Decay Accelerating Factor and B cell Immunity

衰变加速因子和 B 细胞免疫

• 批准号: 10406250
• 负责人: David Dominguez-Sola
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406250
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affinity; Alternative Complement Pathway; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antibody titer measurement; Antigens; Autoimmune; Autoimmunity; B Cell Proliferation; B-Cell Activation; B-Lymphocytes; BCL6 gene; Biological; Biology; C3AR1 gene; C5a anaphylatoxin receptor; CD55 Antigens; Cell Survival; Cell surface; Cellular biology; Chromosome 1; Complement; Complement 3 Convertase; Complement 3a; Complement 3d Receptors; Complement 5a; Complement Activation; Data; Development; Disease; Down-Regulation; Enhancers; Event; Follicular Dendritic Cells; Future; Generations; Genes; Genetic Transcription; Humoral Immunities; Immune response; Immunity; Immunization; Immunoglobulin Somatic Hypermutation; Impairment; Infection; Lifting; Ligation; Light; Link; Mediating; Mediator of activation protein; Memory B-Lymphocyte; Modeling; Molecular; Mus; Outcome; Output; Pathogenicity; Physiological; Plasma Cells; Process; Production; Reaction; Reagent; Receptor Signaling; Regulation; Repression; Research; Role; Signal Pathway; Signal Transduction; Solid; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Transgenic Organisms; Transplantation; Vaccines; chronic graft versus host disease; complement C3d,g; complement pathway; gene repression; genetic regulatory protein; in vivo; insight; lymphoid structures; member; novel; organ transplant rejection; overexpression; pathogen; prevent; programs; promoter; receptor; response; restraint; vaccine strategy

Project Summary Humoral immunity crucially protects against pathogens but can function as a pathogenic mediator of multiple autoimmune and alloimmune disease processes, the latter including chronic graft vs. host disease and antibody-mediated solid organ transplant rejection. Development of antigen-specific antibody responses requires T cell-dependent B cell activation and the formation of germinal centers (GC), transient lymphoid structures where somatic hypermutation and affinity maturation events result in the generation of high affinity, antibody-producing plasma cells (PC) and memory B cells (Bmem). The physiological signals that control GC formation and GC B cell fates are incompletely characterized. Our preliminary data identify a previously unappreciated role for decay accelerating factor (DAF or CD55), a cell surface-expressed complement regulatory protein, in controlling GC reactions and their resultant output, the production of PC and Bmem. Our data support the hypothesis that optimal GC function requires downregulation of cell surface expressed DAF on responding B cells, a process that lifts restraint on local, alternative pathway complement activation and facilitates C3- and C5-convertase formation and production of C3 and C5 cleavage products. This process promotes C3a/C3aR1 and C5a/C5aR1 ligations on GC B cells, which would in turn transduce signals controlling GC B cell proliferation, survival, somatic hypermutation, and/or affinity maturation, and as a consequence, influence differentiation into memory B cells and/or plasma cells. We will test this paradigm- shifting hypothesis using unique biological reagents and through 3 interactive aims: 1) To determine the effects of B cell-expressed DAF, C3aR1 and C5aR1 on T cell-dependent humoral immune responses and distinguish them from the effects of B cell-expressed CD21. 2) To determine the cellular and molecular mechanisms through which DAF downregulation and enhanced signaling through C3aR1/C5aR1 in B cells drive affinity maturation. 3) To determine the molecular basis of DAF downregulation on B cells. This comprehensive analysis performed by a multi-PI team with expertise in complement biology (Heeger) and B cell biology (Dominguez-Sola) is likely to provide new insight into fundamental mechanisms of GC dynamics and function. The results have the potential to guide second order studies aimed at exploiting the complement/B cell axis to either inhibit development of pathogenic B cell responses (e.g. in transplantation or autoimmunity) or augment B cell response (e.g. in response to vaccines).

项目总结