Research - what's new? 2003
A sample of MAJOR articles from the medical literature.
A novel homozygous missense mutation in the GNE gene of a patient with quadriceps-sparing
hereditary inclusion body myopathy associated with muscle inflammation.
Krause S, Schlotter-Weigel B, Walter MC, Najmabadi H, Wiendl H, Muller-Hocker
J, Muller-Felber W, Pongratz D, Lochmuller H.
Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University,
Neuromuscul Disord. 2003 Dec;13(10):830-4.
An adult-onset hereditary inclusion body myopathy with sparing of the quadriceps
muscle was originally described in Iranian Jews and assigned to a locus on chromosome
9p12-p13. Recently, mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine
kinase (GNE) gene were reported to cause hereditary inclusion body myopathy and
one type of distal myopathy in a world-wide distribution. Importantly, the lack
of muscle inflammation was used to distinguish hereditary inclusion body myopathy
from the sporadic form of inclusion body myopathy. We report a case of a quadriceps-sparing
myopathy in a non-Jewish, Iranian patient with a high degree of muscle inflammation.
A novel homozygous G-to-A mutation (128933G-->A) in exon 7 changing a valine
to isoleucine (V367I) in the epimerase domain of the GNE gene was found. We conclude
that muscle inflammation is not sufficient to exclude the diagnosis of hereditary
inclusion body myopathy.
Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies.
Figarella-Branger D, Civatte M, Bartoli C, Pellissier JF.
Laboratoire de Biopathologie Nerveuse et Musculaire (EA 3281), Faculte de Medecine
Timone, Universite de la Mediterranee, 27 Boulevard Jean Moulin, 13385 Marseille,
Muscle Nerve. 2003 Dec;28(6):659-82.
The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM), and
sporadic inclusion-body myositis (s-IBM). In DM, the main immune effector response
appears to be humoral and directed against the microvasculature, whereas in both
PM and s-IBM, cytotoxic CD8+ T cells and macrophages invade and eventually destroy
nonnecrotic muscle fibers expressing major histocompatibility complex class I.
The need for more specific and safer therapies in inflammatory myopathies has
prompted researchers to better decipher the molecular events associated with inflammation
and muscle fiber loss in these diseases. The complex specific migration of leukocyte
subsets to target tissues requires a coordinated series of events, namely activation
of leukocytes, adhesion to the vascular endothelium, and migration. Cell adhesion
molecules (CAM) and chemokines play a major role in this multistep process. In
addition, cytokines by stimulating CAM expression and orchestrating T-cell differentiation
also influence the immune response. This review focuses on recent advances in
defining the molecular events involved in leukocyte trafficking in inflammatory
myopathies. Specific topics include a concise summary of clinical features, pathological
findings and immunopathology observed in inflammatory myopathies, background information
about cytokines, chemokines and cell adhesion molecules, and the expression of
these molecules in inflammatory myopathies.
Proposed pathogenetic cascade of inclusion-body myositis: importance of amyloid-beta,
misfolded proteins, predisposing genes, and aging.
Askanas V, Engel WK.
Department of Neurology, University of Southern California, Keck School of Medicine,
Good Samaritan Hospital, Los Angeles, California 90017-1912, USA. email@example.com
Curr Opin Rheumatol. 2003 Nov;15(6):737-44.
PURPOSE OF REVIEW: Sporadic inclusion-body myositis, the most common muscle
disease of older persons, is of unknown cause, and there is no successful treatment.
