.
A sample of MAJOR articles from the medical literature.
Primary respiratory failure in inclusion body myositis.
Voermans NC, Vaneker M, Hengstman GJ, ter Laak HJ, Zimmerman C, Schelhaas
HJ, Zwarts MJ. Neuromuscular Centre Nijmegen, Department of Neurology, University
Medical Centre Nijmegen, The Netherlands.
Neurology. 2004 Dec 14;63(11):2191-2.
Case Report
The idiopathic inflammatory myopathies are a group of disorders characterized
by acquired muscle weakness and presence of inflammatory infiltrates in skeletal
muscle. The three most common diseases within this group are dermatomyositis
(DM), polymyositis (PM), and inclusion body myositis (IBM). Respiratory muscle
weakness with respiratory failure is a well-recognized complication in PM and
DM but has only rarely been reported in IBM. Symptomatic respiratory failure
in IBM is considered to be secondary to coincidental pulmonary disease. We report
a patient with IBM who developed subacute respiratory failure caused by primary
respiratory muscle weakness.
Tau aggregates are abnormally phosphorylated in inclusion body myositis and have
an immunoelectrophoretic profile distinct from other tauopathies.
Maurage CA, Bussiere T, Sergeant N, Ghesteem A, Figarella-Branger D, Ruchoux
MM, Pellissier JF, Delacourte A. INSERM U422, Faculte de Medecine, 1 place de
Verdun, Lille cedex, France. ca-maurage@chru-lille.fr
Neuropathol Appl Neurobiol. 2004 Dec;30(6):624-34.
Sporadic inclusion body myositis (s-IBM) is the most frequent progressive acquired
inflammatory myopathy in people older than 50 years. Abnormal aggregates of 'Alzheimer's
proteins', including tau proteins, have been previously demonstrated in s-IBM.
In the present study, we have investigated by immunohistochemistry and immunoblotting
analysis the presence of tau proteins in muscle biopsy samples from patients with
s-IBM and other myopathies with rimmed vacuoles, using newly developed antibodies
raised against tau protein epitopes found in Alzheimer's disease brain. Tau immunoreactivity
was shown in rimmed vacuoles or inclusions, preferentially with antibodies directed
against phosphorylated carboxy-terminal epitopes of tau proteins. Cytoplasmic
reactivity was also demonstrated in atrophic, nonvacuolated fibres, as well as
in non-necrotic fibres invaded by inflammatory cells. Abnormally phosphorylated
tau aggregates were also found in other compartments of the muscle fibre in s-IBM
and other myopathies. Tau immunoblotting showed an electrophorectic profile of
a doublet within the range of 60-62 kDa isovariants, which was different from
tauopathies of the central nervous system. Finally, the unique pattern of immunoreactivity
of s-IBM samples towards anti-tau antibodies is a new clue to a possible distinct
subclass of peripheral tauopathy, different from the tauopathies of the central
nervous system.
Associations with autoimmune disorders and HLA class I and II antigens in inclusion
body myositis.
Badrising UA, Schreuder GM, Giphart MJ, Geleijns K, Verschuuren JJ, Wintzen
AR, Maat-Schieman ML, van Doorn P, van Engelen BG, Faber CG, Hoogendijk JE, de
Jager
AE, Koehler PJ, de Visser M, van Duinen SG; Dutch IBM Study Group.
Department of Neurology, K5Q, Leiden University Medical Center, PO Box 9600, 2300
RC Leiden, The Netherlands. ubadrising@lumc.nl
Neurology. 2004 Dec 28;63(12):2396-8.
Whether autoimmune mechanisms play a role in the pathogenesis of inclusion body
myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52 patients,
including 17 with autoimmune disorders (AIDs), showed that patients were more
likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral haplotype
than healthy control subjects, irrespective of the presence of AIDs.
Patients lacked the apparently protective HLA-DR53 antigen. The results provide
further support for an autoimmune basis in IBM. I have
included a pdf file of the whole ARTICLE HERE
The prion protein in human neuromuscular diseases.
Kovacs GG, Kalev O, Gelpi E, Haberler C, Wanschitz J, Strohschneider
M, Molnar MJ, Laszlo L, Budka H. National Institute of Psychiatry and Neurology,
Budapest, Hungary.
J Pathol. 2004 Nov;204(3):241-7.
The basis of human prion diseases affecting the nervous system is accumulation
of a disease-associated conformer (PrPSc) of the normal cellular prion protein
(PrPC). Earlier studies demonstrated increased expression of PrPC in inclusion
body myositis (IBM), dermato-, and polymyositis, as well as neurogenic muscle
atrophy. To define the spectrum and reliability of PrPC immunoreactivity, its
expression was examined systematically in a series of pathologically characterized
muscular disorders by means of immunohistochemistry, confocal laser microscopy,
and immunogold electron microscopy. Anti-PrPC immunolabelling of rimmed vacuoles
was observed in IBM, inclusions of myofibrillary myopathy, targets, regenerating,
and atrophic fibres, mononuclear cells, in addition to ragged red fibres in
mitochondrial myopathies, and focal sarcolemmal immunostaining in non-diseased
controls. Quantitative analysis demonstrated that, in neurogenic muscle lesions,
anti-PrPC staining detects a significantly broader spectrum of fibres than anti-vimentin
or anti-NCAM. In dystrophic muscle, PrPC expression was mainly restricted to
regenerating fibres. In IBM, PrPC expression was not confined to rimmed vacuoles
or vacuolated fibres and only a small percentage (7.1%) of rimmed vacuoles were
PrPC positive. Ultrastructurally, PrPC was observed in the cytoplasm of lymphocytes,
in the myofibrillar network of targets, and in rimmed vacuoles. Knowledge of
disease circumstances with altered expression of PrPC is important in the setting
of a potentially increased chance for extraneural PrPC-PrPSc conversion. In
addition, our observations suggest that PrPC may have a general stress-response
effect in various neuromuscular disorders.
Introduction (p. 241)
Human prion diseases, or transmissible spongiform encephalopathies (TSEs), occur
as sporadic, acquired, and genetic disorders [1]. Change in the conformation
of the normal cellular form of prion protein (PrPC) produces a pathological,
disease-associated PrP (PrPd or PrPSc) which accumulates predominantly in the
brain. Recent studies indicate that PrPd may be present in skeletal muscle,
spleen, vessel wall, and peripheral nerves in sporadic Creutzfeldt-Jakob
disease (CJD) [2-5] in addition to widespread presence in the lymphoid
tissue of variant CJD [6]. Yet, prion disease predominantly affecting extraneural
sites has never been described.
Discussion: (p. 245-47)
In the present study we demonstrate a fairly uniform morphological pattern of
increased PrPC expression in distinct muscular disease entities.
PrPC appears in lymphocytes in inflammatory infiltrates, targets
in neurogenic lesions, rimmed vacuoles in IBM, and regenerating and atrophic
fibres in various diseases. In addition to these, PrPC expression
is found in the sarcoplasm of normal-appearing fibres in IBM, neurogenic lesions,
and muscular dystrophies. This is in contrast to nondiseased controls where
PrPC expression is restricted to the sarcolemma. Occasional nerve
branches and muscle spindles also show PrPC immunoreactivity which
may be relevant to the accumulation of PrPd in skeletal muscle [22].
In fact, quantification demonstrates in neurogenic
lesions that anti- PrPC immunostaining detects a significantly broader spectrum
of fibres than antivimentin or anti-NCAM, which are thought to identify regenerating
and denervated fibres, respectively [23]. This could suggest a neurotrophic
role for PrPC. However, this has not been confirmed in other studies, since
neural regulation of the expression of acetylcholine receptors at neuromuscular
synapses in skeletal muscle is not related to the PrP gene [24].
