Exacerbation of murine experimental autoimmune myositis by Toll-like receptor 7/8

Objective: Toll-like receptor 7 (TLR-7), TLR-8, and interferon (IFN)-induced genes are expressed in patients with idiopathic inflammatory myositis. This study was undertaken to investigate whether their activation influences the natural history of the disease. Methods: Experimental autoimmune myositis was induced in mice by injection of the amino-terminal portion of the murine histidyl-transfer RNA synthetase (HisRS). Disease was compared in the presence or the absence of the TLR-7/8 agonist R-848 in wild-type mice and in mice that fail to express the IFN/alpha/beta receptor (IFN alpha/beta R-null mice). Results: Experimental autoimmune myositis induced by a single intramuscular immunization with HisRS spontaneously abated after 7-8 weeks. In contrast, levels of anti-HisRS autoantibodies, endomysial/perimysial leukocyte infiltration, and myofiber regeneration persisted at the end of the follow-up period (22 weeks after immunization) in mice immunized with HisRS in the presence of R-848. Myofiber major histocompatibility complex (MHC) class I molecules were detectable only in mice immunized with both HisRS and R-848. MHC up-regulation occurred early and in muscles that were not directly injected with HisRS. Muscle MHC expression paralleled with leukocyte infiltration. MHC class I molecules were selectively up-regulated in myotubes challenged with R-848 in vitro. Type I IFN was necessary for the prolonged autoantibody response and for the spreading of the autoimmune response, as demonstrated using IFN alpha/beta R-null mice. Muscle infiltration was maintained in the injected muscle up to the end of the follow-up period. Conclusion: TLR-7/8 activation is necessary to induce and maintain a systemic autoimmune response targeting the skeletal muscle. This experimental autoimmune myositis model reproduces many characteristics of human idiopathic inflammatory myopathies and may represent a tool for preclinical studies