Interest in sporadic inclusion-body myositis has been enhanced by the recent
identification within the sporadic inclusion-body myositis muscle fibers of
several abnormally accumulated proteins, which provides novel and important
clues to the pathogenesis of sporadic inclusion-body myositis. RECENT FINDINGS:
This article summarizes the most recent findings leading to better understanding
of the players in the pathogenetic cascade. It is suggested that lymphocytic
inflammatory component is probably secondary, and it may contribute only slightly
to muscle fiber damage in sporadic inclusion-body myositis. However, it is proposed
that the identified abnormal accumulation, aggregation, and misfolding of proteins,
combined with and perhaps provoked by an aging intracellular milieu, more essentially
lead to the vacuolar degeneration and atrophy of the muscle fibers that are
specific to sporadic inclusion-body myositis. Abnormal accumulations of the
amyloid-beta precursor protein and of its proteolytic fragment, amyloid-beta,
associated with the aging cellular muscle fiber environment, appear to be key
pathogenic events. SUMMARY: In conceptualizing a treatment for sporadic inclusion-body
myositis, the accumulations of amyloid-beta42 and other unfolded proteins are
now phenomena to be reckoned with. One would like to stop intracellular increase
of the unfolded/misfolded proteins by reducing their formation and/or increasing
their disposal. In addition, the identification of factors that would decrease
intra-muscle fiber expressions of beta- and gamma-secretases might lead to decreased
production of putatively myotoxic oligomeric amyloid-beta42. Better understanding
of the mechanisms and consequences of genes that predispose to sporadic inclusion-body
myositis, and of human muscle fiber aging, could also provide new avenues toward
the therapy of sporadic inclusion-body myositis. How to therapeutically capitalize
on the new findings is now the challenge.
High-dose intravenous immunoglobulin in inflammatory myopathies: experience based
on controlled clinical trials.
Neuromuscular Diseases, Section National Institute of Neurological Disorders and
Stroke National Institutes of Health, Bethesda, MD 20892-1382, USA.
Neurol Sci. 2003 Oct;24 Suppl 4:S256-9.
Controlled clinical trials with high-dose intravenous immunoglobulin (IVIg) have
been conducted in patients with DM and IBM, but not PM. A double-blind placebo-controlled
study in DM patients, resistant or partially responsive to conventional therapies,
showed that IVIg is very effective in improving both the muscle strength and the
skin rash. The clinical benefit, which was impressive in patients with early disease,
was associated with improvement in the muscle cytoarchitecture. Quantitative histological
studies in repeated muscle biopsies showed a statistically significant increased
in the size of muscle fibers and the number of capillaries with normalization
of the capillary diameter. Resolution of the aberrant immunopathological parameters
including interception of complement activation products and downregulation of
T cells, ICAM-I, VCAM, TGF-beta and MHC-I molecules was also noted. In IBM, IVIg
showed marginal, and non statistically significant, improvements in muscle strength.
Up to 20% of patients however, demonstrated clinical improvement with increased
activities of daily living while certain muscle groups, such as the muscles of
swallowing, showed significant improvements compared to placebo implying mild
regional benefits. In PM, small uncontrolled series have shown improvements in
muscle strength in up to 70% of the IVIg-treated patients. Because PM, as a stand-alone
clinical entity, is a very rare disease, completion of controlled trials will
be very difficult.
[sIBM has been associated with the DRB3*0101 haplotype - I provide this information
Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a
genetically determined defect of C4 influences immunological parameters of healthy
carriers of the haplotype
Giuseppina Candore, Maria Assunta Modica, Domenico Lio, Giuseppina Colonna-Romano,
Florinda Listì, Maria Paola Grimaldi a, Mariangela Russo, Giovanni Triolo,
Antonia Accardo-Palumbo, Maria Clara Cuccia, Calogero Caruso
Biomedicine & Pharmacotherapy 57 (2003) 274-277
Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases
than those without these alleles. The 8.1 ancestral haplotype (AH) is a common
Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique
in its association with a wide range of immunopathological diseases. To gain insight
into the identification of the mechanism(s) of disease susceptibility of 8.1 AH
carriers, we have investigated the prevalence of circulating immune complexes
and non-organ-specific autoantibodies in healthy carriers of the haplotype. The
results show that carriers of 8.1 AH display both a significant increased prevalence
of immune complexes and higher titers of anti-nuclear autoantibodies. This AH
carries a single segment characterized by no C4A gene. This null allele does not
code for a functional C4A protein that likely plays an anti-inflammatory role
being specialized in the opsonization and immunoclearance processes. So, this
genetic defect has been claimed to allow that an increased production of autoantibodies
directed vs. cells that have undergone apoptosis and are not efficiently disposed
because a reduced antigenic clearance. The results obtained in the present study
fit very well with this hypothesis. In the AH carriers the simultaneous high setting
of tumor necrosis factor (TNF)-alpha may supply the autoantigens
(providing an excess of apoptotic cells) that drive the autoimmune response. In
conclusion, the C4 defect associated to the increased spontaneous release of TNF-alpha,
modifying a certain number of immunological parameter may be the most characterizing
feature of the 8.1 AH. In the majority of individuals, an autoimmune response
clinically relevant will develop only in the presence of other immunological abnormalities.
