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Decay Accelerating Factor and B cell Immunity

衰变加速因子和 B 细胞免疫

基本信息

批准号：
10623288
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
项目类别：
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/10623288
关键词：
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 Memory B-Lymphocyte Modeling Molecular Mus Outcome Output PIK3CG gene 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 transmission process vaccine strategy

项目摘要

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).

项目摘要体液免疫对病原体具有至关重要的保护作用，但也可以作为多发性硬化症的致病媒介。自身免疫和同种异体免疫疾病过程，后者包括慢性移植物抗宿主疾病和抗体介导的实体器官移植排斥反应。抗原特异性抗体反应的研究进展需要依赖T细胞的B细胞的激活和生发中心(GC)、暂时性淋巴的形成其中体细胞超突变和亲和力成熟事件导致产生高亲和力的结构，产生抗体的浆细胞(PC)和记忆B细胞(Bmem)。控制GC的生理信号其形成和GC B细胞的命运尚不完全清楚。我们的初步数据显示，之前衰变加速因子(DAF或CD55)是一种细胞表面表达的补体，其作用未被重视调节蛋白，控制GC反应及其产物PC和Bmem的产生。我们的数据支持这样的假设，即最佳的GC功能需要下调细胞表面表达的DAF 在反应性B细胞上，这一过程解除了对局部替代途径补体激活的限制，并促进C3-和C5-转换酶的形成和C3和C5裂解产物的产生。这一过程促进GC B细胞上C3a/C3aR1和C5a/C5aR1的连接，进而转导信号控制GC B细胞的增殖、存活、体细胞超突变和/或亲和力成熟，并作为一种结果，影响分化为记忆B细胞和/或浆细胞。我们将测试这一范例- 使用独特的生物试剂并通过3个交互目的改变假说：1)确定效果 B细胞表达的DAF、C3aR1和C5aR1对T细胞依赖性体液免疫应答的影响及区别它们来自于B细胞表达CD21的效应。2)确定细胞和分子机制 B细胞中DAF下调和通过C3aR1/C5aR1增强信号驱动亲和力成熟。3)探讨DAF下调B细胞功能的分子基础。这一全面的由具有补体生物学(Heeger)和B细胞生物学专业知识的多PI团队执行的分析 (Dominguez-Sola)可能为GC动力学和功能的基本机制提供新的见解。这些结果有可能指导旨在利用补体/B细胞轴的二级研究抑制致病性B细胞反应的发展(例如，在移植或自身免疫中)或增强 B细胞反应(如对疫苗的反应)。