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Muscle inflammation and MHC class I up-regulation in muscular dystrophy with lack of dysferlin: An immunopathological study

Department of Neuromuscular Diseases, Istituto Nazionale Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy.
Journal of Neuroimmunology (Impact Factor: 2.79). 10/2003; 142(1-2):130-6. DOI: 10.1016/S0165-5728(03)00255-8
Source: PubMed

ABSTRACT 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.

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    • "Hence, one view is that the CD8 + T-cell-mediated reaction in IBM may be secondary to the over-expression of MHC class I molecules and the subsequent presentation of muscle antigens to these T cells. In this line, T-cell infiltrates may be observed as a secondary process in several human genetic myopathies such as dysferlin deficiency (Confalonieri et al., 2003) or facioscapulohumeral muscular dystrophy (Arahata et al., 1995), for instance. An alternative view is that a primary autoimmune process mediated by antigen-specific T cells promotes the vacuolar degeneration and ectopic expression of the potentially toxic proteins characteristic of IBM. "
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    • "Mutations in dysferlin are linked to two clinically distinct muscle-wasting diseases: limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Although autoimmunity is rare in human patients with these and other forms of muscular dystrophy (Confalonieri et al, 2003; Funauchi et al, 2002), SLJ/J mice that also carry mutations in dysferlin are considered a model for experimental autoimmune myopathy (Hart et al, 1987; Vafiadaki et al, 2001). It will be interesting to investigate how muscle fibres compare with other cell types, such as fibroblasts, regarding the amount of immunostimulatory molecules they contain and the rate by which these adjuvants are released on cell injury. "
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    ABSTRACT: Antigens are able to elicit productive immune responses only when second signals are provided by adjuvant molecules. It is well established that exogenously acquired, pathogen-associated molecular patterns fulfil this adjuvant role when recognized by specific receptors on antigen-presenting cells. Recent evidence points to the existence of another class of adjuvant, which is apparently released from injured cells. Such endogenous adjuvants, referred to as 'danger' signals, could alert the immune system to situations that cause cell damage, but not necessarily those that involve infections. Endogenous adjuvants provide a good explanation for immune responses generated against tumours and autologous tissues, but it has been difficult to explain how a constant activation of the immune system is avoided, considering the frequency at which cells are injured in vivo. Here, we suggest that the efficiency with which cells reseal wounds in their plasma membrane might be an important factor in the balance between tolerance and autoimmunity. Recent observations in synaptotagmin-VII-deficient mice suggest that defective membrane repair could lead to autoimmunity in tissues that are more susceptible to mechanical injury.
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    • "Hence, one view is that the CD8 + T-cell-mediated reaction in IBM may be secondary to the over-expression of MHC class I molecules and the subsequent presentation of muscle antigens to these T cells. In this line, T-cell infiltrates may be observed as a secondary process in several human genetic myopathies such as dysferlin deficiency (Confalonieri et al., 2003) or facioscapulohumeral muscular dystrophy (Arahata et al., 1995), for instance. An alternative view is that a primary autoimmune process mediated by antigen-specific T cells promotes the vacuolar degeneration and ectopic expression of the potentially toxic proteins characteristic of IBM. "
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