Intestinal Immune Regulation by IgG and FcRn

IgG 和 FcRn 的肠道免疫调节

• 批准号: 9975815
• 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/9975815
• 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; Epithelial; 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; 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; inflammatory disease of the intestine; 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.

项目总结/文摘