In IBM, PrPC immunoreactivity is infrequent in
rimmed vacuoles. The percentage of PrPC-positive fibres without rimmed vacuoles
in Gömöri-stained sections is significantly higher than that of PrPC-positive
vacuolated fibres. Thus, PrPC-positive vacuolated and non-vacuolated fibres,
as well as inflammatory infiltrates, contribute to the increased expression
of PrPC detected in western blotting [20]. Accumulation of PrPC in targets,
and in tubulofilamentous-like structures in rimmed vacuoles in IBM, seems to
represent a stereotyped response to myofibrillar breakdown or occasional co-aggregation
[25]. This is supported by our observation that the majority of rimmed vacuoles
in IBM do not contain PrPC. Another explanation could be that PrPC, as a potential
stress-response protein, may be partially involved in a cytoprotective
process similar to the ubiquitin-proteosome system. The latter is part
of an intracellular surveillance complex aiming to repair altered proteins (eg
by chaperones) or to isolate and eliminate these from the cell (eg by the autophagic-lysosomal
system) [21]. This is supported by our and previous observations that ubiquitin
is present in autophagic rimmed vacuoles (Figure 2f) [19]. We have seen sarcoplasmic
ubiquitin immunoreactivity overlapping with that of PrPC, suggesting a common
response of these proteins to disease-associated alterations. Interestingly,
in myofibrillar myopathy, PrP-immunoreactive deposits do not overlap exclusively
with specific desmin immunopositivity [26].
As apoptosis and oxidative stress are common pathogenetic
steps in the aforementioned disease states [27], and PrPC has a suggested antioxidant
or antiapoptotic capacity, this may be one reason for its
higher expression [15,16].
Recently, similar to our findings with PrPC, enhanced
alpha-B-crystallin expression was reported in structurally intact fibres (so-called
X fibres) in IBM and other diseases including polymyositis and myofibrillar
myopathy [28]. In that study, in contrast to our findings with PrPC, alpha-B-crystallin-immunopositive
X fibres were much more frequent in IBM than in other disorders. Thus, PrPC
seems to have rather a more general responder effect to various stress actions
irrespective of the type of neuromuscular disease, in contrast to the pathogenetic
stressor action of alpha- B-crystallin mostly limited to IBM.
Overexpression of wild-type hamster or sheep PrPC
transgenes in transgenic mice produces a myopathy characterized by degenerating
muscle fibres with some phagocytosis, variation in fibre size, and central nuclei
[29]. It cannot be excluded that this may play a part in degeneration of muscle
fibres in certain neuromuscular disease states with uncontrolled upregulation
of PrPC expression. Whether PrPC is helpful or harmful in these circumstances
has not yet been characterized. However, our observations suggest that PrPC
may play a general stress response effect in various neuromuscular disorders.
PrPC is known to have a role in T-lymphocyte activation,
and macrophages also express PrP [30,31]. Here we show that, in inflammatory
muscle disease, PrPC is more abundant in lymphocytes than in
macrophages.
Knowledge of disease states with altered expression
of PrPC is important when a potentially increased chance for extraneural PrPC-PrPSc conversion is considered. It may well be that patients with prion disorders who suffer from any kind of additional muscle disease with inflammation,
neurogenic lesions, or widespread regeneration are more prone to accumulation
of pathological PrPd in muscle [3].
* Prion, as defined by MedlinePlus at http://medlineplus.gov/, is "a protein particle that lacks nucleic acid and has been implicated as the cause of various neurodegenerative diseases (as scrapie, Creutzfeldt-Jakob disease, and bovine spongiform encephalopathy)."
Two major histocompatibility complex haplotypes influence susceptibility to
sporadic inclusion body myositis: critical evaluation of an association with
HLA-DR3.
Authors: P. Price; L. Santoso; F. Mastaglia; M. Garlepp; C.C. Kok; R.
Allcock; N. Laing
Tissue Antigens, November 2004, vol. 64, no. 5, pp. 575-580(6)
Abstract: Previous studies of sporadic inclusion body myositis (sIBM) have shown
a strong association with HLA-DR3 and other components of the 8.1 ancestral
haplotype (AH) (HLA-A1, B8, DR3), where the susceptibility locus has been mapped
to the central major histocompatibility complex (MHC) region between HLA-DR
and C4. Here, the association with HLA-DR3 and other genes in the central MHC
and class II region was further investigated in a group of 42 sIBM patients
and in an ethnically similar control group (n = 214), using single-nucleotide
polymorphisms and microsatellite screening. HLA-DR3 (marking DRB1*0301 in Caucasians)
was associated with sIBM (Fisher's test). However, among HLA-DR3-positive patients
and controls, carriage of HLA-DR3 without microsatellite and single-nucleotide
polymorphism alleles of the 8.1AH (HLA-A1, B8, DRB3*0101, DRB1*0301, DQB1*0201)
was marginally less common in patients. Patients showed no increase in carriage
of the 18.2AH (HLA-A30, B18, DRB3*0202, DRB1*0301, DQB1*0201) or HLA-DR3 without
the central MHC of the 8.1AH, further arguing against HLA-DRB1 as the direct
cause of susceptibility. Genes between HLA-DRB1 and HOX12 require further investigation.
BTL-II lies in this region and is expressed in muscle. Carriage of allele 2
(exon 6) was more common in patients. BTL-II(E6)*2 is characteristic of the
35.2AH (HLA-A3, B35, DRB1*01) in Caucasians and HLA-DR1, BTL-II(E6)*2, HOX12*2,
RAGE*2 was carried by several patients. The 8.1AH and 35.2AH may confer susceptibility
to sIBM independently or share a critical allele.
Discussion
This study established that sIBM could be promoted by alleles characteristic
of the 8.1AH or the 35.2AH. HLA-DR3 (8, 9) [or DRB1*03 (7)] has previously been
associated with sIBM. However, when HLA-DR3-positive controls and sIBM patients
were compared, carriage of HLA-DR3 without other components of the 8.1AH was
less common in patients, suggesting HLA-DR3 is not the direct cause
of disease. This is supported by the lack of any association between sIBM and
the 18.2AH (HLA-A30, B18, DRB1*0301) and represents a fundamental break with
the traditional interpretation of HLA-DR3 associations. Hence, it is worth reviewing
previous studies of the cohort and comparing the 8.1 and 18.2AH.
With a subset of the present cohort, Kok et al. (9) used novel markers of the
8.1AH in the HSP70 gene cluster to define a region of the 8.1AH between HLA-DR3
and C4A that was carried by all DR3-positive patients. The authors suggested
that the RAGE gene might mediate the genetic differences, as RAGE is a receptor
for the bA4 fragment of amyloid precursor protein present in the rimmed vacuoles
of skeletal muscle in sIBM and senile plaques of the brain in Alzheimer's disease
(16). However, the HLA-DR typing was serological and hence reflected the DRB1
gene. MHC class II genes telomeric of DRB1 were not considered. Here, carriage
of DR3 with no other markers of the 8.1AH was less common in patients, but the
effect was lost rapidly as we traversed the central MHC so the critical gene
is likely to be close to DRB1.
The 18.2AH and the 8.1AH share HLA-DRB1*0301, DQA1*0501, and DQB1*0201 but differ
in carriage of DRB3*0202 (18.2AH) rather than DRB3*0101 (8.1AH) and at all loci
telomeric of this gene. DRB3 alleles have been associated with susceptibility
to Graves' disease in African Americans (17) and Jamaicans (18). These studies
compared the class II alleles of the 8.1 and 18.2AH (although this terminology
was not used). Central MHC and other class II genes were not addressed and require
further consideration, as the haplotypes diverge immediately telomeric of DRB1.
This provides a precedent for consideration of DRB3 as a candidate gene. Other
candidates (in chromosomal order away from DRB3) are DRA, BTL-II (13), TSBP
(testis-specific basic protein), NOTCH4 (a transmembrane receptor which regulates
cell fate decisions) (19), and G18 (a predicted gene with no known function)
(20).
BTL-II lies between TSBP and DRA and is expressed in skeletal muscle. Carriage
of allele 2 of exon 6 was more common in the patients. As BTL-II(E6)*2 is characteristic
of the 35.2AH (HLA-A3, B35, DR1) in Caucasians, carriage of other haplotypic
markers was investigated. A region of the 35.2AH defined by HLA-DR1, BTLI( E6)*2,
HOX12*T, RAGE*T was more common among patients than controls. As several patients
carried these alleles without any component of the 8.1AH, the two haplotypes
may confer susceptibility to sIBM independently or may share a critical allele.
