Innate and adaptive immunity in celiac disease

描述(申请人提供)：乳糜泻是一种复杂的肠道炎症性疾病，由饮食面筋引起的绒毛萎缩，在人类白细胞抗原DQ2或人类白细胞抗原DQ8个体。这种疾病只是冰山一角，包括更多的亚临床人群，他们对面筋的反应存在不同方面的失调。与面筋摄取相关的免疫学异常包括(1)上皮和固有层中IL-15的慢性上调，(2)自然杀伤样上皮内细胞毒性淋巴细胞(IE-CTL)的大量扩张，(3)DQ2或DQ8限制性的抗面筋CD4T细胞分泌IFNG？在固有层中；(4)抗面筋蛋白的标志性抗体和结合和破坏面筋蛋白的组织转谷氨酰胺酶(TTG)。绒毛萎缩可能依赖于抗面筋IFNG？+CD4T细胞反应、IE-CTL的扩张和IL-15的过度表达，但这些效应机制之间的确切联系尚不清楚。这项建议的主要目的将是利用已建立的转基因系统在体内模拟和研究慢性IL-15表达的后果，并在肠道上皮(Villin启动子，V-IL15tg)和固有层DC上皮外(最小MHC I类DD启动子，DD-IL15tg)中解剖表达IL-15的水平。这些结论随后将与这些免疫异常自然分离的乳糜泻患者的亲属队列进行测试。最终目标是结合DQ8和IL-15来模拟乳糜泻的组织病理学阶段。具体目标1，将分析IL-15在打破口服面筋耐受性中的影响；特定目标2，将分析IL-15在上皮内淋巴细胞获得自然杀伤表型和绒毛萎缩发展中的作用；以及特定目标3，将在人类研究中分析IL-15、抗面筋适应性免疫和上皮内淋巴细胞自然杀伤转化之间的联系。总而言之，这些研究不仅将为乳糜泻的发病机制和IL-15表达失调的主要影响提供新的见解，而且重要的是，还将指导和完善新一代动物模型。由于严格的终身无麸质饮食对患者施加了巨大的限制，这种模型早就应该测试替代疗法，这些疗法将在不久的将来开发。 与公共卫生相关：乳糜泻是一种发病率较高的肠道炎症性肠道疾病(&gt；1%)，由膳食面筋引起。了解免疫系统的不同组成部分是如何导致疾病的，并建立一种乳糜泻的小鼠模型，将对我们对该疾病的理解，以及对乳糜泻患者的治疗和后续治疗产生重大影响。

DESCRIPTION (provided by applicant): Celiac disease is a complex intestinal inflammatory disorder with villous atrophy induced by dietary gluten in HLA-DQ2 or HLA-DQ8 individuals. The disease is the 'tip of an iceberg' including a larger subclinical population with various aspects of dysregulation in response to gluten. Immunological abnormalities associated with gluten uptake include (1) chronic upregulation of IL-15 in the epithelium and lamina propria, (2) massive expansion of natural killer-like intraepithelial cytotoxic lymphocytes (IE-CTL), (3) DQ2 or DQ8-restricted anti- gluten CD4 T cells secreting IFNg? in the lamina propria and (4) signature antibodies against gluten and the tissue transglutaminase (TTG) that binds and deamidates gluten. Villous atrophy may depend on the anti- gluten IFNg?+ CD4 T cell response, the expansion of IE-CTL and the overexpression of IL-15, but the precise links between these effector mechanisms remain unclear. The overarching aim of this proposal will be to model and investigate in vivo the consequences of chronic IL-15 expression using established transgenic systems expressing IL-15 at levels comparable to those observed in disease, and dissecting expression in the intestinal epithelium (villin promoter, V-IL15tg) and outside the epithelium in the lamina propria DC (minimal MHC class I Dd promoter, Dd-IL15tg). The conclusions will then be tested against a cohort of relatives of celiac patients where these immunological abnormalities naturally segregate. The ultimate goal is to combine DQ8 and IL-15 to model the histopathological stages of celiac disease. Specific aim 1, will analyze the impact of IL-15 on the breakdown of oral tolerance to ingested gluten; Specific Aim 2 will analyze the role of IL-15 in the acquisition of a natural killer phenotype by intraepithelial lymphocytes and the development of villous atrophy; and Specific Aim 3, will analyze in human studies the link between IL-15, anti-gluten adaptive immunity and natural killer transformation of intraepithelial lymphocytes. Collectively, these studies will not only provide new insights into the pathogenesis of celiac disease and the major impact of dysregulated IL-15 expression but also, importantly, will guide and refine new generation animal models. Because a strict lifelong gluten-free diet imposes tremendous constraints on patients, such models are long overdue to test alternative therapies that will be developed in the near future. PUBLIC HEALTH RELEVANCE: Celiac Disease is an intestinal inflammatory intestinal disorder with a high prevalence (>1%), that is induced by dietary gluten. Understanding how different components of the immune system contribute to disease and developing a mouse model of celiac disease will have a major impact on our understanding of the disease, and the treatment and follow-up of celiac disease patients.