REGULATION OF PERSISTENT AB RESPONSE BY FC RECEPTORS

抗原特异性抗体的长期存留和抗体的产生 高亲和力记忆B细胞是体液的公认特征 免疫反应。最近的发现支持了这样一个概念，即 生发中心(GC)的特殊微环境是关键 途径，特别是滤泡树突状细胞(FDC)的能力 以免疫复合体的形式保留免疫原性抗原的网络 长周期，触发B细胞增殖，并选择细胞 亲和力增强的抗原受体。此模型的核心是 要求B细胞及其附属细胞识别免疫 并作出适当的反应。有两类受体参与其中 免疫复合体结合：Fc和补体受体家族。这些 两个受体系统在细胞分布和 信令容量。我们建议厘定功能界别的贡献 受体系统对GC反应的产生和维持。 初步研究表明，特定的Fc受体参与了 在免疫原性抗原的保留以及在调节 B细胞刺激。缺乏共同的伽马链的小鼠 刺激性Ig G FCRs(FcRI和III)具有早熟生发中心 免疫复合体的反应和结合增加。相比之下，老鼠 缺乏抑制受体FcRII的人无法调节反馈 调节并显著提高血清免疫球蛋白水平 对抗原刺激的反应。建议进行实验，以 确定：1)FDC绑定增加的机制和后果 免疫复合物在伽马链突变体上的持久性抗体 反应、亲和力成熟和记忆反应：2) FcRII对GC反应、免疫复合物在FDCs上的持久性和反馈的影响 抑制和3)B细胞FcRII的作用 巨噬细胞和FDC FcRII在介导反馈抑制和抑制中的表达 气相色谱反应。这些研究将提供一种分子描述 免疫复合体及其受体在调节合成中的作用 体内抗体的数量。这些通路的扰动可能解释了一些 自身免疫性疾病的病理表现和缺乏 在免疫反应的衰老过程中所见的免疫应答 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.