A schematic figure of muscle tissue from myositis patients with or without inflammatory infiltrates. (1) Early in the disease, before any signs of mononuclear cell infiltrates in the muscle tissue, patients have been found to express autoantibodies (even before the development of myositis), capillaries often having the appearance of high endothelial venules (HEVs) and an expression of adhesion molecules, interleukin-1-alpha (IL-1α) and/or chemokines, major histocompatibility complex (MHC) class I on muscle fibres, and a decreased number of capillaries together with an increased expression of vascular endothelium growth factor (VEGF) on muscle fibres and in sera, suggestive of tissue hypoxia. Additionally, an increased number of fibres expressing high-mobility box chromosomal protein 1 (HMGB1) has been demonstrated early in the disease, and HMGB1 can induce MHC class I on muscle fibres. (2) All of these findings can also be found when inflammatory cell infiltrates are present. However, in these tissues, an increased production of a range of proinflammatory cytokines from mononuclear cells is also found. Moreover, non-necrotic fibres can be surrounded and sometimes invaded by cytotoxic T cells. These different pathogenic expressions from both immune and nonimmune reactions may all lead to muscle impairment. ER, endoplasmic reticulum; ICAM, intercellular adhesion molecule; IFN-α, interferon-alpha; PDC, plasmacytoid dendritic cell; VCAM, vascular cell adhesion molecule. Partly adapted from Servier Medical Art.

Hypothetical involvement of autoantibodies in myositis. (1) An unknown trigger (for example, a viral infection) can enter the respiratory tract, leading to a modification of histidyl-tRNA synthetase in the lungs and to anti-Jo-1 production (2), which is a common finding in patients with interstitial lung disease (ILD) (antisynthetase syndrome). When immature dendritic cells (DCs) take up the pathogen (in this case, the histidyl-tRNA synthetase), they are activated and mature into effective antigen-presenting cells. (3–5) Both immature and mature DCs have been found in muscle tissue and skin of myositis patients. Additionally, plasmacytoid dendritic cells (PDCs), which are known producers of interferon-alpha (IFN-α), are highly expressed in anti-Jo-1-positive patients and IFN-α can be found in (3) muscle tissue, (4) skin, and (5) circulation of these patents. (5) High levels of both anti-Jo-1 and IFN-α are correlated with disease activity. (6) Autoantigens (histidyl-tRNA synthetase and Mi-2) are expressed in muscle tissue, especially in regenerating fibres. Moreover, major histocompatibility complex (MHC) class I is also known to be expressed in regenerating fibres and PDCs are often expressed adjacent to MHC class I-positive muscle fibres. (7) High BAFF levels have also been characterised in the circulation of anti-Jo-1-positive patients together with the expression of B cells and plasma cells that possibly could locally produce autoantibodies and function as autoantigen-presenting cells in a subset of patients. Anti-Jo-1, antihistidyl-tRNA synthetase antibody; BAFF, B cell-activating factor of the tumour necrosis factor family. Partly adapted from Servier Medical Art.