Intestinal Immune Regulation by IgG and FcRn

IgG 和 FcRn 的肠道免疫调节

• 批准号: 9750054
• 负责人: Richard S Blumberg
• 金额: $ 68.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750054
• 关键词: Address; Affect; Albumins; Animal Model; Antigen Presentation Pathway; Antigen-Antibody Complex; Antigen-Presenting Cells; Autoimmune Diseases; B-Lymphocytes; Bacterial Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Calcium; Calmodulin; Catabolism; Cell physiology; Cells; Colorectal Cancer; Cross Presentation; Cytoskeleton; Dendritic Cells; Disease; Distal; Endosomes; Endothelium; Epithelium; Exhibits; Family; Fc Immunoglobulins; Fc Receptor; Genetic Polymorphism; Genotype; Goals; Half-Life; Hematopoietic; Histocompatibility Antigens Class II; Homeostasis; Human; IgG Receptors; Immune; Immune response; Immune signaling; Immune system; Immunoglobulin G; Immunologic Surveillance; Immunologics; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-12; Intestines; Life; Light; Liver; MAP Kinase Gene; Major Histocompatibility Complex; Mediating; Mediator of activation protein; Mission; Mucosal Immune Responses; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Immunity; Neonatal; Neoplasms; Outcome; Pathogenicity; Property; Protein Isoforms; Proteomics; Public Health; Receptor Signaling; Regulation; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Variant; adaptive immune response; adaptive immunity; base; genetic risk factor; genetic variant; humanized mouse; immune function; immunoregulation; in vivo; insight; macrophage; monocyte; mouse model; mucosal site; novel therapeutic intervention; protein transport; receptor; receptor binding; receptor function; response

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.

项目摘要/摘要 新生儿可结晶片段(Fc)受体(FcRN)在整个生命周期中广泛表达于造血系统 细胞。在抗原提呈细胞(APC)中，FcRN起保护单体免疫球蛋白不被降解和调节的作用。 免疫复合物(IC)对免疫球蛋白的晚期先天和获得性免疫反应。目前的研究提案 解决了FcRN如何在免疫球蛋白IC和FcRN中作为信号受体的悬而未决的问题 与Fc受体(FcR)合作。我们的长期目标是确定FcRN通过什么机制 介导来自内体平台的细胞内信号，揭示这些活动如何与- 通过关注FcR、FcR2a(CD32A)的遗传相关亚型与FcR的相互作用，以及 证明FcRN与CD32A的相互作用在基因上是不同的，具有重要的功能意义 通过对炎症性肠病(IBD)人性化动物模型的研究。这项研究的目的是 目的：探讨FcRN对免疫球蛋白IC反应结果的影响及其与肠道炎症的关系。 我们的中心假设是FcR和FcRN功能作为近端和远端的协调者被整合在一起，Re- 特异性地，免疫球蛋白IC的先天反应和获得性反应。在这种关系中，FcRN起着信令环的作用 受体，是近端FcR功能的主要下游介体和核心调节因子。其基本原理是 我们的论证表明，FcRN决定DC和AN产生的IL-12水平。 与MHC-I类相关的CD8+T细胞交叉递呈相关的TIGN加工和递呈 MHC-II类分子通过免疫球蛋白IC向CD4+T细胞递呈，从而对MHC-II类分子产生重要影响。 机体内环境平衡、肠道对细菌抗原的反应及免疫监测 结直肠癌。我们的中心假设将通过三个具体目标进行验证：1)定义信号路径- APC中FcRN依赖的与Ig G IC相互作用的途径；2)证实了FcRN与Ig G IC的功能相互作用。 FcR和FcRN在先天免疫和获得性免疫中的关系；3)决定FcRN是否控制 FcR在体内对免疫球蛋白诱导的炎症的多态反应。在目标1中，我们将使用来自保护的信息- 对携带FcRN的细胞内内体进行组学评估以确定特定的信号通路 FcRN在APC中的影响及其与先天性和获得性免疫反应的特殊关系。在目标2中， 我们将展示FcRN调节人类独有的与IBD相关的CD32A，并去激活CD32A。 细化这种相互作用的机制。在目标3中，我们将确定FcRN控制是否是先天的和适应性的 体内炎症与不同的CD32A基因相关。总的来说，这项提议意义重大，因为它 将增加我们对FcRN在APC中协调粘膜免疫反应和 他们如何与FCR合作，并在这样做的过程中广泛地扩展FcRN功能的含义。根据重新- 抑制FcRN-Ig G相互作用治疗Ig G介导性自身免疫性疾病的研究结果 对IBD的治疗和应用具有重要意义。