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 (His RS ). 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 α/β receptor ( IFN α/βR‐null mice). Results Experimental autoimmune myositis induced by a single intramuscular immunization with His RS spontaneously abated after 7–8 weeks. In contrast, levels of anti‐His RS 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 His RS in the presence of R‐848. Myofiber major histocompatibility complex ( MHC ) class I molecules were detectable only in mice immunized with both His RS and R‐848. MHC up‐regulation occurred early and in muscles that were not directly injected with His RS . 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 α/βR‐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.