The HLA region encompasses over 4 Mb of DNA on the short arm of chromosome 6 and
is traditionally divided into the class I, class II and class III regions. It
is known to contribute to a large number of immune-related disorders and genetic
studies have shown that individuals with certain HLA alleles have a higher risk
of specific autoimmune diseases than subjects without these alleles [4,16]. Particularly,
the association in all Caucasian populations of an impressive number of autoimmune
diseases with genes from the HLAB8, DR3 haplotype that is part of theAH 8.1 HLA-A1,
Cw7, B8, TNFAB*a2b3, NFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501,
DQB1*0201 has been reported by different research groups [2,4,15]. The clusters
of genes that, because of their close linkage on the same chromosome, are inherited
together, i.e. the haplotypes, are called ancestral when they define highly conserved
haplotypes that appear to be derived from a common remote ancestor. These conserved
stretches of genomic DNA account for at least 30% of HLA haplotypes in Caucasians
[2,4,6]. The 8.1 ancestral haplotype (AH), that is the most common haplotype in
Caucasians with its highest frequency in northern and western Europe, is also
associated in healthy subjects with a number of immune system dysfunctions. It
has been proposed that a small number of genes within the 8.1 AH modify immune
responsiveness and hence affect multiple immunopathological diseases [2,4,6,8,15].
The HLA class III region is now known to contain at least 62 genes. As putative
functions are ascribed to the products of these genes, it is becoming increasingly
apparent that many of these are involved in the immune and inflammatory responses
[12,20]. Research is investigating which genes carry polymorphisms that might
affect immunological pathways common to the pathogenesis of several diseases associated
with the 8.1 AH [2,8,13,15]. Complement genes have often been considered in this
context. Three components of the complement system, which is the principal effector
mechanism of humoral immunity and is important in the clearance of immune complexes,
opsonization and cell lysis, are encoded in the class III region. In particular,
C4 participates in the classical pathway, which may be activated by the binding
of C1 to antigen-antibody complexes . Most human chromosomes carry two
C4 genes, C4A and C4B, which form part of a duplicated segment of DNA spanning
~75 kb. However, the number of expressed C4 genes can range from none to four.
The C4A and C4B genes encode proteins that differ by only four amino acids, but
nevertheless have profoundly different covalent binding activities . Both
isotypes of C4 are highly polymorphic and the 8.1 AH carries a single segment
characterized by no C4A gene [2,15]. The null allele, carried by this AH, do not
code for a functional C4 protein. This genetic defect of complement function might
allow the prolonged persistence of immunizing antigens that can lead to an increased
production of autoantibodies directed vs. cells that have undergone apoptosis
and are not efficiently disposed because a reduced antigenic clearance [2,18,19].
To gain insight into the identification of the mechanism(s) of disease susceptibility
of 8.1 AH carriers, we have investigated the prevalence of circulating immune
complexes and nonorgan- specific autoantibodies in healthy carriers of the haplotype,
using as controls young subjects negative for this AH.
