Hsp60 in inflamed muscle tissue is the target of regulatory autoreactive T cells in patients with juvenile dermatomyositis

Abstract

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 ␣, interleukin-1␤ (IL-1␤), 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.

Autophagy, Inflammation and Innate Immunity in Inflammatory Myopathies

“…It has been demonstrated that reactivity to HSP60 is involved in the disease process in JDM [45]. In the present study we found that endogenous HSP60 was highly expressed not only in JDM but also in all the other IIMs.…”

TLR9 agonist CpG enhances protective nasal HSP60 peptide vaccine efficacy in experimental autoimmune arthritis

“…Indeed, our study shows a correlation between clinical improvement and the presence of FoxP3+ Treg that seems antigen specific as this occurred only after peptide-containing treatment. This is in support of our previous work8 and many studies describing the relation between HSP and regulatory T cells 76–80. The preferred homing of HSP-specific T cells to the site of inflammation mentioned above could therefore also account for the (non-significant) increase in Treg cells in joint-draining lymph nodes.…”

Characterization of regulatory T cells in patients with dermatomyositis

“…The present study also showed the presence of few IL-10 þ cells in skin lesions of DM. Recently, it has been shown that heat-shock protein (Hsp) 60 is a disease-relevant autoantigen in juvenile DM and that production of proinflammatory cytokines (i.e., IL-1b and tumor necrosis factor-a) by muscle-derived cells in response to Hsp 60 was associated with a poor clinical prognosis, while human Hsp 60-specific induction of IL-10 was followed by clinical remission [44]. Such findings suggest an important immunomodulatory activity for IL-10 in DM muscles, thus, a reduction of IL-10 þ cells in the skin might contribute to the development of skin lesions in DM.…”