Muscle inflammation is characteristic of inflammatory myopathies but also occurs in muscular dystrophy with lack of the sarcolemmal protein dysferlin. We quantified inflammatory cells and major histocompatibility complex (MHC) expression in muscle from 10 patients with dysferlinopathy. Infiltrating cells were always present although numbers varied considerably; macrophages were more common than T cells, T cytotoxicity was absent, and MHC class I was overexpressed on muscle fibers. These findings differ from polymyositis (PM) but are closely similar to those in SJL/J mice (which lack dysferlin) and emphasize the relationship between absence of dysferlin and immune system abnormalities in muscle.
"C3a is an anaphylotoxin that produces a local inflammatory response, whereas C3b serves as an opsonizing agent by coating the sarcolemma of dysferlin-deficient muscle. Opsonization of the sarcolemma, either with or without C5, enhances the phagocytosis of the target cell by macrophages, which are the predominant infiltrating cells in dysferlin-deficient muscles48,89. Figure 6 shows an estimated inflammatory process in dysferlin-deficient skeletal muscle. "
[Show abstract][Hide abstract] ABSTRACT: Dysferlin (DYSF) is involved in the membrane-repair process, in the intracellular vesicle system and in T-tubule development in skeletal muscle. It interacts with mitsugumin 53, annexins, caveolin-3, AHNAK, affixin, S100A10, calpain-3, tubulin and dihydropyridine receptor. Limb-girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy (MM) are muscular dystrophies associated with recessively inherited mutations in the DYSF gene. The diseases are characterized by weakness and muscle atrophy that progress slowly and symmetrically in the proximal muscles of the limb girdles. LGMD2B and MM, which are collectively termed "dysferlinopathy", both lead to abnormalities in vesicle traffic and membrane repair at the plasma membrane in muscle fibers. SJL/J (SJL) and A/J mice are naturally occurring animal models for dysferlinopathy. Since there has been no an approach to therapy for dysferlinopathy, the immediate development of a therapeutic method for this genetic disorder is desirable. The murine models are useful in verification experiments for new therapies and they are valuable tools for identifying factors that accelerate dystrophic changes in skeletal muscle. It could be possible that the genetic or immunological background in SJL or A/J mice could modify muscle damage in experiments involving these models, because SJL and A/J mice show differences in the progress and prevalent sites of skeletal muscle lesions as well as in the gene-expression profiles of their skeletal muscle. In this review, we provide up-to-date information on the function of dysferlin, the development of possible therapies for muscle dystrophies (including dysferlinopathy) and the detection of new therapeutic targets for dysferlinopathy by means of experiments using animal models for dysferlinopathy.
"Disruption of annexin A1 also leads to complications in the inflammatory responses although the inflammatory responses in annexin A1-null mice have not been attributed to its role in membrane repair [69,70]. Dysferlinopathy is well known for the presence of a prominent muscle inflammation [71-73], and some of the dysferlinopathy patients were even initially misdiagnosed as having polymyositis [74,75]. Moreover, although highly resistant to lengthening-contraction-induced injury [14,57], dysferlin-deficient muscle experienced a strong inflammatory response that delayed its recovery from injury caused by lengthening contractions [76,77]. "
[Show abstract][Hide abstract] ABSTRACT: Repair of plasma membrane tears is an important normal physiological process that enables the cells to survive a variety of physiological and pathological membrane lesions. Dysferlin was the first protein reported to play a crucial role in this repair process in muscle, and recently, several other proteins including Mitsugumin 53 (MG53), annexin and calpain were also found to participate. These findings have now established the framework of the membrane repair mechanism. Defective membrane repair in dysferlin-deficient muscle leads to the development of muscular dystrophy associated with remarkable muscle inflammation. Recent studies have demonstrated a crosstalk between defective membrane repair and immunological attack, thus unveiling a new pathophysiological mechanism of dysferlinopathy. Here I summarize and discuss the latest progress in the molecular mechanisms of membrane repair and the pathogenesis of dysferlinopathy. Discussion about potential therapeutic applications of these findings is also provided.
"In two patients with dysferlinopathy, there was no or only mild expression of MHC class I on the sarcolemma in spite of the inflammatory infiltrates. There had been one previous study which demonstrated the expression of MHC class I on the sacolemma of non-necrotic muscle fibers in dysferlinopathy with inflammation (25). However, the up-regulation of MHC class I was not accompanied by T-cell cytotoxicity, which is similar to the result of our study. "
[Show abstract][Hide abstract] ABSTRACT: This study was performed in order to characterize the types of the infiltrating cells, and the expression profiles of major histocompatibility complex (MHC) class I and membrane attack complex (MAC) in patients with inflammatory myopathies and dysferlinopathy. Immunohistochemical stains were performed using monoclonal antibodies against several inflammatory cell types, MHC class I, and MAC in muscles from inflammatory myopathies and dysferlinopathy. There was significant difference in the types of infiltrating cells between polymyositis (PM), dermatomyositis (DM), and dysferlinopathy, including significantly high CD4+/CD8+ T cell ratio and B/T cell ratio in DM. In dysferlinopathy, CD4+ T cells were the most abundant and the proportions of infiltrating cell types were similar to those of DM. MHC class I was expressed in muscle fibers of PM and DM regardless of the presence of inflammatory infiltrates. MAC was expressed in necrotic fibers and vessels of PM and DM. One patient with early stage DM had a MAC deposits on endomysial capillaries. In dysferlinopathy, MAC deposit was also observed on the sarcolemma of nonnecrotic fibers. The analysis of inflammatory cells, MHC class I expressions and MAC deposits may help to differentiate dysferlinopathy from idiopathic inflammatory myopathy.
Journal of Korean medical science 12/2009; 24(6):1015-23. DOI:10.3346/jkms.2009.24.6.1015 · 1.27 Impact Factor
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