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Mechanisms of Disease: signaling pathways and immunobiology of inflammatory myopathies

A Corrigendum to this article was published on 01 July 2006

Abstract

The signaling pathways involved in the immunobiology of polymyositis, dermatomyositis, and inclusion-body myositis are outlined in this Review, which is based on research performed during the past 10 years. In dermatomyositis, the complement cascade is activated and the expression of cytokines and chemokines is upregulated. In polymyositis and inclusion-body myositis, autoinvasive CD8+ T cells are clonally expanded. This T-cell subset possesses conserved amino-acid sequences in complementarity-determining region 3 of the T-cell receptor and, via the perforin pathway, exerts a myotoxic effect on muscle fibers that express major histocompatibility complex (MHC) class I molecules. In all inflammatory myopathies, molecules associated with T-cell transmigration and cytokine signaling, as well as chemokines and their receptors, are strongly expressed by endothelial and inflammatory cells. Early in the pathogenesis of polymyositis and inclusion-body myositis, expression of MHC class I molecules on muscle fibers is upregulated, even in the absence of autoinvasive CD8+ T cells. Emerging data indicate that such continuous upregulation of the expression of MHC class I molecules on muscle fibers leads to an endoplasmic reticulum stress response, intracellular accumulation of misfolded glycoproteins, and activation of nuclear factor κB pathways, which can further stimulate formation of MHC class I–CD8 complexes, resulting in a self-sustaining inflammatory response. Advances in our understanding of the signaling pathways involved in the pathogenesis of these inflammatory myopathies are expected to result in the identification of novel therapeutic targets for these diseases.

Key Points

  • Dermatomyositis is a complement-mediated microangiopathy, which leads to destruction of endomysial capillaries

  • In polymyositis and inclusion-body myositis (IBM), the muscle fibers overexpress major histocompatibility complex class I molecules and autoinvasive T cells are clonally expanded

  • In polymyositis and IBM, the T cells form immunologic synapses with the muscle fibers; however, the antigen or antigens they recognize are still unknown

  • In IBM, an autoimmune and a degenerative process occur in parallel; the continuous upregulation of major histocompatibility complex class I molecules on muscle fibers is a major culprit in inducing an endoplasmic reticulum stress response and accumulation of misfolded glycoproteins within the muscle fibers

  • New immunomodulating agents against signaling pathways involved in T-cell or B-cell activation offer promise for future therapies

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Figure 1: Sequence of immunopathologic changes in dermatomyositis.
Figure 2: Immunopathogenesis of polymyositis and inclusion-body myositis.
Figure 3: Assembly of major histocompatibility complex (MHC) class I peptide complexes in the endoplasmic reticulum of the muscle fiber.
Figure 4: Proposed mechanisms for the pathogenesis of polymyositis and inclusion-body myositis.

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

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Correspondence to Marinos C Dalakas.

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Dalakas, M. Mechanisms of Disease: signaling pathways and immunobiology of inflammatory myopathies. Nat Rev Rheumatol 2, 219–227 (2006). https://doi.org/10.1038/ncprheum0140

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