Immunopathogenesis of dermatomyosis

Activation of complement C3 is an early event leading to formation of C3b, C3bNEO, and membrane attack complexes, which are deposited on the endothelial cell wall of the endomysial capillaries and result in destruction of capillaries, ischemia, or microinfarcts, most prominently in the periphery of the fascicles, and perifascicular atrophy. Cytokines released by activated complement lead to activation of CD4+ T cells, macrophages, B cells, and CD123+ plasmacytoid dendritic cells; enhance the expression of vascular cell adhesion molecules (VCAM) and intercellular adhesion molecule (ICAM) on the endothelial cell wall; and facilitate lymphoid cell transmigration to endomysial tissue by their integrins, late activation antigen-4, and lymphocyte function–associated antigen-1, which bind VCAM and ICAM. The perifascicular regions contain fibers in a state of remodeling and regeneration (expressing TGF-beta, NCAM, Μi-2), cell-stress (expressing HSP 70,90), immune activation (expressing MHC-1, chemokines, STAT-1), and molecules associated with innate immunity (such as MxA, ISG15, Rig-1). The role of innate immunity in inflammation and perifascicular atrophy is clearly secondary to hypoxic and ischemic damage sensed by the retinoic acid-inducible gene-1 (Rig-1) signaling, which, in turn, leads to auto-amplification of the local inflammation via beta-interferon. Abbreviations: ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function–associated antigen 1; MAC, membrane attack complex; MaC-1, macrophage 1 antigen; MxA, myxovirus (influenza virus) resistance protein 1; NO, nitrous oxide; STAT-1, signal transducer and activator of transcription protein 1; TGF-beta, transforming growth factor-beta; TNF-alpha, tumor necrosis factor-alpha; VCAM-1, vascular cell adhesion molecule-1; VLA-1, very late antigen-1. (Contributed by Dr. Marinos Dalakas.)