Th17-IgA Axis in Regulation of Intestinal Inflammation

 描述(申请人提供)：肠粘膜表面由分泌型免疫球蛋白A(SIgA)介导的一线防御保护。在严重的IgA缺乏症(SLgAD)或常见的可变免疫缺陷(CVID)患者中，IgA的产生受损会引发包括胃肠道感染在内的持续性症状，这一观察结果强烈表明，IgA在肠道内稳态中发挥着关键作用。在IgA缺乏的患者中，常可见肠道炎症和小肠结节状病变，这一现象归因于共生菌的异常扩张。多种信号，包括T细胞依赖和非依赖途径，调节IgA的诱导。然而，人们对它们的相对重要性以及它们如何受到监管仍知之甚少。然而，更好地了解IgA反应是了解肠道免疫动态平衡和炎症性肠病(IBD)发病机制的关键。Th17细胞产生IL-17(IL-17A)、IL-17F、IL-21和IL-22，最近被证明除了具有促炎功能外，还在维持免疫稳态方面起着重要作用。虽然肠道中都存在大量的IgA和Th17细胞，但关于这两个系统如何响应微生物区系的抗原，或者这两个系统是否在这一努力中相互作用，调节宿主对微生物区系的反应和IBD的发病机制的数据很少。在这个项目中，我们将研究Th17细胞如何促进肠道IgA的产生，以及Th17细胞是否调节记忆性IgA+B细胞的分化和维持。最后，我们将验证我们的假设，即在肠道IgA的背景下，Th17细胞调节共生细菌的定植和易位，从而有助于肠道内稳态，并保护肠道免受微生物区系的炎症。在肠道IgA反应受损的情况下，失控的Th17细胞是促炎细胞，能够诱发结肠炎。完成后，拟议的研究将建立一条新的Th17细胞途径，通过诱导肠道IgA反应来调节肠道免疫平衡，保护肠道免受微生物区系的炎症反应，以及炎症性肠道疾病的发病机制。

 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.