Hsp60 in inflamed muscle tissue is the target of regulatory autoreactive T cells in patients with juvenile dermatomyositis
Objective. Juvenile dermatomyositis (DM) is an autoimmune disease of unknown origin characterized by muscle weakness and skin manifestations. No definite autoantigen has yet been identified. Heat-shock proteins (HSPs) can be up-regulated at sites of inflammation, and immune reactivity to Hsp60 is suggested to play a regulatory role in various chronic inflammatory diseases. The purpose of this study was to determine whether Hsp60 could serve as an autoantigen in juvenile DM. Methods. Muscle tissue from 4 patients with juvenile DM and 1 healthy control subject without evidence of muscle disease was stained for Hsp60. Peripheral blood mononuclear cells (PBMCs) from 22 patients and 10 healthy control subjects were tested for T cell proliferation induced by human and microbial Hsp60. Cytokine production in response to Hsp60 was examined in 15 patients and 6 healthy controls. T cell reactivity to Hsp60 was determined in muscle biopsy samples from 2 patients. Results. We found significantly increased T cell proliferation to human Hsp60 in PBMCs from juvenile DM patients, which was higher during disease remission. Following in vitro activation with Hsp60, significant amounts of tumor necrosis factor α, interleukin-1β (IL-β), and IL-10 were produced. In contrast to muscle biopsy samples from healthy controls, samples from juvenile DM patients showed up-regulation of Hsp60, induction of T cell proliferation, and production of cytokines. Production of proinflammatory cytokines by muscle-derived cells in response to Hsp60 was associated with a poor clinical prognosis, whereas human Hsp60-specific induction of IL-10 was followed by clinical remission. Conclusion. These findings suggest that human (self) Hsp60 is a disease-relevant autoantigen in juvenile DM. The difference in T cell response with regard to disease activity indicates an immune regulatory effect of Hsp60-specific T cells, opening up perspectives for antigen-specific immunotherapy.