Cytokines in juvenile dermatomyositis pathophysiology: Potential and challenge

Purpose of review: Cytokines are criticalmediators of the immune response. This review focuses on cytokine-specific information from children with juvenile dermatomyositis, and includes pertinent data from adults with polymyositis and dermatomyositis. Recent findings: Much of the new data concern the role of possible antigens and the definition of genetic control of the immune response in juvenile dermatomyositis. Gene expression profile data of DQA1*0501 (present in 85% of patients) compared with age-matched control subjects show that the initial immune response is an interferon-α/β- induced cascade with secondary stimulation of interferon-γ. Specific epitopes of group A β-hemolytic streptococcal M protein, with sequence homology for myosin, elicit both cell-mediated cytotoxicity and tumor necrosis factor-α production when incubated with mononuclear cells from children with active juvenile dermatomyositis. Tumor necrosis factor-α synthesis is increased in juvenile dermatomyositis patients with the tumor necrosis factor-α-308A allele, and is associated with increased thrombospondin-1 (an antiangiogenic agent) production and small vessel occlusion in untreated juvenile dermatomyositis. Studies in adults with polymyositis and dermatomyositis implicate interleukin-1α, transforming growth factor-β, and endothelial cell perturbation early in the disease course. Cultured myoblasts were found to produce interleukin-15, which impacts local T-cell activation and proliferation. Summary: The limited data suggest that a possible viral/microbial antigen may elicit an interferon-α/ β-induced response, and that antigenic epitopes may be shared. Increased synthesis of tumor necrosis factor-α, more common in juvenile dermatomyositis with the tumor necrosis factor-α-308A polymorphism, may augment this response and is associated with a wide range of pathologic consequences, as well as disease chronicity and calcifications. The muscle fibers themselves can regulate local inflammation by production of tumor necrosis factor-α, interleukin-15 and interleukin-1α, and transforming growth factor-β.