Viral infections and celiac disease pathogenesis

描述（由申请人提供）：拟议研究的中心目标是确定病毒感染导致口服耐受性丧失并诱发乳糜泻（CD）的机制。病毒感染越来越被认为是复杂炎症性疾病发病机制中的重要因素。然而，人们对病毒引发炎症性疾病的生物学特性知之甚少。乳糜泻是一种复杂的T细胞介导的肠道疾病，其自身免疫成分以炎症性抗麸质免疫反应为特征，仅发生在具有HLA DQ2或DQ8等位基因的麸质暴露人群中。知识上的差距阻碍了对高危个体的精确识别和对预防和治疗乳糜泻新方法的开发。大约45%的美国人表达DQ2或DQ8分子，但只有1%的人患上了这种疾病。这一观察结果表明，额外的环境因素有助于疾病的诱发。虽然乳糜泻的一个共同特征是失去对谷蛋白的口服耐受性（LOT），但我们有新的证据表明乳糜泻是一种异质性疾病，由两种主要类型组成。A型CD是由IL-15介导的，而B型CD是由病毒感染和1型干扰素的分泌介导的。呼肠孤病毒是研究cd增强病毒感染的特别有吸引力的模型。这些病毒属于呼肠孤病毒科的人类dsRNA病毒，与CD发病率增加有关。呼肠孤病毒感染小鼠肠道，可以通过基因操纵来鉴定自身免疫宿主反应的病毒决定因素。该提议的中心假设是，对病毒感染的反应构成了另一种选择

DESCRIPTION (provided by applicant): The central goal of the proposed research is to determine mechanisms by which viral infections lead to loss of oral tolerance and induce celiac disease (CD). Viral infections are increasingly recognized as contributing factors in the pathogenesis of complex inflammatory diseases. However, little is known about the biological features that enable a virus to provoke development of inflammatory disorders. CD is a complex T cell- mediated intestinal disorder with an autoimmune component characterized by an inflammatory anti-gluten immune response that occurs exclusively in gluten-exposed persons with HLA DQ2 or DQ8 alleles. Gaps in knowledge preclude precise identification of at-risk individuals and development of new ways to prevent and treat CD. Approximately 45% of the U.S. population expresses DQ2 or DQ8 molecules, yet only 1% of the population develops the disease. This observation indicates that additional environmental factors contribute to disease induction. Although a common feature of CD is loss of oral tolerance (LOT) to gluten, we have new evidence that CD is a heterogeneous disorder consisting of two main types. Type A CD is mediated by IL-15, whereas Type B CD is mediated by viral infections and elaboration of type-1 interferons. Reoviruses are particularly attractive models for studies of CD-potentiating viral infections. These viruses are human dsRNA viruses that belong to the Reoviridae, which are associated with an increased CD incidence. Reoviruses infect the murine intestine and can be genetically manipulated to identify viral determinants of autoimmune host responses. The central hypothesis of this proposal is that responses to viral infections constitute an alternative pathway to IL-15 signaling or effector responses that leads to CD by dysregulating immune responses to oral antigen (Ag). This hypothesis will be tested in two well-integrated specific aims. In Specific Aim 1, we will identify viral determinants that shape the virus-host interaction implicated in LOT by using reassortant viruses generated from two well-characterized reovirus strains that differ in LOT capacity. In Specific Aim 2, we will establish evidence for virus-induce CD by characterizing the capacity of reovirus infection to induce potential CD in HLA-DQ8 tg mice as well as establishing evidence for a Type A and Type B CD while defining transcriptional signatures for virus-induced CD. Insights gained from these studies will enable identification of candidate pathways for virus-induced Type B CD. This project brings together three internationally recognized PIs with complementary expertise in CD, mucosal immunology, virology, and systems biology. Knowledge gained through these efforts will enhance an understanding of how viral infections lead to development of complex disorders. Furthermore, by dissecting pathways involved in CD pathology triggered by different stimuli, we will personalize CD and promote prevention and treatment based on specific CD mechanisms.