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Mechanisms of Disease: autoantigens as clues to the pathogenesis of myositis

Nature Clinical Practice Rheumatology volume 4, pages 201–209 (2008)Cite this article

Abstract

Autoimmune inflammatory myopathies, referred to as myositis, comprise a heterogeneous group of chronic inflammatory muscle diseases that present with various clinical phenotypes, histologic changes and autoantibodies, resulting in progressive inflammatory muscle damage and weakness. In up to 20% of myositis patients, particularly those with dermatomyositis, there is an association with cancer that is most frequently diagnosed within 1 year of presentation of myositis. Accumulating data show that autoantibodies in myositis target a specific group of intracellular molecules that are not muscle-specific in their expression. The striking association between autoantibodies recognizing ubiquitously expressed molecules and distinct clinical phenotypes suggests that the target tissues themselves might regulate and shape the phenotype-specific immune response in myositis. Studies indicate that changes in phenotype-specific autoantigens, such as altered structure, enhanced expression, and acquisition of adjuvant properties during various forms of cellular stress, apoptosis, and transformation, might be mechanistically important in this regard. This Review discusses these developments and highlights a central role of autoantigens themselves as a critical partner in driving autoimmune diseases, and the potential for their therapeutic manipulation. In addition, we will highlight insights that the cancer–autoimmunity interface in this group of diseases provides into the relationship between the anticancer immune response and autoimmune diseases.

Key Points

  • The specificity of the immune response in autoimmune inflammatory myopathies provides important insights into the disease mechanism, identifying the injured and healing muscle as an active participant in tissue damage through mutually amplifying interactions with the immune system

  • Damage-induced enhancement of autoantigen expression and adjuvant activity might contribute to an amplification loop in autoimmunity, in which tissue damage and healing provide fuel for further immune responses

  • Amplification cycles have an important role in self-sustaining phenotypes, and might be important targets of therapy

  • Relevant amplification loops in myositis include immune effector pathways generating muscle damage (e.g. the cytotoxic T lymphocyte granule pathway), antigen expression pathways, regeneration and differentiation pathways, and Toll-like receptor or interferon pathways

  • The association of malignancy with myositis and the shared antigen expression patterns in regenerating muscle and adenocarcinomas suggest that in some patients, myositis might represent a paraneoplastic syndrome reflecting an anticancer response that spreads to normal tissues

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Figure 1: Factors implicated in the amplification of injury in myositis.
Figure 2: Hypothetical reciprocal relationship between cancer and autoimmunity.
Figure 3: Proposed mechanisms in cancer-associated myositis.

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Acknowledgements

This work was supported by NIH grants, by a Hugh and Renna Cosner scholarship in Translational Research, and by the Blum Kovler Foundation.

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Authors and Affiliations

  1. and A Rosen is Mary Betty Stevens Professor of Medicine in the Division of Rheumatology, Department of Medicine, TL Suber is an MD, PhD graduate student in Cellular and Molecular Medicine, L Casciola-Rosen is Associate Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,

    Tomeka L Suber, Livia Casciola-Rosen & Antony Rosen

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  1. Tomeka L Suber
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Correspondence to Antony Rosen.

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Suber, T., Casciola-Rosen, L. & Rosen, A. Mechanisms of Disease: autoantigens as clues to the pathogenesis of myositis. Nat Rev Rheumatol 4, 201–209 (2008). https://doi.org/10.1038/ncprheum0760

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