Studies of further sIBM patients, including the rare cases from other ethnic
groups, may help identify MHC genes responsible for susceptibility to sIBM.
Myositis: an update on pathogenesis
Lisa Christopher-Stine and Paul H. Plotz
Curr Opin Rheumatol 16:700-706. [November 2004]
Excerpt from article (pages 703-705)
Inclusion body myositis
Autoimmunity
It is debated whether sIBM is primarily immunemediated; some experts, particularly
neurologists, prefer the name inclusion body myopathy. A recent case describing
the concomitant findings of anti-PM-SCl antibodies in a patient with IBM supports
a role for autoimmunity pathogenesis of IBM [37]. In addition, IBM has been described
in concert with autoimmune rheumatic diseases, albeit rarely. Most recently, the
combination of SLE, Sjogren syndrome, and IBM was reported for the first time
[38]. The patient had SLE for over a decade when she presented with muscle weakness.
Electron microscopy demonstrated intranuclear and intracytoplasmic tubulofilamentous
inclusions; the patient improved with high-dose methotrexate therapy.
Muntzing et al. [39] demonstrated the presence of clonal restriction of TCR expression
in muscle-infiltrating lymphocytes in IBM. Identical T-cell clones predominate
in different muscles and exist for many years, suggesting an antigen-driven inflammatory
reaction in IBM.
Protein folding and trafficking
The "unfolded protein response" (UPR) is a functional mechanism whereby
cells protect themselves from endoplasmic reticulum (ER) stress by assuring proper
folding and preventing buildup of unfolded proteins in the ER. This is accomplished
with the help of molecular chaperones such as calnexin, calreticulin, GRP94, BiP/GRP78,
and ERp72. Expression and immunolocalization of these proteins was studied in
patients with sIBM and controls, and in amyloid-ß-precursor protein (AßPP)
overexpressing cultured human muscle fibers [40]. All five ER chaperones physically
associated with AßPP in sIBM muscle, implying that they may play a role
in AßPP folding and processing.
The lysosomal system of muscle fibers may also play a critical role in rimmed
vacuole formation [41]. Work by Kumamoto et al. [42] showed that the transport
of newly synthesized lysosomal enzymes via the Golgi apparatus and autophagic
vacuole formation in the lysosome system is activated in sIBM. This was demonstrated
by the observation of clathrin and M6PR, which facilitate receptor- mediated intracellular
transport inside rimmed vacuoles and in the sarcoplasm of vacuolated or nonvacuolated
fibers, but not in control specimens. PrPSc, a hallmark of prion diseases such
as spongiform encephalopathies, was demonstrated to be a prominent constituent
in sporadic IBM muscle tissue of a patient with concomitant Creutzfeldt-Jakob
Disease (CJD)[43]. The existence of muscle disease in subtypes of CJDmay deserve
further systematic investigation, as distinct glycotyopes of PrSc may be present
in muscle and brain. The muscle glycotype in this case report resembled that found
in vCJD brain.
Although it is attractive to connect vacuolar trafficking abnormalities of glycoproteins
to IBM because of the known genetic lesion in one type of hereditary IBM (see
below), for the moment, it seems safest to consider these observations as evidence
of yet another group of proteins being trapped in IBM inclusions.
UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) mutation
The genetic absence of GNE activity leads to muscle weakness in hereditary inclusion
body myositis (HIBM), perhaps by interfering with the trafficking of glycoproteins.
Huizing et al. [44] examined the glycosylation status of [alpha]-dystroglycan
(a central protein of skeletal muscle dystrophin) in muscle biopsies of four HIBM
patients and found absent or markedly reduced [alpha]-dystroglycans using antibodies
specific for ß-dystoglycan and laminin [alpha]-2. They suggest that HIBM
may therefore be a "dystroglycanopathy," similar to the process in congenital
muscular dystrophies-perhaps providing one mechanism for the muscle weakness of
HIBM patients.
In an important series of observations, inflammation has now been clearly recognized
in hereditary IBM. Yabe et al. [45] reported two cases of distal myopathy with
rimmed vacuoles (DMRV) in a Japanese family in which inflammation (an unusual
feature of DMRV) was present as well as a compound heterozygous mutation in their
GNE gene. Mutations associated with DMRV in this study were localized to the kinase
domain. An additional novel homozygous mutation was discovered in a nonJewish
Iranian population with quadriceps-sparing myopathy consistent with adult onset
hIBM: G-to-A mutation in exon 7 changing valine to isoleucine in the epimerase
domain of GNE [46]. Muscle inflammation was present in this case as well.
These important observations blur the boundary between purely hereditary and sporadic
IBM, in particular by raising the possibility that the inflammation seen in apparently
sporadic IBM might be a downstream secondary event following damage induced by
as-yet unrecognized genetic mutations.
The Middle East cluster of hIBM is the result of a founder mutation with incomplete
penetrance and is not limited only to the Jewish population. One hundred twenty-nine
patients in 55 families with a known history of hIBM were homozygous for the M712T
mutation, initially described as the "Persian Jewish Mutation" [47].
Argov et al. [47] have found that the phenotypic spectrum is wider than initially
thought. In a study by Del Bo et al., genetic analysis of the GNE gene in an Italian
family with autosomal recessive h-IBM demonstrated two novel mutations: a heterozygous
deletion involving exons 1-9 and the missense R162C mutation [48]. The quadriceps
weakness was apparently distinct from that found in the quadriceps sparing nonPersian
Jewish families with a different GNE mutation.
Hereditary IBM with early-onset Paget disease of bone and frontotemporal dementia
(IBMPFD) is a rare form of hereditary myopathy. Its clinical attributes distinguish
it from the other forms of hIBM linked to chromosome 9. Watts et al. [49] found
no relation of GNE mutations with IBMPFD, confirming genetic heterogeneity with
IBM2.
Other genetic evidence
The muscle morphology in X-EDMD is not pathognomonic; rather, there are nonspecific
myopathic changes including endomysial connective tissue proliferation, fiber
splitting, type II fiber predominance, and type I fiber atrophy. A recent paper
reported the co-existence of x-linked Emery-Dreifuss muscular dystrophy (EDMD)
and IBM [50]. Thus typical IBM morphologic features may be found in other neuromuscular
disorders.
Conclusion
Although the pathogenesis of the inflammatory myopathies remains obscure, great
strides over the past year have placed us closer to understanding the etiologies
of these diverse disease entities. We have deepened our understanding that although
these diseases may share some components of the clinical phenotype as well as
some serologic similarities, they differ on a molecular and cellular level. The
inflammatory myopathies result from a combination of interactions between environmental
and genetic risk factors, and the need for definitive, safer therapeutic options
in inflammatory myopathies makes the search for defining detailed pathogenesis
of inflammation and muscle fiber damage at the molecular level essential.
Have recent immunogenetic investigations increased our understanding of disease
mechanisms in the idiopathic inflammatory myopathies?
Hector Chinoy, William E.R. Ollier and Robert G. Cooper
Current Opinion in Rheumatology 2004, 16:707-713 [Nov 2004]
Rheumatic Diseases Centre, Hope Hospital, Salford M6 8HD, UK.
PURPOSE OF REVIEW: The idiopathic inflammatory myopathies (IIM) continue to
provide a challenge given the variable effectiveness of the available treatments,
and immunogenetic studies are ongoing to further elucidate IIM disease mechanisms.
This review examines how recent research has improved our understanding of the
mechanisms that lead to IIM.
RECENT FINDINGS: HLA-DRB1 studies in a large homogenous cohort of UK Caucasian
patients have confirmed that polymyositis (PM) and dermatomyositis (DM) are
not genetically identical diseases while other studies have shown that tumor
necrosis factor alpha is genetically implicated in disease susceptibility. Some
remarkable results from an international collaboration, correlating gene-environment
interactions, clearly suggest that ultraviolet light is capable of modulating
both clinical and immunologic features of IIMs. Studies on microchimerism are
unraveling interesting associations in juvenile DM patients, and bolstering
the hypothesis that myositis may be an 'allo-immune' disease. mRNA gene expression
profiling is helping to increase our understanding of myositis pathogenesis,
whilst animal models have provided new information on the roles of Th1 responses
and nitric oxide synthase in muscle disease. New candidate genes have been examined
in inclusion body myositis (IBM), and a novel gene transfer experiment has been
conducted, which led to significant changes in expression of the IBM phenotype.
