Figure 2

Adaptive immune mechanisms of muscle damage in myositis. DAMP signaling through TLRs in the innate immune cells activates various antigen-presenting cells (APC) in the muscle (shown in Figure 1). These APCs activate CD4 T-cells via MHC class I and CD8 T-cells initiate autoantigen specific T-cell responses (Step 1) [26]. Activated CD4+ T-cells differentiate into T-helper (Th)-17 (TGF-β), Th2 (IL-4), and Th1(IL-12) effector T-cells in the presence of respective cytokines, and in turn produce discrete sets of cytokines that affect a variety of cell types (Step 2) [53]. Th1 cells through IFN-γ generate M1 macrophages, which secrete TNF-α, IL-6 and IL-1, and damage cells. Th2 cells, through IL-4, TGFβ and IL-10, generate M2 macrophages that are known to help tissue repair and remodeling in the affected tissues [54, 55]. Th2 cells also help stimulate B-cell maturation and differentiation into plasma cells that produce autoantibodies and further initiate complement mediated damage to capillaries and induce hypoxia (Step 3). Cytotoxic CD28^−/− T-cells and regulatory T-cells (Tregs) reduce inflammation and tissue damage by inhibiting the function of antigen presenting cells and T-effector cells [56, 57]. It is also known that activated CD8 T-cells differentiate into cytotoxic T-cells (CTL) and exert cytotoxic effects on the affected muscle through secretion of perforin-1 and granzyme-B enzymes (Step 4) [58]. Thus the myositis muscle microenvironment is complex, with both tissue repair and tissue-damaging mechanisms in play at all times. The relative ratios of these pathways determine the disease severity and progression.