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).

项目概要体液免疫对于抵御病原体至关重要，但也可以作为多种病原体的致病介质。自身免疫和同种免疫疾病过程，后者包括慢性移植物抗宿主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发展需要 T 细胞依赖性 B 细胞激活和生发中心 (GC)、瞬时淋巴样的形成体细胞超突变和亲和力成熟事件导致高亲和力产生的结构，产生抗体的浆细胞 (PC) 和记忆 B 细胞 (Bmem)。控制GC的生理信号 GC B 细胞的形成和命运尚未完全表征。我们的初步数据确定了先前衰变加速因子（DAF 或 CD55）（一种细胞表面表达的补体）的作用未被充分认识调节蛋白，控制 GC 反应及其结果输出、PC 和 Bmem 的产生。我们的数据支持这样的假设：最佳 GC 功能需要下调细胞表面表达的 DAF 对响应 B 细胞的影响，这是一个解除对局部替代途径补体激活的限制的过程，促进 C3 和 C5 转化酶的形成以及 C3 和 C5 裂解产物的产生。这个过程促进 GC B 细胞上的 C3a/C3aR1 和 C5a/C5aR1 连接，从而转导信号控制 GC B 细胞增殖、存活、体细胞超突变和/或亲和力成熟，并作为结果，影响分化为记忆 B 细胞和/或浆细胞。我们将测试这个范例 - 使用独特的生物试剂并通过 3 个交互目标改变假设：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反应的影响并区分它们免受 B 细胞表达的 CD21 的影响。 2) 确定细胞和分子机制 DAF 下调并通过 B 细胞中的 C3aR1/C5aR1 增强信号传导驱动亲和力成熟。 3)确定B细胞上DAF下调的分子基础。这个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 团队进行分析（Dominguez-Sola）可能会为 GC 动力学和功能的基本机制提供新的见解。该结果有可能指导旨在利用补体/B 细胞轴来抑制致病性 B 细胞反应的发展（例如移植或自身免疫）或增强 B 细胞反应（例如对疫苗的反应）。