Stanford University, Stanford, CA 94305, USA. Steinman@stanford.edu
Publication Types:
Review
PMID: 16432146 [PubMed - indexed for MEDLINE]
113: Neurology. 2006 Jan 24;66(2 Suppl 1):S49-55.
Mitochondrial abnormalities in inclusion-body myositis.
Oldfors A, Moslemi AR, Jonasson L, Ohlsson M, Kollberg G, Lindberg C.
Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
anders.oldfors@pathology.gu.se
Mitochondrial changes are frequently encountered in sporadic inclusion-body
myositis (s-IBM). Cytochrome c oxidase (COX)-deficient muscle fibers and
large-scale mitochondrial DNA (mtDNA) deletions are more frequent in s-IBM than
in age-matched controls. COX deficient muscle fibers are due to clonal expansion
of mtDNA deletions and point mutations in segments of muscle fibers. Such
segments range from 75 microm to more than 1,000 microm in length. Clonal
expansion of the 4977 bp "common deletion" is a frequent cause of
COX deficient
muscle fiber segments, but many other deletions also occur. The deletion
breakpoints cluster in a few regions that are similar to what is found in human
mtDNA deletions in general. Analysis in s-IBM patients of three nuclear genes
associated with multiple mtDNA deletions, POLG1, ANT1 and C10orf2, failed to
demonstrate any mutations. In s-IBM patients with high number of COX-deficient
fibers, the impaired mitochondrial function probably contribute to muscle
weakness and wasting. Treatment that has positive effects in mitochondrial
myopathies may be tried also in s-IBM.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16432145 [PubMed - indexed for MEDLINE]
114: Neurology. 2006 Jan 24;66(2 Suppl 1):S39-48.
Inclusion-body myositis: a myodegenerative conformational disorder associated
with Abeta, protein misfolding, and proteasome inhibition.
Askanas V, Engel WK.
USC Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA,
USA. askanas@usc.edu
Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of
older
persons, is of unknown cause and there is no successful treatment. We summarize
our most recent findings, which provide a better understanding of the steps
in
the pathogenetic cascade. We suggest that s-IBM is primarily a myodegenerative
disease. Intriguing are the phenotypic similarities between s-IBM muscle fibers
and the brains of Alzheimer disease, the most common neurodegenerative disease
of
older persons. In s-IBM, abnormal accumulation of the amyloid-beta (Abeta)
precursor protein and its proteolytic fragment, Abeta, associated with the aging
intracellular milieu of the muscle fiber, appear to be key upstream pathogenic
events. We propose that the identified abnormal accumulation, misfolding, and
aggregation of proteins, perhaps provoked by the aging milieu and aggravated
by
the oxidative stress, lead to the s-IBM-specific vacuolar degeneration and
atrophy of muscle fibers.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432144 [PubMed - indexed for MEDLINE]
115: Neurology. 2006 Jan 24;66(2 Suppl 1):S33-8.
Inflammatory, immune, and viral aspects of inclusion-body myositis.
Dalakas MC.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and
Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
dalakasm@ninds.nih.gov
Muscle biopsies from patients with sporadic inclusion-body myositis (sIBM)
consistently demonstrate that the inflammatory T cells almost invariably invade
intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded
by T cells. This indicates two concurrently ongoing processes, an autoimmune
mediated by cytotoxic T cells and a degenerative manifested by the vacuolated
muscle fibers and deposits of amyloid-related proteins. The autoimmune features
of IBM are highlighted by the strong association of the disease with: a) HLA
I,
II antigens, in frequency identical to classic autoimmune diseases; b) other
autoimmune disorders in up to 32% of the patients, autoantibodies,
paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with
increasingly recognized frequency (up to 13 known cases); and d)
antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells
with
rearranged T-cell receptor genes that persist over time, even in different
muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory
molecules. In contrast to IBM, in various dystrophies the inflammatory cells
are
clonally diverse and the muscle fibers do not express MHC-I or costimulatory
molecules in the pattern seen in IBM. Like other chronic autoimmune conditions
with coexisting inflammatory and degenerative features (i.e., primary progressive
MS), IBM is resistant to conventional immunotherapies. Recent data suggest that
strong anti-T cell therapies can be promising and they are the focus of ongoing
research.
