Pathogenesis of Theiler's virus-induced demyelinating disease

 描述(由申请人提供)：泰勒氏小鼠脑脊髓炎病毒(TMEV)DA株引起TMEV诱导的脱髓鞘疾病(TMEV-IDD)，作为多发性硬化症(MS)的实验模型：这两种疾病都有相似的免疫介导的脱髓鞘病理。相比之下，TMEV的GDVII株可引起致命性脑脊髓炎，但没有脱髓鞘或病毒持久性。DA L和GDVII L蛋白都能抑制干扰素-β转录，但它们在IRF-3途径中的不同位置起作用。大L，因此DA病毒感染，阻断了irf-3的激活，而gdvii L，因此gdvii病毒感染(以及一种名为DALGDvii的突变病毒的感染，其中DA L被gdvii L取代)，激活了irf-3，但阻断了irf-3与干扰素-β启动子的结合。值得注意的是，激活的IRF-3对IL-27的合成至关重要，IL-27抑制Th17细胞；减少CD4+记忆细胞分泌IL-17；对分泌IL-10的TR1细胞的分化很重要；TR1细胞是一种调节性T细胞，可以化解炎症并恢复耐受；负调控T细胞中粒细胞-巨噬细胞集落刺激因子(GM-CSF)的表达，这在介导实验性变态反应性脑脊髓炎(EAE)中起重要作用。激活的IRF-3还干扰IL-12和IL-23的亚基IL-12p40的产生，阻止幼稚T细胞极化为促炎Th1细胞(由IL-12诱导)和Th17细胞(由IL-23诱导)。在目前的建议中，我们假设IRF-3的激活或失败(以及IL-27/Th17的平衡)在TMEV引起的脱髓鞘以及(部分)确定TMEV两个亚型的疾病表型中是重要的。在感染各种病原体后，由于不能激活β-3而导致的干扰素-IRF反应的拮抗作用，这可能是在感染这些病原体后发生MS和/或MS攻击(或另一种自身免疫性疾病)的原因。更好地了解TMEV-IDD先天免疫系统的这些活动可能会阐明其发病机制，并为MS开辟新的治疗方向。

 DESCRIPTION (provided by applicant): DA strain of Theiler's murine encephalomyelitis virus (TMEV) causes TMEV-induced demyelinating disease (TMEV-IDD), which serves as an experimental model of multiple sclerosis (MS): both diseases have similar immune-mediated demyelinating pathology. In contrast, GDVII strain of TMEV causes a fatal encephalomyelitis without demyelination or virus persistence. Both DA L and GDVII L protein block IFN-β transcription, however, they do so at different sites in the IRF-3 pathway. DA L, and therefore DA virus infection, blocks the activation of IRF-3, while GDVII L, and therefore GDVII virus infection (as well as infection by a mutant virus called DALGDVII, in which DA L is replaced by GDVII L), activates IRF-3, but blocks the binding of IRF-3 to the IFN-β promoter. Of note, activated IRF-3: is critical for IL-27 synthesis, which inhibits Th17 cells; decreases IL-17 secretion by CD4+ memory cells; is important in the differentiation of IL-10- secreting Tr1 cells, a regulatory T cell that can resolve inflammation and restore tolerance; negatively regulates granulocyte-macrophage-colony stimulating factor (GM-CSF) expression in T cells, which is important in mediating experimental allergic encephalomyelitis (EAE). Activated IRF-3 also interferes with production of IL- 12p40, a subunit of IL-12 and IL-23, preventing polarization of naïve T cells into proinflammatory Th1 cells (induced by IL-12) and Th17 cells (induced by IL-23). In the present proposal, we hypothesize that the activation or the failure of activation of IRF-3 (and the balance of IL-27/Th17) is important in the demyelination induced by TMEV, and in (partly) determining the two TMEV subgroup disease phenotypes. Antagonism of the IFN-β response because of a failure to activate IRF-3 may occur following infections with varied pathogens, and this may be the reason that the initiation of MS and/or an MS attack (or of another autoimmune disease) occurs after infection with these pathogens. A better understanding of these activities of the innate immune system in TMEV-IDD may clarify its pathogenesis and open up new therapeutic directions in MS.