Pathogenesis of autoantibodies in inflammatory myopathies

While autoantibodies targeting extracellular antigens, such as those in myasthenia gravis, are established mediators of disease, autoantibodies recognizing intracellular antigens in inflammatory myopathies have traditionally been considered nonpathogenic. This review examines evidence challenging that paradigm and highlights recent advances in understanding the origins and pathogenic functions of autoantibodies in myositis.

In several forms of myositis, immunoglobulin accumulates within muscle fibers in a distribution mirroring that of the cognate autoantigen. Muscle biopsies demonstrate functional consequences consistent with disruption of the targeted autoantigen, as well as secondary muscle damage and inflammation. These effects are reproduced in vitro by forced autoantibody internalization. Local plasma cells may facilitate this process by releasing cytoplasmic contents into neighboring cells, including immunoglobulin RNA. In paraneoplastic dermatomyositis, genetic alterations of the targeted autoantigen are frequently identified in tumors, suggesting that immune responses to somatic tumor mutations may initiate autoantibody production. In immune checkpoint inhibitor-associated myositis, autoantibodies may contribute to disease by acting as chemoattractants for drug-activated T cells.

Recent findings support a direct pathogenic role for autoantibodies in several autoantibody-defined myositis subtypes and provide new insights into their origins and contribution to immune-mediated muscle injury, while also suggesting broader roles.