Intestinal Immune Regulation by IgG and FcRn

项目总结/摘要 新生儿可结晶片段（Fc）受体（FcRn）在造血干细胞中广泛表达。 细胞在抗原呈递细胞（APC）中，FcRn的功能是保护单体IgG免于降解和再活化。 对作为免疫复合物（IC）的IgG的晚期先天性和适应性免疫应答。目前的研究建议 解决了FcRn在IgG IC背景下如何作为信号传导受体发挥作用的未回答问题， 与Fc γ受体（Fc γ R）合作。我们的长期目标是确定FcRn 从内体平台介导细胞内信号传导，揭示这些活动如何与 通过关注Fc γ R的遗传相关亚型Fc γ R2 a（CD 32A），研究与Fc γ R的相互作用， 表明FcRn与CD 32A的相互作用在基因型上是不同的，具有重要的功能意义 通过在炎症性肠病（IBD）的人源化动物模型中的研究。本研究的目的是 确定FcRn如何影响IgG IC应答的结果以及与肠道炎症的关联。 我们的中心假设是Fc γ R和FcRn功能作为近端和远端协调子整合，重新整合。 对IgG IC的先天性和适应性反应的研究。在这种关系中，FcRn起信号传导作用， 受体，并作为主要的下游介质和近端Fc受体功能的核心调节剂。 从我们的证明中得出，FcRn决定DC产生的白细胞介素-12水平， 与MHC I类相关的交叉呈递给CD 8 + T细胞相关的抗原加工和呈递 和MHC II类相关呈递给CD 4 + T细胞，以响应IgG IC，其严重影响μ- 结肠内环境稳定，肠道炎症反应的细菌抗原和免疫监视， 结肠直肠癌我们的中心假设将通过三个具体目标进行测试：1）定义信号路径- 与APC中FcRn依赖性与IgG IC相互作用相关的方式; 2）证明功能性相互作用， 先天性和适应性免疫中Fc β R和FcRn之间的依赖性，以及; 3）确定FcRn是否控制 体内IgG驱动炎症的Fc γ R多态性反应。在目标1中，我们将使用来自保护区的信息， 对携带FcRn的细胞内核内体进行组学评估，以确定 FcRn在APC中的影响及其与先天性和适应性免疫应答的特定关系。在目标2中， 我们将证明，FcRn调节CD 32A，这是人类独有的，与IBD相关， 这种相互作用的机制。在目标3中，我们将确定FcRn是否控制先天性和适应性 与不同CD 32A基因型相关的体内炎症。总的来说，这项建议意义重大，因为它 将增加我们对APC内FcRn在协调粘膜免疫应答中的功能的理解， 它们是如何与Fc γ R合作的，并且这样做广泛地扩展了FcRn功能的含义。鉴于重新- 我们的研究结果表明，在治疗IgG介导的自身免疫性疾病方面， 对IBD的治疗和应用具有重要意义。

PROJECT SUMMARY/ABSTRACT The neonatal crystallizable fragment (Fc) receptor (FcRn) is widely expressed throughout life in hematopoietic cells. In antigen presenting cells (APC), FcRn functions to protect monomeric IgG from degradation and regu- late innate and adaptive immune responses to IgG as an immune complex (IC). The current research proposal addresses the unanswered question of how FcRn functions as a signaling receptor in the context of IgG IC and in cooperation with Fc receptors (FcR). Our long-term goals are to identify the mechanisms by which FcRn mediates intracellular signaling from an endosomal platform, reveal how these activities overlap with and in- volve interactions with FcR through a focus on a genetically relevant isoform of FcR, FcR2a (CD32A), and demonstrate that FcRn interactions with CD32A are genotypically distinct with important functional implications by studies in humanized animal models of inflammatory bowel disease (IBD). The objective of this research is to determine how FcRn affects the outcome of IgG IC responses and association with intestinal inflammation. Our central hypothesis is that FcR and FcRn functions are integrated as proximal and distal coordinators, re- spectively, of innate and adaptive responses to IgG IC. In this relationship, FcRn functions as a signaling re- ceptor and acts as a major downstream mediator and core regulator of proximal FcR function.The rationale is derived from our demonstration that FcRn determines the levels of interleukin-12 produced by DC and the an- tigen processing and presentation associated with MHC class I-associated cross-presentation to CD8+ T cells and MHC class II-associated presentation to CD4+ T cells in response to IgG IC which critically influences mu- cosal homeostasis, intestinal inflammation in response to bacterial antigens and immune-surveillance against colorectal cancer. Our central hypothesis will be tested with three specific aims: 1) Define the signaling path- ways associated with FcRn-dependent interactions with IgG IC in APC; 2) Demonstrate the functional interde- pendence between FcR and FcRn in innate and adaptive immunity, and; 3) Determine whether FcRn controls FcR polymorphic responses to IgG-driven inflammation in vivo. In Aim 1, we will use information from a prote- omic assessment of FcRn-bearing intracellular endosomes to determine the specific signaling pathways that FcRn influences in APC and their specific relationships with innate and adaptive immune responses. In Aim 2, we will demonstrate that FcRn regulates CD32A which is unique to humans and associated with IBD, and de- fine the mechanism of this interaction. In Aim 3, we will determine whether FcRn controls innate and adaptive inflammation in vivo associated with different CD32A genotypes. Overall, this proposal is significant because it will increase our understanding of FcRn function within APC in coordinating mucosal immune responses and how they cooperate with FcR and in so doing broadly extend the implications of FcRn function. In light of re- cent efforts to inhibit FcRn-IgG interactions for the treatment of IgG-mediated autoimmune diseases our results will have important implications for the therapy of IBD and their application.