SUMMARY: Improving the understanding of the immunogenetics and immunopathogenesis
of the IIMs may in the future provide novel therapeutic targets, and thus improve
outcomes in these difficult diseases.
Excerpt from article (710-711)
Inclusion body myositis
As IBM usually presents with distal, rather than proximal, muscle weakness,
and thus mimicking peripheral neuropathy, it is rarely seen by rheumatologists.
However, due to presence of inflammation in muscle biopsies, sporadic IBM is
considered one of the IIMs and is therefore included in this update. Several
HLA and non-HLA loci are already known risk factors for sporadic IBM [3]. HLA
class I and II associations have recently been examined in 47 sporadic IBM patients
and 29,670 controls [38]. HLA-A*03 (OR 2.6, 95% CI 1.6-4.1), B*08 (OR 2.8, 95%
CI 1.6-4.6), DRB1*03 (OR 3.5, 95% CI 2.1-5.6), and DQB1*05 (2.0, 95% CI 1.2-3.3)
alleles were all significantly increased compared with controls, even after
adjustment for multiple comparisons. The ethnicity of the cases in this study
was not stated and these results should thus be interpreted with caution. There
are currently no clinical or biochemical parameters that predict the outcome
of IBM or response to treatment, and HLA typing may help subgroup IBM patients
and predict such parameters.
Sporadic IBM muscle biopsies possess structural abnormalities similar to those
in brain tissue plaques from Alzheimer's disease patients, including amyloid-
precursor protein (AßPP), amyloid- ß(Aß), and apolipoprotein
E (apoE) [39]. Using an adenovirus vector, A gene transfer into normal cultured
human muscle fibers induced phenotypic abnormalities similar to those found
in IBM, suggesting the likelihood of a key role of AßPP/A in IBM pathogenesis
[40]. The same gene was transferred into muscle fibers from a patient with known
sporadic IBM and associated cardiac amyloidosis in whom a Val122Ile transthyretin
(TTR) mutation was also expressed [41]. The resulting overexpression of the
A gene amplified the abnormalities found in this patient's cultured muscle fibers,
including accelerated degeneration, inclusions, and vacuole formation, which
were over and above those seen in the normal muscle. The TTR mutation could
either be a genetic risk factor, or perpetuate the existing IBM. Polymorphisms
of two further intracellular amyloid deposits, ApoE and [alpha](1)-antichymotrypsin,
have been tested in the peripheral blood of 35 sporadic IBM patients [42], but
no significant associations or correlations with age of onset were found. An
important gene expression profiling study has also found increased expression
of amyloid-ß and ApoE in IBM, but significantly elevated levels of the
same genes were also demonstrated in PM and DM, suggesting that accumulation
of such proteins in IBM may be due to posttranscriptional events [43].
T cell receptors
Immunohistochemistry studies of biopsies from patients with PM have demonstrated
a predominance of CD8+ T lymphocytes invading non-necrotic muscle fibers that
express HLA class I on their cell surface [44]. Previous studies have demonstrated
clonally expanded T cell receptor (TCR) families in muscle fibers of patients
with PM. To characterize the role of these T cells further, a process of CDR3
spectratyping was combined with laser microdissection and single-cell polymerase
chain reaction (PCR), to select individual pathogenically relevant T cells from
PM muscle biopsies [45]. After examining repeat biopsies in one patient, it
was shown that T cell clones could persist for many years. In another patient,
several T cells had minor nucleotide changes in the CDR3 region of the T cell
receptor, which did not alter the amino acid sequences, thus suggesting the
presence of different T cell clones driving a common antigendriven response.
Oligoclonal CDR3 spectratype peaks disappeared during immunosuppressive treatment.
Recent TCR expression work has also been performed in IBM, again suggesting
only a limited number of antigens drive the inflammatory reaction [46]. These
pathogenically relevant T cells may represent future epitopes for targeted immunotherapy.
Animal models
Myositis is thought to be predominantly Th1 driven, initiated by an (unknown)
antigen and MHC interaction, leading to T cell expansion, maturation, and subsequent
cytokine proliferation (eg, IFN-[gamma] , IL-1, IL-18). Theoretically, dampening
down of the Th1 cell response, and switching to a Th2-driven system, producing
alternative cytokines (eg, IL-4, IL-6, IL-10), could dampen down the pathogenicity
of autoreactive T cells [47]. A strain of nonobese diabetic (NOD) mice has been
developed, rendered Th1-deficient by a CD2 promoter driven IFN-[gamma] receptor
ß-chain transgene [47]. An unexpected consequence was the development
of an early lethal myopathy due to a CD8+ T cell-dependent myositis syndrome,
characterized by a massive leukocyte inflammatory response in the muscle fibers.
By interacting with other genetic components in the NODmodel, the inhibition
of Th1 responses may conversely have exacerbated certain autoimmune responses.
Another way of influencing the inflammatory response in muscle is through nitric
oxide (NO), which can be pro- or anti-inflammatory depending on its concentration
and locality. A further transgenic mouse model has been developed with muscle-specific
overexpression of neuronal nitric oxide synthase (nNOS), driven by a human skeletal
muscle actin promoter [48]. Using a rodent hindlimb unloading/reloading model,
overexpression of nNOS inhibited neutrophil production, and prevented any increases
in muscle membrane damage. Muscle-derived NO evidently functions as an anti-inflammatory
molecule, and may provide a future potential therapeutic target.
New and future approaches
The work done by Okada et al. [16] and ourselves demonstrates the advantages,
and indeed necessity, of undertaking national/international genetic collaborations.
The results of these larger studies illustrate the importance during genetic
testing of treating IIM subtypes as discrete, rather than grouped, diagnoses.
Due to the rarity of IIMs, only further collaboration is likely to elucidate
the complex interactions between genetic and environmental factors. Recently
doubt has been cast on the diagnostic category PM, as some patients have been
shown to have IBM or muscular dystrophy [49]. mRNA microarray gene expression
profiling studies may assist in a more robust molecular reclassification of
the IIMs [43], whilst also providing novel molecular insights into the role
of genes in IIM subtypes (reviewed in [50]). It is relatively easy to obtain
muscle biopsies, allowing ready analysis of target tissue in IIM patients. Measurements
of mRNA levels allow the demonstration of which genes are upregulated or downregulated
(albeit without establishing cause and effect), and clarification of which genes
to analyze in further candidate gene studies. A recent landmark study examined
the molecular profiles of patients with IIMs, showing distinct changes from
normal muscle and differing between the IIMs [43]. An important distinguishing
feature of DM, compared with PM and IBM, was the increased expression of interferoninducible
genes, and this finding was reproduced in a JDM study [20], raising the hypothesis
that DM has an antigen-driven pathogenesis, and again supporting the idea that
PM and DM are genetically different. In the future, improved techniques and
reduced costs may allow the use of powerful high-density SNP arrays to conduct
whole genome scans by association [50-52].
Research continues worldwide into our understanding of the underlying pathogenesis
of the IIMs. A basic science approach led to the elucidation of the key role of
TNF alpha in RA, and the subsequent use of anti-TNFalphatherapy. By analogy, ongoing
collaborative genetic work may help identify key hierarchical molecules implicated
in IIM pathology.
Transglutaminase catalyzes differential crosslinking of small heat shock proteins
and amyloid-beta.
Boros S, Kamps B, Wunderink L, de Bruijn W, de Jong WW, Boelens WC. Department
of Biochemistry 161, Nijmegen Center for Molecular Life Sciences, University of
Nijmegen, P.O. Box 9101, 6500HB Nijmegen, The Netherlands.
FEBS Lett. 2004 Oct 8;576(1-2):57-62.
Crosslinking of proteins by tissue transglutaminase (tTG) is enhanced in amyloid
(Abeta) deposits characteristic of Alzheimer's disease and sporadic inclusion
body myositis. Small heat shock proteins (sHsps) also occur in amyloid deposits.
