Decay Accelerating Factor and B cell Immunity

项目摘要 体液免疫至关重要地保护免受病原体，但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， 抗体介导的实体器官移植排斥反应。抗原特异性抗体应答的产生 需要T细胞依赖性B细胞活化和生发中心（GC）、瞬时淋巴细胞 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（B细胞）。控制GC的生理信号 形成和GC B细胞命运的特征不完全。我们的初步数据显示， 衰变加速因子（CD 55），一种细胞表面表达的补体， 调节蛋白，在控制GC反应和其最终输出，PC和甜菜碱的生产。我们 数据支持最佳的GC功能需要下调细胞表面表达的GC的假设。 在应答B细胞上，这是一个解除对局部替代途径补体激活的抑制的过程， 促进C3-和C5-转化酶的形成和C3和C5裂解产物的产生。这个过程 促进GC B细胞上的C3 a/C3 aR 1和C5 a/C5 aR 1连接，这反过来会抑制信号传导 控制GC B细胞增殖、存活、体细胞超突变和/或亲和力成熟，以及作为 从而影响分化成记忆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和通过3个互动的目标来改变假设：1）确定影响 B细胞表达的C3 aR 1和C5 aR 1对T细胞依赖性体液免疫应答的影响， 它们来自B细胞表达的CD 21的作用。2)以确定细胞和分子机制 通过该途径，在B细胞中通过C3 aR 1/C5 aR 1的mRNA下调和增强的信号传导驱动亲和力 成熟3)目的：探讨β-CD抑制B细胞增殖的分子基础。这一全面 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细胞应答的发展（例如在移植或自身免疫中）或增强 B细胞应答（例如对疫苗的应答）。

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).