Pathogenesis of Theiler's virus-induced demyelinating disease

泰勒病毒引起的脱髓鞘病的发病机制

• 批准号: 9093302
• 负责人: RAYMOND Philip ROOS
• 金额: $ 23.7万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093302
• 关键词: Acute; Antibodies; Autoimmune Diseases; Binding; CD8B1 gene; Cardiomyopathies; Cells; Chronic; Data; Demyelinating Diseases; Demyelinations; Development; Diabetes Mellitus; Disease; Encephalomyelitis; Equilibrium; Event; Experimental Autoimmune Encephalomyelitis; Experimental Models; Failure; Genetic Transcription; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Histocompatibility Antigens Class II; IRF3 gene; Immune; Immune system; Immunologic Factors; Immunophenotyping; Infection; Inflammation; Inflammatory; Interferon-beta; Interferons; Interleukin-10; Interleukin-12; Interleukin-17; Lead; Mediating; Memory; Modeling; Multiple Sclerosis; Mus; Neuraxis; Pathogenesis; Pathology; Pathway interactions; Production; Proteins; Regulatory T-Lymphocyte; Research Personnel; Role; SJL Mouse; Signal Transduction; Site; Subgroup; T-Lymphocyte; TMEV; Th1 Cells; Viral Genome; Virus; Virus Diseases; cytokine; disease phenotype; interleukin-23; macrophage; member; mutant; novel therapeutics; pathogen; prevent; promoter; response; transcription factor; virus-induced demyelination

 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.

 描述（由申请人提供）：泰勒氏鼠脑脊髓炎病毒（TMEV）的DA毒株引起TMEV诱导的脱髓鞘疾病（TMEV-IDD），其用作多发性硬化症（MS）的实验模型：两种疾病具有相似的免疫介导的脱髓鞘病理学。相比之下，TMEV的GDVII株引起致命的脑脊髓炎，而没有脱髓鞘或病毒持续存在。DA L和GDVII L蛋白都阻断IFN-β转录，然而，它们在IRF-3途径中的不同位点这样做。DA L以及因此DA病毒感染阻断IRF-3的活化，而GDVII L以及因此GDVII病毒感染（以及被称为DALGDVII的突变病毒感染，其中DA L被GDVII L替代）活化IRF-3，但阻断IRF-3与IFN-β启动子的结合。值得注意的是，活化的IRF-3：对IL-27合成至关重要，其抑制Th 17细胞;减少CD 4+记忆细胞的IL-17分泌;在分泌IL-10的Tr 1细胞的分化中重要，Tr 1细胞是一种调节性T细胞，可以解决炎症和恢复耐受性;负调节T细胞中粒细胞-巨噬细胞-集落刺激因子（GM-CSF）的表达，其在介导实验性变态反应性脑脊髓炎（EAE）中是重要的。活化的IRF-3还干扰IL-12和IL-23亚基IL-12 p40的产生，阻止幼稚T细胞极化为促炎性Th 1细胞（由IL-12诱导）和Th 17细胞（由IL-23诱导）。在目前的建议中，我们假设IRF-3的激活或激活失败（和IL-27/Th 17的平衡）在TMEV诱导的脱髓鞘中是重要的，并在（部分）确定两个TMEV亚组疾病表型。由于无法激活IRF-3，IFN-β应答的拮抗作用可能在感染各种病原体后发生，这可能是MS和/或MS发作（或另一种自身免疫性疾病）在感染这些病原体后开始的原因。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，并开辟MS新的治疗方向。