We here report the substrate characteristics for tTG of six sHsps. Hsp27, Hsp20
and HspB8 are both lysine- and glutamine-donors, alphaB-crystallin only is a lysine-donor,
HspB2 a glutamine-donor, and HspB3 no substrate at all. Close interaction of proteins
stimulates crosslinking efficiency as crosslinking between different sHsps only
takes place within the same heteromeric complex. We also observed that alphaB-crystallin,
Hsp27 and Hsp20 associate with Abeta in vitro, and can be readily crosslinked
by tTG.
Direct evidence for a chronic CD8+-T-cell-mediated immune reaction to tax within
the muscle of a human T-cell leukemia/lymphoma virus type 1-infected patient with
sporadic inclusion body myositis.
Ozden S, Cochet M, Mikol J, Teixeira A, Gessain A, Pique C. Unite d'Epidemiologie
et Physiopathologie des Virus Oncogenes, Paris, France.
J Virol. 2004 Oct;78(19):10320-7.
Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infection can lead to the
development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP),
concomitantly with or without other inflammatory disorders such as myositis. These
pathologies are considered immune-mediated diseases, and it is assumed that migration
within tissues of both HTLV-1-infected CD4(+) T cells and anti-HTLV-1 cytotoxic
T cells represents a pivotal event. However, although HTLV-1-infected T cells
were found in inflamed lesions, the antigenic specificity of coinfiltrated CD8(+)
T cells remains to be determined. In this study, we performed both ex vivo and
in situ analyses using muscle biopsies obtained from an HTLV-1-infected patient
with HAM/TSP and sporadic inclusion body myositis. We found that both HTLV-1-infected
CD4(+) T cells and CD8(+) T cells directed to the dominant Tax antigen can be
amplified from muscle cell cultures. Moreover, we were able to detect in two successive
muscle biopsies both tax mRNA-positive mononuclear cells and T cells recognized
by the Tax11-19/HLA-A*02 tetramer and positive for perforin. These findings provide
the first direct demonstration that anti-Tax cytotoxic T cells are chronically
recruited within inflamed tissues of an HTLV-1 infected patient, which validates
the cytotoxic immune reaction model for the pathogenesis of HTLV-1-associated
inflammatory disease.
Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion-body myositis muscle
fibers.
NEUROLOGY 2004;63:1114-1117
Fratta P, Engel WK, Van Leeuwen FW, Hol EM, Vattemi G, 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.
Abstract - Mutant ubiquitin (UBB+1), a product of "molecular misreading," is toxic
to cells because its ubiquitinated form inhibits the proteasome, contributing
to accumulation of misfolded proteins and their ensuing toxicity. The authors
demonstrate in 10 sporadic inclusion body myositis (s-IBM) muscle biopsies that
UBB+1 is accumulated in aggregates containing amyloid-beta and phosphorylated-tau.
In s-IBM, UBB+1 may be pathogenic by inhibiting proteasome, thereby promoting
accumulation of cytotoxic misfolded amyloid-beta and phosphorylated-tau.
Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis
and inclusion body myositis.
Dalakas MC.
Current Opinion in Neurology. 2004 Oct;17(5):561-567.
Neuromuscular Diseases Section, National Institute of Neurological Disorders
and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
PURPOSE OF REVIEW: To provide an update on the major advances in inflammatory
myopathies.
RECENT FINDINGS: Polymyositis is an uncommon disorder that can be misdiagnosed
when the old, and never validated, criteria of Bohan and Peter are used. New
diagnostic criteria were recently introduced, in which the MHC/CD8 complex is
considered a specific immunopathological marker because it distinguishes the
antigen-driven inflammatory cells that characterize polymyositis and sporadic
inclusion-body myositis from the non-specific, secondary inflammation seen in
other disorders, such as dystrophies. In sporadic inclusion-body myositis the
inflammatory cells invade non-vacuolated fibers, whereas the vacuolated fibers
are not invaded by T cells, implying two independent processes, a primary immune
process with antigen-driven T cells identical to polymyositis, and a degenerative
process in which beta-amyloid and amyloid-related proteins participate in vacuolar
degeneration. In polymyositis and sporadic inclusion-body myositis, antigen-specific
and clonally expanded autoinvasive T cells persist for years, even in different
muscles, as reconfirmed by proof-of-principle techniques involving CDR3 spectratyping
combined with laser microdissected single-cell polymerase chain reaction of
the T-cell receptor genes. The formation of immunological synapse between autoinvasive
T cells and muscle fibers was recently strengthened by the upregulation of co-stimulatory
molecules ICOS/ICOS-L and PD-L1. A new, distinct myopathy characterized by T-cell-triggered
macrophage hyperactivation has now been recognized in patients with dermatomyositis-like
disease.
SUMMARY: Despite recent progress, the antigen(s) responsible for T-cell activation
in polymyositis and sporadic inclusion-body myositis and the cause of vacuolar
degeneration in sporadic inclusion-body myositis remain unclear. Newer, more aggressive
immunotherapies may be encouraging, but control trials are needed to prove efficacy.
Journey into muscular dystrophies caused by abnormal glycosylation.
Muntoni F. Dubowitz Neuromuscular Centre, Department of Paediatrics, Imperial
College of Medicine, Hammersmith Hospital, London, UK. f.muntoni@imperial.ac.uk
Acta Myol. 2004 Sep;23(2):79-84.
An increasing number of genes encoding for putative or demonstrated glycosyltransferases
are being associated with muscular dystrophies of variable severity, ranging from
severe congenital onset and associated structural eye and brain changes, to relatively
mild forms with onset into adulthood. Five of these genes (POMT1; POMGnT1; FXRP;
Fukutin; LARGE) encode for proteins involved in the glycosylation of alpha-dystroglycan
and, indeed, abnormal glycosylation of this molecule is a common finding in all
the respective conditions (Walker Warburg syndrome; Muscle-Eye-Brain disease;
congenital muscular dystrophy type 1C and Limb girdle muscular dystrophy type
21; Fukuyama muscular dystrophy; congenital muscular dystrophy type 1D). A 6th
gene, GNE, responsible for the hereditary form of inclusion body myositis, encodes
for a glycosyltransferase the substrate(s) of which is, however, still unclear.
This article provides an overview of the clinical, biochemical and genetic features
of this group of disorders.
Randomized pilot trial of high-dose betaINF-1a in patients with inclusion body
myositis.
Muscle Study Group. Neuromuscular Disease Center, 601 Elmwood Avenue, Box
673, Rochester, NY 14642-8673. Rabi_Tawil@URMC.Rochester.edu
Neurology. 2004 Aug 24;63(4):718-20.
Beta-interferon-1a (betaINF-1a) is well tolerated at low dose (30 microg IM/week)
in inclusion body myositis (IBM). The authors investigated the safety and tolerability
of high-dose (60 microg IM/week) betaINF-1a in a randomized, placebo-controlled
trial in IBM. Twenty-seven of the 30 subjects enrolled completed the study. The
adverse event profile was similar for the placebo and betaINF-1a groups. betaINF-1a,
at a dose of 60 microg IM/week, is well tolerated in IBM, but no differences in
muscle strength or mass were observed between the placebo and betaINF-1a groups
at 6 months in this pilot study.
Interferon beta-responsive inclusion body myositis in a hepatitis C virus carrier.
Yakushiji Y, Satoh J, Yukitake M, Yamaguchi K, Nakamura I, Nishino I, Kuroda
Y.
The Division of Neurology, Department of Internal Medicine, Saga University School of Medicine, Saga, Japan. yakushij@hsp.ncvc.go.jp
Neurology. 2004 Aug 10;63(3):587-8.
Case Report
Sporadic inclusion body myositis: morphology, regeneration, and cytoskeletal structure
of muscle fibres.
Arnardottir S, Borg K, Ansved T. Department of Clinical Neuroscience, Division
of Neurology, Karolinska Hospital, Stockholm, Sweden. snjolaug.arnardottir@ks.se
J Neurol Neurosurg Psychiatry. 2004 Jun;75(6):917-20.