Publication Types:
Review
PMID: 16432143 [PubMed - indexed for MEDLINE]
116: Neurology. 2006 Jan 24;66(2 Suppl 1):S30-2.
The current status of treatment for inclusion-body myositis.
Griggs RC.
Department of Neurology, University of Rochester School of Medicine and
Dentistry, Rochester, NY 14642, USA. Robert_Griggs@URMC.Rochester.edu
There is no established treatment that improves, arrests, or slows the
progression of inclusion-body myositis (IBM). Many anti-inflammatory,
immunosuppressant, or immunomodulating agents have been administered to patients
with IBM but the design of clinical trials was such that it can only be concluded
that none produced rapid improvement. The natural history of the disease is
for
stabilization or improvement in a third of patients for 6 months or more. Thus
some agents that did not produce dramatic benefit may have been prematurely
abandoned. However, because high-dose prednisone worsens strength while
decreasing inflammation but increases amyloid accumulation, alternative targets
for intervention and novel treatment strategies are needed.
Publication Types:
Review
PMID: 16432142 [PubMed - indexed for MEDLINE]
117: Neurology. 2006 Jan 24;66(2 Suppl 1):S20-9.
Inclusion-body myositis: clinical, diagnostic, and pathologic aspects.
Engel WK, Askanas V.
The Neuromuscular Center, Department of Neurology, University of Southern
California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA,
USA. askanas@hsc.usc.edu
The diagnostic aspects of sporadic inclusion-body myositis (s-IBM), and a few
comments on our own approach to its treatment, are presented to foster the goals
of this symposium, which was organized to provoke new ideas concerning the cause
and treatment of this currently unsolvable disease. s-IBM is the most common,
progressive, debilitating muscle disease beginning in persons over age 50 years,
and it is more common in men. Diagnostic parameters reviewed are clinical,
muscle-biopsy histochemistry, electrophysiologic and CSF evaluations. Overall,
the degenerative phenomena in s-IBM muscle fibers seem to be the major cause
of
the progressive, unstoppable weakness, rather than the lymphocytic inflammation.
Available treatments are of only slight, temporary benefit for only some s-IBM
patients, indicating a desperate need for definitive therapies.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432141 [PubMed - indexed for MEDLINE]
118: Neurology. 2006 Jan 24;66(2 Suppl 1):S123-4.
Pilot trial of etanercept in the treatment of inclusion-body myositis.
Barohn RJ, Herbelin L, Kissel JT, King W, McVey AL, Saperstein DS, Mendell JR.
Department of Neurology, University of Kansas Medical Center, Kansas City,
KS
66160, USA. rbarohn@kumc.edu
Inclusion-body myositis (IBM) is an inflammatory muscle disease that has proven
resistant to treatment. Tumor necrosis factor molecules have been detected in
muscle biopsies from patients with IBM. Etanercept is a TNFalpha receptor fusion
protein that binds and inactivates tumor necrosis factor. Nine patients were
treated with etanercept at a dose of 25 mg, two times a week for an average
of 17
+/- 6.1 months. Each patient was evaluated using quantitative strength testing.
Their data were compared to two different control groups. The first control
group
consisted of patients who participated in trials of beta-interferon-1A and had
received placebo. There was no significant difference. The second control group
was a natural history cohort of IBM patients. There was no statistically
significant difference between the treated group and the natural history group
at
6 and 12 months when looking at elbow flexors, or 6 months when looking at hand
grip. In the treated patients there was a small but significant improvement
(p =
0.002) in handgrip at 12 months.
