Pathogenic aspects of dermatomyositis, polymyositis and overlap myositis

Abstract

Inflammatory myopathies (IMs) often have distinct histopathologic features suggesting humorally mediated involvement of the microcirculation in dermatomyositis (DM), including early capillary deposition of the complement C5b-9 membranolytic attack complex (MAC) and secondary ischaemic changes; and CD8 T-cell-mediated and MHC1-restricted autoimmune attack of myofibers in polymyositis (PM) and inclusion body myositis. Novel insights in these specific diseases include emerging evidence that capillary loss involves whole microvascular units in DM, and that regulatory T-cells strongly protect myofibers from experimental autotoxic attack in PM. However, all IMs do not exhibit pathophysiology-relevant histopathologic features of DM or PM. Autoimmune necrotizing myopathies (AINM) occur in the absence of endomysial inflammatory cells and may be specifically associated with anti-SRP autoantibodies. Moreover, IM histopathological features may be scarce, unspecific and overlapping. Therefore, increasing attention is paid to features shared by IMs regardless of their type, relevant to the innate immune response and to non-immune mechanisms. Innate immune responses to myodamage (and/or as yet unknown stimuli), involves release of chemokines, activation of specific Toll-like receptors (TLRs) and complex Th-1, Th-17 and other cytokine interplays; it triggers DC recruitment and maturation, and is associated with type 1 IFN signature (especially in DM where type 1 IFN-producing cells called plasmacytoid DCs are mainly detected). Non-immune mechanisms mainly include endoplasmic reticulum (ER) stress induced in myofibers by up-regulation of MHC-class I antigens (as typically observed in PM with a diffuse pattern and in DM with perifascicular predominance). ER stress may favour autoimmune reactions but may also be associated with myofiber damage and dysfunction in the absence of lymphocytes. Overlap myositis (OM) may be associated with other connective tissue diseases and a variety of autoantibodies, such as those directed against tRNA synthetase. Myositis specific autoantibodies are mainly expressed by regenerating myofibers, that may also express MHC-1 and endogenous ligand-binding TLRs, thus drawing a picture in which the regenerating myofiber plays a central pathophysiologic role.