OBJECTIVE: To characterise morphological abnormalities in relation to muscle fibre
type in sporadic inclusion body myositis (s-IBM). METHODS: 14 muscle biopsies
from 11 patients with s-IBM were characterised for morphological abnormalities
and fibre type composition as well as muscle fibre regeneration and cytoskeletal
structure, using histochemical and immunohistochemical techniques. RESULTS: Morphological
abnormalities included inflammatory infiltrates and "rimmed vacuoles,"
and pronounced variation in fibre size. There were no significant differences
in fibre type composition between s-IBM patients and controls based on the myofibrillar
ATPase staining. A differential effect on muscle fibre sizes was noted, type II
fibres being smaller in the s-IBM patients than in the controls. Conversely, the
mean type I muscle fibre diameter in the s-IBM patients was larger than in the
controls, though this difference was not significant. An ongoing intense regeneration
process was present in s-IBM muscle, as indicated by the expression of neonatal
myosin heavy chain, vimentin, and CD56 (Leu-19) in most of the muscle fibres.
The cytoskeletal proteins dystrophin and desmin were normally expressed in s-IBM
muscle fibres that were not undergoing degeneration or regeneration. CONCLUSIONS:
There are extensive morphological and morphometric alterations in s-IBM, affecting
different muscle fibre types in different ways. The cytoskeletal structure of
type I and II muscle fibres remains unaffected in different stages of the disease.
Insulin-like growth factor I in inclusion-body myositis and human muscle cultures.
Broccolini A, Ricci E, Pescatori M, Papacci M, Gliubizzi C, D'Amico A,
Servidei S, Tonali P, Mirabella M. Department of Neuroscience, Catholic University,
Rome, Italy. a.broccolini@rm.unicatt.it
J Neuropathol Exp Neurol. 2004 Jun;63(6):650-9.
Possible pathogenic mechanisms of sporadic inclusion-body myositis (sIBM) include
abnormal production and accumulation of amyloid beta (A beta), muscle aging, and
increased oxidative stress. Insulin-like growth factor I (IGF-I), an endocrine
and autocrine/paracrine trophic factor, provides resistance against A beta toxicity
and oxidative stress in vitro and promotes cell survival. In this study we analyzed
the IGF-I signaling pathway in sIBM muscle and found that 16.2% +/- 2.5% of nonregenerating
fibers showed increased expression of IGF-I, phosphatidylinositide 3'OH-kinase,
and Akt. In the majority of sIBM abnormal muscle fibers, increased IGF-I mRNA
and protein correlated with the presence of A beta cytoplasmic inclusions. To
investigate a possible relationship between A beta toxicity and IGF-I upregulation,
normal primary muscle cultures were stimulated for 24 hours with the A beta(25-35)
peptide corresponding to the biologically active domain of A beta. This induced
an increase of IGF-I mRNA and protein in myotubes at 6 hours, followed by a gradual
reduction thereafter. The level of phosphorylated Akt showed similar changes.
We suggest that in sIBM. IGF-I overexpression represents a reactive response to
A beta toxicity, possibly providing trophic support to vulnerable fibers. Understanding
the signaling pathways activated by IGF-I in sIBM may lead to novel therapeutic
strategies for the disease.
Apolipoprotein E and alpha-1-antichymotrypsin polymorphisms in sporadic inclusion
body myositis.
Gossrau G, Gestrich B, Koch R, Wunderlich C, Schroder JM, Schroeder S,
Reichmann H, Lampe JB.
Department of Neurology, Medical Clinic II, Technical University Dresden, Dresden,
Germany. ggossrau@uni-bonn.de
Eur Neurol. 2004;51(4):215-20. Epub 2004 May 17.
Sporadic inclusion body myositis (s-IBM) is a progressive muscle disease of unknown
aetiology. Characteristically, intracellular amyloid deposits are detectable,
including beta-amyloid precursor protein, phosphorylated tau, alpha1-antichymotrypsin
(alpha1-ACT) and apolipoprotein E (ApoE). Polymorphisms and mutations of the encoding
genes have been identified in a variety of neurodegenerative diseases including
Alzheimer's disease (AD). Beside other factors, polymorphisms may lead to protein
accumulation in both diseases. In particular, polymorphisms within the ApoE and
alpha1-ACT gene have been implicated in the aetiology of AD and s-IBM. We analysed
ApoE and alpha1-ACT gene polymorphisms in 35 s-IBM patients. We could not identify
any statistical significant correlation between distinct ApoE and alpha1-ACT genotypes
and the risk of developing s-IBM. Additionally, ApoE and alpha1-ACT genotypes
seem not to influence the onset age of s-IBM. A combination of different alpha1-ACT
and ApoE genotypes appears not to enhance the risk of developing s-IBM. Therefore,
allelic variations of alpha1-ACT and ApoE are unlikely to be genetic key factors
in the aetiology of s-IBM.
Proteasomal expression, induction of immunoproteasome subunits, and local MHC
class I presentation in myofibrillar myopathy and inclusion body myositis.
Ferrer I, Martin B, Castano JG, Lucas JJ, Moreno D, Olive M. Instituto
de Neuropatologia, Servicio de Anatomia Patologica, Hospital Universitario de
Bellvitge, Hospitalet de Llobregat, Spain. 8082ifa@comb.es
J Neuropathol Exp Neurol. 2004 May;63(5):484-98.
Inclusion body myositis (IBM) and myofibrillar myopathy (MM) are diseases characterized
by the abnormal accumulation of proteins in muscle fibers, including desmin, alphaB-crystallin,
gelsolin, actin, kinases, and phospho-tau, along with ubiquitin in muscle fibers,
suggesting abnormal protein degradation as a possible cause of the surplus myopathy.
Since the ubiquitin-proteasome system plays a crucial role in non-lysosomal protein
degradation, the present study has examined by immunohistochemistry the expression
of components of the catalytic core of 20S proteasomes and its regulators: 19S
and PA28alpha/beta, and the expression of immunoproteasome subunits LMP2, LMP7,
and MECL1 in 8 patients with MM and 10 patients with IBM. The patients with MM
were from 6 unrelated families, 2 sporadic cases, I with autosomal recessive and
5 with autosomal dominant inheritance. One sporadic patient had a de novo R406W
mutation in the desmin gene, and 1 patient with autosomal dominant MM had a single
amino acid deletion at position 366 in the desmin gene. Increased immunoreactivity
to 20S, 19S, and PA28alpha/beta colocalizing abnormal protein deposits, as revealed
in consecutive serial sections, was seen in all cases with MM and IBM. In all
cases, the subunits of the immunoproteasome LMP2, LMP7, and MECL1 colocalized
with proteasomal immunoreactivity and abnormal protein accumulation. Immunohistochemistry
revealed focal MHC class I immunoreactivity in the cytoplasmic membrane of muscle
fibers in IBM and in association with protein aggregates in IBM, and to a lesser
degree, in MM. The present findings provide a link between abnormal protein accumulation
and altered proteasomal expression in IBM and MM.
Intravenous Immunoglobulin in Autoimmune Neuromuscular Diseases
Dalakas, MC
JAMA. May 19, 2004; Volume 291, pages: 2367-2375.
From page 2373: Inclusion Body Myositis. Inclusion body myositis is the most common
acquired inflammatory myopathy in patients older than 50 years. Patients present
with distal and proximal muscle weakness, frequent falls, and dysphagia. Immunopathologically,
inclusion body myositis is identical to polymyositis, but histologically, it is
differentiated by the presence of vacuolated fibers and amyloid deposits. Inclusion
body myositis is notoriously resistant to treatment with immunosuppressive medications.
Therefore, the efficacy of IVIG was tested in 19 patients in a placebo-controlled
crossover trial similar to that of the dermatomyositis trial. Although muscle
strength scores improved more in IVIG randomized patients, the differences were
not statistically significant, except for regional differences, most notable in
the muscles used for swallowing. A second study showed similar results. A third
study, carried out to investigate the potential synergistic effect of IVIG and
prednisone, randomly assigned 36 patients to IVIG, 2 g/kg, or placebo once a month
for 3 months. All patients received prednisone concurrently (tapered from 60 mg/d).