Publication Types:
Clinical Trial
Comparative Study
PMID: 16432140 [PubMed - indexed for MEDLINE]
119: Neurology. 2006 Jan 24;66(2 Suppl 1):S114-7.
RNA interference as potential therapy for neurodegenerative disease: applications
to inclusion-body myositis?
Paulson H.
Department of Neurology, Carver College of Medicine, University of Iowa, Iowa
City, IA 52242, USA. henry-paulson@uiowa.edu
The discovery of RNA interference (RNAi) has led to powerful new approaches
to
silence targeted genes in a sequence-specific manner. The potential therapeutic
application of RNAi to neurologic disease is highlighted by the recent success
of
several laboratories in suppressing the expression of neurodegenerative disease
genes in transgenic mouse models. Here I discuss potential applications of RNAi
to inclusion-body myositis (IBM) after first reviewing its application more
generally to neurologic disease. The clearest application of RNAi to IBM is
as a
research tool to identify critical target genes that contribute to pathogenesis.
Provided that proximal pathogenic targets are identified, RNAi could surface
as a
potential therapeutic strategy to modulate their expression.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432138 [PubMed - indexed for MEDLINE]
120: Neurology. 2006 Jan 24;66(2 Suppl 1):S110-3.
Comment in:
Neurology. 2006 Jun 27;66(12):1959; author reply 1959.
Treatment and prevention of the amyloidoses: can the lessons learned be applied
to sporadic inclusion-body myositis?
Buxbaum JN.
Department of Molecular and Experimental Medicine, The Keck Autoimmune Disease
Center, The Scripps Research Institute, La Jolla, CA, USA. jbux@scripps.edu
The amyloid fibril represents a final common pathologic pathway for a variety
of
human proteins, all of which have a propensity to misfold. Each seems to require
a predisposing event to realize its fibrillogenic potential. It may be mutation,
inappropriate or incomplete cleavage, overproduction, or the availability of
a
template for misfolding. Therapies have been based on decreasing the stimulus
(inflammation in the case of AA) reducing the number of producing cells (AL)
and
a variety of approaches to removing the extracellular aggregates. Sporadic
inclusion-body myositis (sIBM), while physically resembling the extracellular
amyloidoses, is an intracellular disease, hence imposes the additional
requirement of developing a therapy that can access and function inside the
affected or potentially affected, cell. Current approaches to the treatment
of
other forms of amyloidosis are discussed in the context of their applicability,
or lack thereof, to sIBM.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Review
PMID: 16432137 [PubMed - indexed for MEDLINE]
121: Neurology. 2006 Jan 24;66(2 Suppl 1):S1-6.
A perspective on sporadic inclusion-body myositis: the role of aging and
inflammatory processes.
Finch CE.
Andrus Gerontology Center, Department of Biological Sciences, University of
Southern California, Los Angeles, CA 90089-0191, USA. cefinch@usc.edu
Sporadic inclusion-body myositis (sIBM) is an age-related condition manifested
after midlife. This review points out salient features of sIBM that are shared
with normal aging in muscle and with inflammatory changes in vascular atheromas
and senile plaques of Alzheimer disease (AD). The amyloid precursor protein
(APP)
and derived Abeta peptides are found in both AD and sIBM. Because transgenic
expression of human APP induces sIBM like changes, it is of potential interest
that an inducer of APP, IL-1, increases during aging in mouse muscle. Because
various subsets of the usual aging changes in aging brain, muscle, and vessels
can be attenuated in rodents by caloric intake and possibly in humans by drugs
with anti-inflammatory and anticoagulant activities, this study suggests that
diet and inflammation may be useful experimental variations in exploring the
pathogenesis of sIBM.
Publication Types:
Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16432135 [PubMed - indexed for MEDLINE]
122: Autoimmun Rev. 2006 Feb;5(2):93-100. Epub 2005 Jun 17.
Difference in adhesion molecule expression (ICAM-1 and VCAM-1) in juvenile
and
adult dermatomyositis, polymyositis and inclusion body myositis.
