Th17-IgA Axis in Regulation of Intestinal Inflammation

 描述（由申请人提供）：肠粘膜表面受到分泌型伊加（SIgA）介导的一线防御的保护。伊加在肠道内稳态中起关键作用，这是由以下观察结果强烈表明的：在患有重度伊加缺乏症（SlgAD）或常见变异性免疫缺陷症（CVID）的患者中，受损的伊加产生触发包括胃肠道感染在内的持续症状。IgA缺乏的患者常出现肠道炎症和小肠结节性病变，这种现象归因于肠道细菌的异常扩张。多种信号，包括T细胞依赖性和非依赖性途径，调节伊加诱导。然而，人们对每一项的相对重要性以及如何对其进行监管仍然知之甚少。然而，更好地了解伊加反应是理解肠道免疫稳态和炎症性肠病（IBD）发病机制的关键。产生IL-17（IL-17 A）、IL-17 F、IL-21和IL-22的Th 17细胞最近已被证明除了其促炎功能之外，在维持免疫稳态中也是重要的。虽然大量的伊加和Th 17细胞都组成性地存在于肠道中，但很少有数据说明这些系统中的每一个如何响应微生物群的抗原，或者这两个系统是否在调节宿主对微生物群的响应和IBD的发病机制方面相互作用。本课题主要研究Th 17细胞如何促进肠道伊加的产生，以及Th 17细胞是否调节记忆伊加+ B细胞的分化和维持。最后，我们将测试我们的假设，即在肠道伊加的背景下，Th 17细胞调节肠道细菌定植和易位，从而有助于肠道内稳态，并保护肠道免受微生物群的炎症反应。在肠道伊加应答受损的条件下，失调的Th 17细胞是促炎性的，并且能够诱导结肠炎。完成后，拟议的研究将通过诱导肠道伊加反应来调节肠道免疫稳态和保护肠道免受微生物群炎症的影响，以及炎症性肠病的发病机制，建立Th 17细胞的新途径。

 DESCRIPTION (provided by applicant): Intestinal mucosal surfaces are protected by a first-line defense mediated by secretory IgA (SIgA). That IgA plays a key role in gut homeostasis is strongly suggested by the observations that in patients with severe IgA deficiency (SlgAD) or common variable immunodeficiency (CVID), impaired IgA production triggers persistent symptoms including gastrointestinal infections. Development of intestinal inflammation and small intestinal nodular lesions is often seen in IgA-deficient patients, a phenomenon attributed to aberrant expansion of commensal bacteria. Multiple signals, including T cell-dependent and -independent pathways, regulate IgA induction. However, the relative importance of each and how they are regulated remain poorly understood. Yet, a better understanding of the IgA response is key to understanding intestinal immune homeostasis and the pathogenesis of inflammatory bowel disease (IBD). Th17 cells, which produce IL-17 (IL-17A), IL-17F, IL-21 and IL-22, have recently been shown to be important in the maintenance of immune homeostasis, in addition to their pro-inflammatory function. Although high amounts of IgA and Th17 cells are both present constitutively in the intestine, there are sparse data that address how each of these systems respond to antigens of the microbiota, or whether these two systems interact in that effort, in regulation of host response to microbiota and the pathogenesis of IBD. In this project, we will investigate how Th17 cells promote intestinal IgA production, and whether Th17 cells regulate the differentiation and maintenance of memory IgA+ B cells. Finally, we will test our hypothesis that in context with intestinal IgA, Th17 cells regulate commensal bacteria colonization and translocation and thus contribute to intestinal homeostasis and protect the intestine from inflammation in response to microbiota. Under the conditions of an impaired intestinal IgA response, disregulated Th17 cells are proinflammatory and able to induce colitis. Upon completion, the proposed studies will establish a novel pathway of Th17 cells through induction of an intestinal IgA response in the regulation of intestinal immune homeostasis and protection of the intestines from inflammation in response to microbiota, as well as the pathogenesis of inflammatory bowel diseases.