After 3 months of treatment, there was no significant difference in muscle strength
between the IVIG-plus prednisone group and the placebo-plus prednisone group.
Despite these negative findings, some inclusion body myositis patients may derive
modest, transient benefit from IVIG therapy, sufficient to justify a 2- to 3-month
trial, especially in those with severe dysphagia, as recently noted.
Inclusion body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein
Authors: Giles D J Watts, Jill Wymer, Margaret J Kovach, Sarju G Mehta,
Steven Mumm, Daniel Darvish, Alan Pestronk, Michael P Whyte & Virginia E Kimonis
Nature Genetics 36, 377 - 381 (April 2004)
Abstract: Inclusion body myopathy associated with Paget disease of bone and frontotemporal
dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome
9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using
a candidate-gene approach. We found six missense mutations in the gene encoding
valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively
in all 61 affected individuals. Haplotype analysis indicated that descent from
two founders in two separate North American kindreds accounted for IBMPFD in about
50% of affected families. VCP is associated with a variety of cellular activities,
including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation
pathway. Identification of VCP as causing IBMPFD has important implications for
other inclusion-body diseases, including myopathies, dementias and Paget disease
of bone (PDB), as it may define a new common pathological ubiquitin-based pathway.
From page 377: Hereditary inclusion body myopathy (IBM) associated with PDB and
frontotemporal dementia (FTD), or IBMPFD, is a rare, complex and ultimately lethal
autosomal dominant disorder (OMIM 605382; ref. 1 [see link below]). IBMPFD features
adult-onset proximal and distal muscle weakness (clinically resembling limb girdle
muscular dystrophy), early-onset PDB in most cases and 'premature' FTD2. Although
the disorder was mapped to chromosome 9p21-p12, the genetic basis was not known.
From page 379: VCP is commonly present in aggregates from muscle with IBMPFD and
s-IBM, although the predominant pattern of localization for VCP differs between IBMPFD and s-IBM. . . .
VCP is essential in the cell cycle and apoptosis pathways, neither of which seems
to be disrupted in IBMPFD, as affected individuals are obviously viable. Clues
about the nature of the mutations we identified in VCP can be drawn from pathways
that have been implicated in other aggresome-associated degenerative disorders,
which all involve protein quality control and the ubiquitin protein degradation
pathways ref 21-24. A number of independent studies support the fact that disruption
of a specific function of VCP leads to inclusion body formation. First, experiments
identifying the involvement of VCP in endoplasmic reticulum-associated degradation
showed that dysfunction of VCP caused vacuole and inclusion body formation, ultimately
leading to cell death ref 18, 19, 25. Second, VCP interacts directly with polyubiquitinated
proteins ref 18-20. Third, VCP colocalizes with ubiquitin-containing nuclear inclusions
in the cerebral cortex in a number of neuronal degenerative disorders involving
protein quality control and the ubiquitin protein degradation pathways, such as
Huntington, Alzheimer, Creutzfeldt-Jakob and Parkinson disease (in particular
the Lewy bodies), as well as in motor neuron disease with dementia ref 26. Fourth,
mutations in the ubiquitin-binding domain of sequestosome 1 (SQSTMl, also called
p62; refs. 27,28) cause autosomal dominant PDB (PDB3). We propose that mutations
in VCP, as in SQSTMl, cause PDB by compromising ubiquitin-binding and target similar
cellular pathways or proteins. Furthermore, p62 colocalizes with inclusion bodies
in a number of degenerative disorders ref 22, 23. Thus, IBMPFD is probably a new
member of the family of aggresome-associated disorders, and mutations in VCP may
represent a new link in the pathway that leads to aggresome formation. Because
IBMPFD is a dominant progressive syndrome, the mutations we identified are probably
relatively subtle and aging, oxidative stress and endoplasmic reticulum stress
probably define a threshold at which the IBMPFD phenotype becomes manifest. Rather
than the mutations disrupting a normal function of VCP, they may add new, toxic
functions that result in new VCP actions. Alternatively, the mutations could be
dominant negative and disrupt normal hexamer formation of VCP.
Also see: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=167320
Inflammatory Myopathies.
Grogan PM, Katz JS.
Department of Neurology, Wilford Hall Medical Center, 2200 Bergquist Drive, Suite
1,San Antonio, TX 78236, USA.
Curr Treat Options Neurol. 2004 Mar;6(2):155-161.
Therapies that suppress or modify the immune system remain the primary treatment
for the idiopathic inflammatory myopathies. Dermatomyositis (DM) and polymyositis
(PM) are the two conditions that respond best to immunotherapy. Although there
are no randomized controlled trials, corticosteroids, specifically high-dose oral
prednisone, remain the cornerstone of management. Recent controlled clinical trials
show that intravenous immunoglobulin (IVIg) is an efficacious treatment in DM.
Expert clinicians are generally using this as a second-line agent or as an adjunct
to prednisone. IVIg has a relatively benign side effect profile compared with
chronic steroid use, but the cost of treatment, the need for repetitive treatment
cycles, and the potential for serious adverse effects have kept it from being
a first-line agent in DM. There have been no trials performed using IVIg in PM.
Chronic immunosuppressant medications, including azathioprine, cyclosporine, and
methotrexate, are also available for long-term management in patients with recalcitrant
disease or side effects from extended corticosteroid use. These agents lack the
troubling side effects of prednisone and are less costly than IVIg, but require
close medical monitoring for adverse reactions to blood, kidney, lung, or liver.
Newer medications with potentially more benign side effect profiles, such as mycophenolate
mofetil and etanercept, are currently being studied, but knowledge of how effective
they are and how quickly they work are not yet available. Inclusion body myositis
has proven resistant to immunosuppressive medications. The response has been so
consistently poor and so easily contrasted with DM that the authors wonder why
these conditions are so routinely lumped together in chapters and review articles.
Clearly, this is based solely on the common pathologic feature of inflammation,
rather than a clear understanding of how these conditions occur, or why they do
or do not respond to treatment.
"Coles Notes" condensation by Bill:
Summary
In the muscles of patients with sporadic inclusion body myositis (sIBM) some of the muscle fibres come to display an immune "flag" (antigen presentation), on their surface. This flag acts as a signal to the immune system. A chain of events is triggered that leads to the activation of a response from the immune system. Immune cells invade the muscle cell and kill it.
There are several steps in the chain of events between the immune system seeing the flag and the invasion. One step is that other molecules (co-stimulators) need to be present to help stimulate the immune cell invaders. Researchers are discovering these links in the chain and how they interact with each other. Part of the immune chain involved consists of interactions between the inducible co-stimulatory molecule (ICOS) and its "partner" (called a ligand), the ICOS-ligand (ICOS-L). These interactions are crucial for co-stimulation of the immune invader cells (T-cells) and for other critical steps in the immune response (effector cell differentiation and memory CD8+ T-cell activation).
This research strengthens the idea that sIBM is caused by some sort of problem in the immune system. It offers the chance that medications can be developed to target breaking a link in the chain of these immune interactions. It is possible that if a medication could break the interaction of ICOS and ICOS-L, the destruction of the muscle cells could be stopped.
Overexpression of semicarbazide-sensitive amine oxidase in human myopathies.
Olive M, Unzeta M, Moreno D, Ferrer I.
Institut de Neuropatologia, Hospital Universitari de Bellvitge, 08907 Hospitalet
de Llobregat, Barcelona, Spain. 25169mop@comb.es
Muscle Nerve. 2004 Feb;29(2):261-6.
Oxidative stress has been implicated in the pathogenesis of several muscle diseases. Semicarbazide-sensitive amine oxidase (SSAO) metabolizes oxidative deamination of primary aromatic and aliphatic amines. In the oxidative reactions, amine substrates are converted into the aldehyde, followed by the production of ammonia and H(2)O(2). Although normal levels in muscle are very low, SSAO is expressed in almost all mammalian tissues. In this study, we examined the possible implication of SSAO as an additional source of oxidative stress in the pathogenesis of muscle disorders.
