Intestinal Immune Regulation by IgG and FcRn

描述（由申请方提供）：粘膜免疫系统对于建立健康的局部和全身免疫至关重要。IgG的特异性双向转运蛋白，即IgG的新生儿Fc受体（FcRn），通过其回收IgG复合物管腔抗原并将其递送至局部树突状细胞（DC）的能力赋予该免疫球蛋白独特的功能，而局部树突状细胞（DC）又利用FcRn引发有效的CD 4+和CD 8 + T细胞应答。目前的研究计划解决了FcRn [在抗原呈递细胞（APC）中]如何促进稳态和致病性粘膜免疫应答的未回答问题。我们的长期目标是了解如何调节FcRn的这些作用可用于治疗肠道炎症，如炎症性肠病（IBD）中所发现的，以及增强对癌症的免疫监视。本研究的目的是阐明在分子和生理水平上，DC内的FcRn如何发挥作用以建立稳态和病理性肠道T细胞应答。[Our中心假设是FcRn在FcgR下游的DC内的多聚体连接募集了一组特定的信号传导和效应蛋白，其驱动抗原加工并促进Th 1细胞因子产生和细胞毒性，能够促进肠道炎症，但也能够实现针对由病毒感染和瘤形成诱导的细胞畸变的免疫监视。这一基本原理不仅来源于越来越多的证据将粘膜稳态缺陷（包括CD 8 + T细胞应答和IgG受体多态性）与IBD的发生联系起来，还来源于靶向抑制或利用IgG-FcRn相互作用的治疗方法的不断发展。我们的中心假设将以三个特定目标进行检验：1）[确定FcRn在抗原呈递细胞中的细胞内行程并阐明其与hFcgRIIa（IBD风险基因）的功能关系]; 2）确定FcRn在粘膜部位的Th 1/Th 2稳态和T细胞记忆的发展中的作用; 3）确定FcRn在粘膜部位的炎症和非炎症诱导的瘤形成的发展中的作用。在目标1中，我们试图定义FcRn路由IgG IC的细胞内机制，[定义该途径如何与hFcgRIIa（IBD的遗传风险因子）交叉，并确定hFcgRIIa诱导的炎症是否依赖于FcRn作为最终共同途径]。在目的2中，我们将确定DC内的IgG IC的FcRn介导的路由如何导致肠道内Th 1和Tc 1效应子应答的建立。在目标3中，我们将证明，Th 1和Tc 1效应子响应，使FcRn导向的IgG IC运输导致保护粘膜部位的肿瘤发展。总的来说，这一提议是重要的，因为它将促进我们理解FcRn的作用及其与DC内hFcgRIIa在协调肠道稳态、炎症和癌症预防所需的粘膜免疫应答中的关系。除了确定治疗IBD和许多其他炎症性疾病的新治疗靶点外，这项研究还将为扩大FcRn靶向治疗的机会提供坚实的基础。 公共卫生相关性：拟议的研究与公共卫生有关，因为了解FcRn如何协调粘膜部位的抗原呈递，进而调节免疫系统先天和适应性分支的激活，将为维持粘膜稳态或驱动主动炎症反应和肿瘤形成的机制提供新的见解。拟议的研究与NIDDK的使命相关，因为它们有望确定新的治疗策略，用于抑制与炎症性肠病相关的炎症或增强癌症和感染治疗中的免疫力。

DESCRIPTION (provided by applicant): The mucosal immune system is critical for establishing healthy local and systemic immunity. The specific bidirectional transporter for IgG, the neonatal Fc receptor for IgG (FcRn), confers a unique function to this immunoglobulin by its ability to retrieve IgG-complex luminal antigens and deliver these to local dendritic cells (DC) which, in turn, utilize FcRn to prime effective CD4+ and CD8+ T cell responses. The current research proposal addresses the unanswered question of how FcRn [in antigen presenting cells (APC)] contributes to ho- meostatic and pathogenic mucosal immune responses. Our long-term goal is to understand how modulating these actions of FcRn can be applied to treat intestinal inflammation, as is found in inflammatory bowel disease (IBD), as well as enhancing immune surveillance to cancer. The objective of this research is to elucidate how, at both the molecular and physiological levels, FcRn within DC acts to establish homeostatic and pathological gut T cell responses. [Our central hypothesis is that multimeric ligation of FcRn within DC downstream of FcgR recruits a specific cohort of signaling and effectors proteins which drive antigen processing and promote Th1 cytokine production and cytotoxicity, capable of promoting intestinal inflammation but also of enabling immune- surveillance against cellular aberrations induced by viral infection and neoplasia.] This rationale is derived not only from the increasing evidence linking defects in mucosal homeostasis, including CD8+ T cell responses and IgG-receptor polymorphisms, to the development of IBD but also from the increasing development of therapeutics targeted at inhibition or exploitation of the IgG-FcRn interaction. Our central hypothesis will be tested with three specific aims: 1) [Determine the intracellular itinerary of FcRn in antigen presenting cells and elucidate its functional relationship with hFcgRIIa; an IBD risk gene]; 2) Determine the role of FcRn in the development of Th1/Th2 homeostasis and T cell memory at mucosal sites; 3) Determine the role of FcRn in the development of inflammation and non-inflammation induced neoplasia at mucosal sites. In Aim 1, we seek to define the intracellular mechanisms by which FcRn routes IgG IC,[define how this pathway intersects with hFcgRIIa, a genetic risk factor for IBD, and determine whether hFcgRIIa-induced inflammation is dependent upon FcRn as a final common pathway]. In Aim 2, we will determine how FcRn-mediated routing of IgG IC within DC leads to the establishment of Th1 and Tc1 effectors responses within the gut. In Aim 3, we will demonstrate that the Th1 and Tc1 effectors responses enabled by FcRn-directed IgG IC trafficking leads to protection against neoplastic development at mucosal sites. Overall, this proposal is significant because it will promote our understanding of the role of FcRn and its relationship with hFcgRIIa within DC in coordinating mucosal immune responses required for intestinal homeostasis, inflammation and cancer prevention. In addition to identifying new therapeutic targets for the treatment of IBD and a host of other inflammatory diseases, this research will provide a firm basis upon which to extend the opportunities for FcRn-targeted therapies. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because understanding how FcRn coordinates antigen presentation at mucosal sites, which in turn regulates activation of the innate and adaptive branches of the immune system, will provide new insights into the mechanisms that either maintain mucosal homeostasis or drive active inflammatory responses and neoplasia. The proposed studies are relevant to the mission of the NIDDK because they are expected to identify new therapeutic strategies for inhibiting inflammation associated with inflammatory bowel disease or enhancing immunity in the treatment of cancers and infections.