REGULATION OF PERSISTENT AB RESPONSE BY FC RECEPTORS

抗原特异性抗体的长期存在和 高亲和力记忆B细胞是体液免疫的公认特征， 免疫反应 最近的研究结果支持了这样一个概念， 生殖中心（GC）的特殊微环境是这些的关键。 途径，特别是滤泡树突细胞（FDC）的能力， 网络以保持免疫复合物形式的免疫原性抗原， 长时间，触发B细胞增殖并选择具有 亲和力增加的抗原受体。该模型的核心是 需要B细胞及其辅助细胞识别免疫 复杂，并作出适当的反应。两类受体参与 免疫复合物结合：Fc和补体受体家族。这些 两种受体系统在细胞分布方面不同， 信号能力。我们建议厘定财务委员会的供款 受体系统对GC反应的产生和维持起重要作用。 初步研究表明，特异性Fc受体参与 在免疫原性抗原的保留中，以及在调节 B细胞刺激。缺乏共同γ链的小鼠 具有早熟生发中心刺激性IgG FcR（FcRI和III） 反应和增加的免疫复合物的结合。 相比之下， 缺乏FcRII（一种抑制性受体）的人不能介导反馈 调节并具有显著升高的血清免疫球蛋白水平 对抗原刺激作出反应。实验被提议为 确定：1）FDC结合增加的机制和后果 免疫复合物在γ链突变体上的持久性抗体 反应、亲和力成熟和回忆反应：2） FcRII对GC反应、FDC上的免疫复合物持久性和反馈的影响 抑制和3）与对照相比，B细胞FcRII的贡献 巨噬细胞和FDC FcRII表达介导反馈抑制， GC反应这些研究将提供一个分子描述的 免疫复合物及其受体在调节合成 抗体在体内。这些途径的干扰可能会导致一些 自身免疫性疾病的病理表现和缺乏 免疫应答在免疫应答的衰老过程中观察到， 衰老

Long-term persistence of antigen-specific antibody and the generation of high affinity memory B cells are well-recognized features of the humoral immune response. Recent findings have supported the concept that the specialized microenvironment of the germinal center (GC) is key to these pathways, in particular the ability of the follicular dendritic cell (FDC) network to retain immunogenic antigen in the form of immune complexes for long periods, triggering B cells to proliferate and selecting cells with antigen receptors of increasing affinities. Central to this model is the requirement that B cells and their accessory cells recognize immune complexes and respond appropriately. Two receptor classes are involved in immune complex binding: the Fc and the complement receptor families. These two receptor systems differ in respect to cellular distribution and signalling capacity. We propose to determine the contributions of the Fc receptor system to the generation and maintenance of the GC reaction. Preliminary studies have indicated that specific Fc receptors are involved in the retention of immunogenic antigen, as well as in the regulation of B cell stimulation. Mice deficient in the common gamma chain of the stimulatory IgG FcRs (FcRI and III) have precocious germinal center reactions and increased binding of immune complexes. In contrast, mice deficient in FcRII, an inhibitory receptor, are unable to mediate feedback regulation and have significantly elevated levels of serum immunoglobulin in response to antigenic stimulation. Experiments are proposed to determine: 1) the mechanism and consequences of increased FDC binding of immune complexes in gamma chain mutants on the persistent antibody response, affinity maturation and anamnestic responses: 2) the role of FcRII on the GC reaction, immune complex persistence on FDCs, and feedback inhibition and 3) the contribution of B cell FcRII as compared to macrophage and FDC FcRII expression in mediating feedback inhibition and GC reactions. These studies will provide a molecular description of the role of immune complexes and their receptors in regulating the synthesis of antibody in vivo. Perturbations of these pathways may account for some of the pathological manifestations of autoimmune disease and the lack of immune responsiveness seen in the senescence of the immune response during aging.