Role of Type I Interferons in a Self-Sustaining Murine Model of Myositis

描述（由申请人提供）：特发性炎性肌病包括一组结缔组织疾病，包括皮肌炎、多发性肌炎和包涵体肌炎。每一种情况都以慢性骨骼肌炎症和肌纤维损伤为特征。在这些情况下，MHC I类分子的持续过度表达和相关的未折叠蛋白反应（UPR）在受影响的肌纤维中都表明了慢性肌纤维损伤的共同机制。一个小鼠模型表明，MHC I类的中心致病作用是由一种转基因MHC I类分子H-2Kb的条件表达引起的慢性肌炎，特别是在骨骼肌纤维中，通常表达很少内源性MHC I类，转基因H-2Kb的表达淹没了肌肉纤维的蛋白质折叠系统并激活了UPR，这似乎模仿了人类肌炎中发生的情况。值得注意的是，转基因H-2Kb表达数周就能诱导自持性肌炎，这种肌炎是由肌纤维中内源性MHC类分子表达增加引起的，这种表达在转基因H-2Kb表达被抑制后持续很长时间。诱导和维持内源性MHC I类表达的机制尚不清楚，尽管我们推测I型干扰素参与其中，因为它们是MHC I类表达的有效诱导剂，并且有证据表明I型干扰素在小鼠和人类肌炎的受影响肌肉组织中起作用。此外，我们最近发现，UPR可以强烈增强I型干扰素的表达，特别是在并发先天免疫激活的情况下。这一发现表明MHC I类诱导的UPR和MHC I类诱导的I型干扰素之间存在一种新的联系，这使我们假设UPR诱导的I型干扰素是由受影响的骨骼肌纤维产生的，并且是小鼠肌炎模型中持续内源性MHC I类表达的关键介质。我们将通过描述肌肉细胞和组织中对MHC I类过度表达和UPR激活的I型干扰素产生的特征来验证这一假设，并通过评估I型干扰素受体缺乏的影响来确定I型干扰素在肌炎小鼠模型中的作用。最终，在小鼠模型中阐明慢性肌炎的机制将对理解慢性人类肌炎的机制做出重要贡献，并为开发新的治疗人类肌炎的方法提供强有力的理论依据，这些方法可以破坏慢性疾病的自我维持周期。

DESCRIPTION (provided by applicant): Idiopathic inflammatory myopathies comprise a group of connective tissue diseases that include dermatomyositis, polymyositis, and inclusion body myositis. Each of these conditions is characterized by chronic skeletal muscle inflammation and muscle fiber damage. Demonstration of persistent excessive expression of MHC class I molecules and an associated unfolded protein response (UPR) in affected muscle fibers in each of these conditions suggests a common mechanism for chronic muscle fiber injury. A central pathogenic role for MHC class I is indicated by a mouse model, in which chronic myositis is induced by conditional expression of a transgenic MHC class I molecule, H-2Kb, specifically in skeletal muscle fibers, which typically express very little endogenous MHC class I. Transgenic H-2Kb expression overwhelms the protein folding system of muscle fibers and activates an UPR, which appears to mimic what occurs in human myositis. Remarkably, several weeks of transgenic H-2Kb expression is all that is needed to induce self-sustaining myositis that is driven by increased expression of endogenous MHC class I molecules in muscle fibers, which persists long after transgenic H-2Kb expression is suppressed. The mechanism for induction and maintenance of endogenous MHC class I expression is unclear, though we theorize that type I interferons are involved, since they are potent inducers of MHC class I expression, and there is evidence for type I interferon action in affected muscle tissue in both mouse and human myositis. Additionally, we have recently discovered that the UPR can strongly enhance expression of type I interferons, particularly in the context of concurrent innate immune activation. This finding suggests a novel connection between the MHC class I-induced UPR and MHC class I-inducing type I interferons that leads us to hypothesize that UPR-induced type I interferons are produced by affected skeletal muscle fibers and are critical mediators of sustained endogenous MHC class I expression in the murine model of myositis. We will test this hypothesis by characterizing type I interferon production in muscle cells and tissue in response to excessive MHC class I expression and UPR activation, and by determining the role of type I interferon action in the mouse model of myositis by assessing the impact of type I interferon receptor deficiency. Ultimately, elucidating the mechanism of chronic myositis in the mouse model should make important contributions to understanding the mechanism of chronic human myositis, and provide strong rationale for development of novel treatments for human myositis that disrupt the proposed self-sustaining cycle of chronic disease.