Complement has both inflammatory and antiinflammatory functions, the latter
reflected by its role in clearing immune complexes from the circulation and
removing them from tissues. When immune complexes cannot be eliminated, the
complement activation triggers inflammation. There is an apparent paradox since
patients with hereditary deficiencies of complement proteins of the classical
pathway are at increased risk for the prototypic autoantibody-mediated disease,
systemic lupus erythematosus. However this paradox is only apparent. In fact,
complement also binds to cells that have undergone apoptosis, helping to eliminate
them from tissues. In complement deficiency, these partially degraded cellular
components might accumulate and evoke an autoimmune response [2,18,19]. According
to this hypothesis, the stage at which complement may have a pathogenic role
in autoimmunity is the failure to clear autoantigens. The complement component
C4 is involved in the early stages of the complement cascade. The two isoforms
C4A and C4B show considerable polymorphism and the number of C4 genes present
on a haplotype can vary [12,18]. The 8.1 AH carries a single segment characterized
by a short C4B gene and no C4A gene [2,15, see also Table 1]. The C4A*Q0 allele,
carried by HLA 8.1 haplotype, does not code for a functional C4 protein. This
duplication of C4 gene allows the qualitative diversities for their proteins
[12,18]. The C4B protein likely plays a proinflammatory role by propagating
the complement activation pathways that leads to the generation of the membrane
attack complex and the generation of anaphylatoxins. On the other hand, the
C4A protein likely plays an anti-inflammatory role being specialized in the
opsonization and immunoclearance processes. In any case, the serum C4 levels
as assayed by routine nephelometry mostly depend on C4B gene [12,18]. Thus, functional consequences
of C4Q0 do not include a reduced level of the C4 protein (Table 2) but a prolonged
persistence of immunizing antigens, as documented by a reduced clearance of
circulating immune-complexes (Table 3), that can lead to an altered immune response
against self antigens as documented by increased levels of ANA
(Table 4) [2,8,15,18,19].
The pleiotropic proinflammatory cytokine TNF-alpha maps
to chromosome 6 within HLA. Several polymorphic areas are documented within the
TNF gene cluster. In particular, the TNF-alpha -308 polymorphism,
substituting G/A, influences TNF-alpha production in vitro.
The -308 A allele is preferentially carried by 8.1 AH, that is in fact characterized
by an high setting of TNF-alpha [8,10]. This constitutive
high production determines increased cortisol production and in turn both increase
of apoptotic processes and increased production of type 2 cytokine interleukin-10
that facilitates the production of certain immunoglobulin isotypes [2,8]. So,
in the AH carriers the simultaneous high setting of TNF-alpha
may supply the autoantigens (providing an excess of apoptotic cells) that drive
the autoimmune response. The uptake of autoantigen by immature dendritic cells
in the presence of inflammatory cytokines as TNF-alpha
causes these cells to mature into antigen-presenting cells, allowing the presentation of autoantigens to T cells. Finally, T cells will provide help to autoreactive B cells, which have taken up autoantigen by means of their immunoglobulin receptors. Such B cells mature into plasma cells that secrete autoantibodies [2,8,13].
In conclusion, the C4 defect associated to the increased spontaneous release
of TNF-alpha, modifying a certain number of immunological parameter may be the most
characterizing feature of the 8.1 AH. The consequent modification of the immunological
scenario might be involved in the predisposition to the impressive number of
diseases and the changes in immune response observed in these subjects. In the majority of subjects, an autoimmune
response clinically relevant will develop only in the presence of other abnormalities.
For instance in Lupus have been described severe apoptotis defects that can supply
a large amount autoantigens that drive the autoimmune response [2,19].
Note: see the About IBM (section 16) for a description of these terms.
Analysis of HLA class I and II alleles in sporadic inclusion-body myositis.
Lampe JB, Gossrau G, Kempe A, Fussel M, Schwurack K, Schroder R, Krause
S, Kohnen R, Walter MC, Reichmann H, Lochmuller H. Klinik fur Neurologie, Technische
Universitat Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. firstname.lastname@example.org
J Neurol. 2003 Nov;250(11):1313-7.
Sporadic inclusion body myositis (s-IBM) is characterised by progressive weakness
of proximal and distal limb muscles. Most patients are aged over 50 years at disease
onset. Muscle biopsy reveals an inflammatory myopathy and cytoplasmic amyloid
deposits. The mononuclear infiltrate is dominated by CD8+ T-cells. Several investigators
have described associations between s-IBM and certain HLA antigens and alleles.
