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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, Munich, Germany.
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, France. Dominique.Figarella-Branger@medecine.univ-mrs.fr
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. askanas@hsc.usc.edu
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.
Dalakas MC.
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 for background]
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
Abstract
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 [19]. 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 [12]. 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.
4. Discussion
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. johannes.lampe@schering.de
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, USA.
-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.
-Case Study
-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 pilot study.
-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, Sweden.
-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 here:

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