Sallum AM, Kiss MH, Silva CA, Wakamatsu A, Vianna MA, Sachetti S, Marie SK.
Department of Pediatrics--University of São Paulo Medical School, Brazil.
adrianasallum@ig.com.br
To assess the differential expression of adhesion molecules ICAM-1 and VCAM-1
in
vessels and muscle fibers in acquired inflammatory myopathy, a series comprising
thirty-seven muscle biopsy specimens from patients with JDM, fifteen with DM,
fifteen with PM and seven with IBM was studied. Histochemical and
immunohistochemical tests (StreptABCcomplex/HRP) for ICAM-1 and VCAM-1
(Dakopatts) were performed in serial frozen sections. ICAM-1 expression in
vessels was significantly (p<0.0001) more present in JDM than PM, DM or IBM.
However, in muscle fibers, ICAM-1 expression was absent in both JDM and IBM,
but
present in 33.4% and 40% in PM and DM respectively (p<0.0001). VCAM-1 expression
in vessels was significantly more present in PM and DM than JDM and IBM
(p<0.0001) while VCAM-1 expression in muscle fibers was almost absent in
the four
groups (p=0.2632). These findings emphasize the importance of adhesion molecules
in the pathophysiology of the inflammatory myopathies, mainly the marked ICAM-1
expression in vessels in JDM, corroborating the microvascular involvement in
this
disease. In contrast, VCAM-1 seems not to play a major role in JDM, as previously
described in PM, DM and IBM. Adhesion molecule expression in JDM presents a
differential characteristic when compared to PM, DM and IBM.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 16431335 [PubMed - indexed for MEDLINE]
123: Ann Rheum Dis. 2006 Feb;65(2):242-5.
Clinical characteristics of patients with myositis and autoantibodies to
different fragments of the Mi-2 beta antigen.
Hengstman GJ, Vree Egberts WT, Seelig HP, Lundberg IE, Moutsopoulos HM, Doria
A,
Mosca M, Vencovsky J, van Venrooij WJ, van Engelen BG.
Neuromuscular Centre Nijmegen, Department of Neurology, University Medical
Centre
Nijmegen, PO Box 9101, Internal Code 935, 6500 HB Nijmegen, The Netherlands.
g.hengstman@neuro.umcn.nl.
OBJECTIVES: To assess the clinical implications of autoantibodies directed
against different parts of the Mi-2 beta autoantigen in patients with myositis.
METHODS: A systematic assessment of the clinical, laboratory, and histological
characteristics of 48 anti-Mi-2 positive patients from six European centres
was
made. Anti-Mi-2 autoantibodies were determined with an ELISA using four
overlapping fragments spanning the entire amino acid sequence of the autoantigen.
Data were compared with results for a large group of anti-Mi-2 negative patients
with myositis published previously. RESULTS: Anti-Mi-2 autoantibodies were found
in dermatomyositis, polymyositis, and inclusion body myositis. In general,
myositis with anti-Mi-2 autoantibodies was characterised by relatively mild
disease, sometimes accompanied by extra-muscular symptoms, including arthralgia,
arthritis, Raynaud's phenomenon, and interstitial lung disease. Cardiac disease
was not seen, and treatment response was fair. No differences were found between
patients with autoantibodies to different fragments of the Mi-2 beta antigen,
except for a potentially increased risk of cancer in patients with antibodies
directed to the N-terminal fragment of the autoantigen. CONCLUSIONS: Anti-Mi-2
autoantibodies are not a marker of a specific subtype of myositis. No significant
differences between patients with autoantibodies to different fragments of the
Mi-2 beta autoantigen are found, with the possible exception of an increased
risk
of cancer in patients with antibodies to the N-terminal fragment.
Publication Types:
Comparative Study
Multicenter Study
Research Support, Non-U.S. Gov't
PMID: 16410528 [PubMed - indexed for MEDLINE]
.