However, to date neither HLA class I nor II alleles have been analysed in a large
series of patients. We typed various HLA class I and II alleles in 47 patients
suffering from s-IBM using sequence specific-primer pairs (SSPPCR). The results
were compared with published German controls. Additional Bonferroni adjustment
was performed over all allele groups corresponding to serologically defined antigens
within one HLA class I or II locus. After Bonferroni adjustment, we found a significant
increase in frequency of the following HLA alleles for s-IBM patients when compared
with normal controls: A*03 (p = 0.0002), B*08 (p = 0.002), DRB1*03 (p = 0.0000002),
and DQB1*05 (p = 0.02). HLA typing may be helpful to distinguish between subgroups
of s-IBM patients. Moreover, HLA analysis may aid in identifying patients who
might profit from future therapeutic strategies.
-Immunotherapy of idiopathic inflammatory neuropathies.
-Donofrio PD. Department of Neurology, Wake Forest University School
of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1078,
-Muscle Nerve. 2003 Sep;28(3):273-92.
-Evaluation of peripheral neuropathy is a common reason for referral to a neurologist.
Recent advances in immunology have identified an inflammatory component in many
neuropathies and have led to treatment trials using agents that attenuate this
response. This article reviews the clinical presentation and treatment of the
most common subacute inflammatory neuropathies, Guillain-Barre syndrome (GBS)
and Fisher syndrome, and describes the lack of response to corticosteroids and
the efficacy of treatment with plasma exchange and intravenous immunoglobulin
(IVIG). Chronic inflammatory demyelinating polyneuropathy, although sharing
some clinical, electrodiagnostic, and pathologic similarities to GBS, improves
after treatment with plasma exchange and IVIG and numerous immunomodulatory
agents. Controlled trials in multifocal motor neuropathy have shown benefit
after treatment with IVIG and cyclophosphamide. Also discussed is the treatment
of less common inflammatory neuropathies whose pathophysiology involves monoclonal
proteins or antibodies directed against myelin-associated glycoprotein or sulfatide.
Little treatment data exist to direct the clinician to proper management of
rare inflammatory neuropathies resulting from osteosclerotic myeloma; POEMS
syndrome; vasculitis; Sjogren's syndrome; and neoplasia (paraneoplastic neuropathy).
Muscle Nerve 28: 273-292, 2003
-Resolution of chronic inflammatory demyelinating polyneuropathy-associated
central nervous system lesions after treatment with intravenous immunoglobulin.
-Fee DB, Fleming JO. Department of Neurology, University of Wisconsin Hospital
and Clinics, Madison, WI, USA.
-Chronic inflammatory demyelinating polyneuropathy (CIDP) is a condition affecting
the peripheral nervous system; however, it has been associated with central nervous
system (CNS) involvement. The natural history and response to treatment of these
CNS lesions are unknown. We report the case of a patient with CIDP which met research
criteria for definite CIDP and associated symptomatic CNS lesions. She had resolution
of her CNS-based clinical and radiographic findings with intravenous immunoglobulin
(IVIG) therapy. IVIG is a reasonable treatment option when symptomatic, CIDP-associated
CNS lesions are present.
-Inclusion body myositis: clonal expansions of muscle-infiltrating T cells
persist over time.
-Muntzing K, Lindberg C, Moslemi AR, Oldfors A. Department of Pathology,
Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden.
-Scand J Immunol. 2003 Aug;58(2):195-200.
-Inclusion body myositis (IBM) is a chronic inflammatory myopathy. The muscle
histology is characterized by infiltration of T cells, which invade and apparently
destroy muscle fibres. This study was performed to investigate whether predominant
clones of muscle-infiltrating T cells are identical in different muscles and whether
they persist over time in IBM. By reverse transcriptase-polymerase chain reaction,
25 T-cell receptor (TCR) variable beta (Vbeta) chain families and the complementarity-determining
region 3 (CDR3) of the TCR were analysed in two different muscle biopsies of four
patients with IBM. In two of the patients, the muscle biopsies were obtained from
different muscles at one time point, whereas in two patients, the second biopsy
was obtained 9 years after the first biopsy. T cells expressing predominant Vbeta
families were analysed for clonality by fragment length analysis of the CDR3.
