Intestinal Immune Regulation by IgG and FcRn

描述（由申请人提供）：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的特异性双向转运体，新生儿IgG Fc受体（FcRn），赋予这种免疫球蛋白一种独特的功能，它能够检索IgG复合物的腔内抗原，并将这些抗原传递给局部树突状细胞（DC），后者反过来利用FcRn来启动有效的CD4+和CD8+ T细胞应答。目前的研究计划解决了抗原呈递细胞（APC）中的FcRn如何参与非转移性和致病性粘膜免疫反应这一悬而未决的问题。我们的长期目标是了解如何调节FcRn的这些作用可以应用于治疗肠道炎症，如在炎症性肠病（IBD）中发现的，以及增强对癌症的免疫监测。本研究的目的是阐明DC中的FcRn如何在分子和生理水平上建立稳态和病理性肠道T细胞反应。[我们的中心假设是，FcRn在DC下游的多聚体连接招募了一组特定的信号和效应蛋白，这些蛋白驱动抗原加工，促进Th1细胞因子的产生和细胞毒性，能够促进肠道炎症，但也能够对病毒感染和肿瘤诱导的细胞畸变进行免疫监视。]这一理论不仅源于越来越多的证据表明粘膜稳态缺陷（包括CD8+ T细胞反应和igg受体多态性）与IBD的发展有关，还源于针对抑制或利用IgG-FcRn相互作用的治疗方法的不断发展。我们的中心假设将通过三个特定目的进行验证：1)[确定抗原提呈细胞中FcRn的细胞内行程并阐明其与hFcgRIIa的功能关系；IBD风险基因]；2)确定FcRn在粘膜部位Th1/Th2稳态和T细胞记忆发展中的作用；3)确定FcRn在粘膜部位炎症和非炎症性瘤变发生中的作用。在Aim 1中，我们试图确定FcRn途径IgG IC的细胞内机制，[定义该途径如何与IBD的遗传危险因素hFcgRIIa相交，并确定hFcgRIIa诱导的炎症是否依赖于FcRn作为最终的共同途径]。在Aim 2中，我们将确定fcrn介导的DC内IgG IC通路如何导致肠道内Th1和Tc1效应物反应的建立。在Aim 3中，我们将证明由fcrn导向的IgG IC运输所激活的Th1和Tc1效应物反应可以防止粘膜部位的肿瘤发展。总的来说，这一建议具有重要意义，因为它将促进我们对FcRn的作用及其与DC中hFcgRIIa的关系的理解，以协调肠道稳态、炎症和癌症预防所需的粘膜免疫反应。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。

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.