The expression of SSAO was examined immunohistochemically in muscle biopsy specimens from patients with inclusion-body myositis (IBM; n = 5), desmin-related myopathy (DRM; n = 3), dermatomyositis (n = 3), granulomatous (sarcoid) myopathy (n = 2), muscle denervation-reinnervation (n = 3), and rhabdomyolysis (n = 2), as well as from control subjects (n = 3). Strong SSAO immunoreactivity was present in vacuolated and nonvacuolated fibers in IBM, in abnormal fibers in DRM, and in degenerating and regenerating fibers in dermatomyositis and rhabdomyolysis. In addition, SSAO overexpression was observed in muscle fibers adjacent to granulomas in sarcoid myopathy. These results suggest that SSAO is a source of oxidative stress in diseased human skeletal muscle and that it contributes to oxidative stress-induced damage in various inflammatory and other myopathies. Alternatively, the expression of SSAO in muscle fibers may be a consequence of muscle fiber injury.
BOOK REVIEW: Living with Myositis
J. Fenton (Ed.); Thoughtful Publications, 2003; ISBN
0-9545307-0-5 (£13.99)
Neuromuscular Disorders Volume14 (February, 2004) page. 179
"I've got IBM". "Really. I'm still using my old Apple-Mac"
or "Oh!. What operating system are you running?" Almost without exception
the people I meet have never heard of Inclusion Body Myositis (IBM). Not surprising
really, why should they have? Until I was diagnosed as having IBM and until I
had read this book I had never heard of it or of dermatomyositis (DM) or polymyositis
(PM). The first 140 or so pages are in part ego trip and in part an attempt to
put a positive spin on what are truly awful diseases. They may indeed help health-care
professionals (horrible collective term) to appreciate the torments myositis sufferers
can go through, but I would not recommend that the book be offered to early diagnosed
patients. They have enough to worry them with the diagnosis without reading what
they may have to go through during the next indeterminate number of years. However,
taking the book as a whole there is no doubt in my mind that all doctors will
benefit from reading it, especially those practitioners who have not yet had a
patient who has presented the symptoms of myositis. One message that seems to
come through, not always overtly, is that drugs are not the only treatment. Listening,
understanding, accepting that the patient knows his or her own body better than
anyone and tender loving care, go a long way in coping with the disease. Another
is that proof positive is necessary for the correct treatment to be started; don't
be embarrassed to make an early referral. My doctor did and my wife and I are
grateful for although, as yet, there is no treatment for IBM, knowing the prognosis
we are able to plan accordingly. Keep a copy of this book on your shelf ready
to lend out, but remember, to some it will be a horror story, to others a good
reference book, choose carefully.
After reading it I'm glad I only have IBM!
J. Hutson
3 York Road, Headington,
Oxford OX3 8NW, UK
Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis
muscle.
Vattemi G, Engel WK, McFerrin J, Askanas V.
Department of Neurology, University of Southern California Neuromuscular Center,
University of Southern California Keck School of Medicine, Good Samaritan Hospital,
Los Angeles, California 90017-1912, USA.
Am J Pathol. 2004 Jan;164(1):1-7.
Proteins in the endoplasmic reticulum (ER) require an efficient system of molecular
chaperones whose role is to assure their proper folding and to prevent accumulation
of unfolded proteins. The response of cells to accumulation of unfolded proteins
in the ER is termed "unfolded protein response" (UPR). UPR is a functional
mechanism by which cells attempt to protect themselves against ER stress, resulting
from the accumulation of the unfolded/misfolded proteins. Because intracellular
inclusions, containing either amyloid-beta (Abeta) or phosphorylated tau, are
the characteristic feature of sporadic inclusion body myositis (s-IBM) muscle
biopsies, we studied expression and immunolocalization of five ER chaperones,
calnexin, calreticulin, GRP94, BiP/GRP78, and ERp72, in s-IBM and control muscle
biopsies. Physical interaction of the ER chaperones with amyloid-beta precursor
protein (AbetaPP) was studied by a combined immunoprecipitation/immunoblotting
technique in s-IBM and control muscle biopsies, and in AbetaPP-overexpressing
cultured human muscle fibers. In all s-IBM muscle biopsies, all five of the ER
chaperones were immunodetected in the form of inclusions that co-localized with
amyloid-beta. By immunoblotting, expression of ER chaperones was greatly increased
as compared to the controls. By immunoprecipitation/immunoblotting experiments,
ER chaperones co-immunoprecipitated with AbetaPP. Our studies provide evidence
of the UPR in s-IBM muscle and demonstrate for the first time that the ER chaperones
calnexin, calreticulin, GRP94, BiP/GRP78, and ERp72 physically associate with
AbetaPP in s-IBM muscle, suggesting their playing a role in AbetaPP folding and
processing.
Creutzfeldt-Jakob disease and inclusion body myositis: abundant disease-associated
prion protein in muscle.
Kovacs GG, Lindeck-Pozza E, Chimelli L, Araujo AQ, Gabbai AA, Strobel T,
Glatzel M, Aguzzi A, Budka H.
Institute of Neurology, University of Vienna, and Austrian Reference Centre for
Human Prion Diseases, Vienna, Austria.
Ann Neurol. 2004 Jan;55(1):121-5.
Pathologicalprion protein (PrP(Sc)) is the hallmark of prion diseases affecting
primarily the central nervous system. Using immunohistochemistry, paraffin-embedded
tissue blot, and Western blot, we demonstrated abundant PrP(Sc) in the muscle
of a patient with sporadic Creutzfeldt-Jakob disease and inclusion body myositis.
Extraneural PrP(C)-PrP(Sc) conversion in Creutzfeldt-Jakob disease appears to
become prominent when PrP(C) is abundantly available as substrate, as in inclusion
body myositis muscle.
Comment: In ONE case study of a 68 year old man who had CJD AND IBM, the
abnormal form of prion protein was found OUTSIDE his neural tissues and was found
in the muscle. Pathological prion protein (PrPSc) is the hallmark of prion diseases
affecting primarily the central nervous system. Researchers demonstrated abundant
(abnormal prion) PrPSc in the muscle of a patient with sporadic Creutzfeldt-Jakob
disease and inclusion body myositis. Extraneural PrPC-PrPSc conversion in Creutzfeldt-Jakob
disease appears to become prominent when PrPC is abundantly available as substrate,
as in inclusion body myositis muscle.
The exact relationships between CJD and prion abnormalities in the muscle and
IBM are unknown at present. This line of research will be interesting to watch.
Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies.
van der Pas J, Hengstman GJ, ter Laak HJ, Borm GF, van Engelen BG. Neuromuscular
Centre, Institute of Neurology, University Medical Centre, Nijmegen, Netherlands.
J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):136-9.
BACKGROUND: Identification of mononuclear cellular infiltrates in skeletal muscle
tissue is the histological cornerstone of the diagnosis of idiopathic inflammatory
myopathy (IIM). However, these infiltrates are not always present.
OBJECTIVE: To determine whether MHC class I antigen expression on the sarcolemma,
which is absent in normal muscle tissue, is upregulated in IIM and could serve
as an additional diagnostic test.
METHODS: Expression of MHC class I antigens was studied in 224 muscle samples
of 61 adult patients with IIM (9 dermatomyositis, 23 polymyositis, 29 inclusion
body myositis) and 163 controls (normal subjects and patients with various neuromuscular
disorders) in a prospective blinded manner.
RESULTS: The sensitivity of the test for diagnosing IIM was 78% (95% confidence
interval (CI), 66% to 88%), with a specificity of 95% (91% to 98%). The sensitivity
before the start of immunosuppressive treatment was 89% (76% to 96%). The sensitivity
was not changed by including all patients who had been on immunosuppressive
treatment for less than four weeks before muscle biopsy (sensitivity 90% (79%
to 97%)). False positive results were found in only seven controls (4%), six
of whom had a muscular dystrophy.
CONCLUSIONS: Detection of sarcolemmal MHC class I is a valid test for IIM. It
is not affected by the short term use of immunosuppressive agents (less than four
weeks) and it should be incorporated in the histological evaluation when the diagnosis
of IIM is under consideration or needs to be excluded.