Predominant Vbeta families were analysed by DNA sequencing to identify identical
clones. Immunohistochemical staining of Vbeta families was performed to study
the distribution of T cells expressing identified predominant Vbeta families.
The muscle-infiltrating lymphocytes showed restricted expression of TCR Vbeta
families. DNA sequencing proved that clonally expanded T cells were identical
in different muscles and persisted 9 years after the first biopsy. Immunohistochemical
analysis with Vbeta family-specific antibodies demonstrated the endomysial localization
of these T cells in inflammatory cell infiltrates. Our results show that in IBM
there is clonal restriction of TCR expression in muscle-infiltrating lymphocytes.
Identical T-cell clones predominate in different muscles, and these clones persist
for many years. These results indicate an important, continuous, antigen-driven
inflammatory reaction in IBM.
-Anti-T-lymphocyte globulin treatment in inclusion body myositis: A randomized
-Lindberg C, Trysberg E, Tarkowski A, Oldfors A. Departments of Neurology
(Dr. Lindberg), Rheumatology (Drs. Trysberg and Tarkowski), and Pathology (Dr.
Oldfors), Sahlgrenska University Hospital, Sahlgrenska NeuroMuscular Center, Gothenburg,
-Neurology. 2003 Jul 22;61(2):260-2.
-The authors performed an open, randomized trial in patients with inclusion body
myositis comparing 1) 12-month treatment with oral methotrexate 7.5 mg/week alone
(MTX group) with 2) 12-month MTX treatment preceded by 7 days of IV anti-T-lymphocyte
immunoglobulin treatment (ATG group). Eleven patients were randomized; 10 patients
completed 12 months follow-up. Myometry showed that patients in the ATG group
(n = 6) increased in mean muscle strength by 1.4% compared with the MTX group
(n = 5), whose muscle strength decreased by 11.1% (p = 0.021).
INFLAMMATORY MYOPATHIES: CLINICAL,
DIAGNOSTIC AND THERAPEUTIC ASPECTS
FRANK L. MASTAGLIA, MD, MICHAEL J. GARLEPP, PhD,
BEVERLEY A. PHILLIPS, PhD, and PAUL J. ZILKO, MB, BS
Muscle Nerve 27: 407-425, 2003
ABSTRACT: The three major forms of immune-mediated in.ammatory myopathy are dermatomyositis
(DM), polymyositis (PM), and inclusion-body myositis (IBM). They each have distinctive
clinical and histopathologic features that allow the clinician to reach a specifc
diagnosis in most cases. Magnetic resonance imaging is sometimes helpful, particularly
if the diagnosis of IBM is suspected but has not been formally evaluated. Myositis-specifc
antibodies are not helpful diagnostically but may be of prognostic value; most
antibodies have low sensitivity. Muscle biopsy is mandatory to con.rm the diagnosis
of an infammatory myopathy and to allow unusual varieties such as eosinophilic,
granulomatous, and parasitic myositis, and macrophagic myofasciitis, to be recognized.
The treatment of the in.ammatory myopathies remains largely empirical and relies
upon the use of corticosteroids, immunosuppressive agents, and intravenous immunoglobulin,
all of which have nonselective effects on the immune system. Further controlled
clinical trials are required to evaluate the relative ef.cacy of the available
therapeutic modalities particularly in combinations, and of newer immunosuppressive
agents (mycophenolate mofetil and tacrolimus) and cytokine-based therapies for
the treatment of resistant cases of DM, PM, and IBM. Improved understanding of
the molecular mechanisms of muscle injury in the in.ammatory myopathies should
lead to the development of more speci.c forms of immunotherapy for these conditions.
**Using gene therapy, the levels of a protein implicated in Alzheimer's
disease have been dramatically reduced in mice. Click