FUNCTION OF CD19 IN B CELL DEVELOPMENT & DIFFERENTIATION

描述(改编自《调查者摘要》)：抗原 受体介导的信号是控制B淋巴细胞的关键决定因素 激活、分化或死亡。调制信号的分子 通过B细胞受体(BCR)可以帮助确定B细胞 细胞的命运。细胞内的中间体受到了极大的关注 在BCR的下游行动。这项提议涉及到生物作用。 在适当的情况下，B细胞的“共受体”CD19可以 增强BCR介导的B细胞活化和增殖。调查员 发现CD19基因缺陷的小鼠B细胞淋巴细胞生成受损， 在对T细胞依赖抗原的反应中，他建议确定 这些缺陷的分子基础在CD19与 BCR和CD19/CD21(补体受体2)/CD81复合体。在目标1中 CD19在早期B细胞发育中的作用将被研究，重点是 发育检查点受BCR前信号或BCR信号调节。这 涉及对CD19-/-和野生型小鼠的比较分析，这将是 利用前bcr突变小鼠和免疫球蛋白转基因小鼠进行提纯 培育到CD19零背景上。由于CD19-/-小鼠表现出严重的 B-1(以前的ly-1)B细胞的减少，在目标1b中，他们将确定 这种不足是否主要归因于发电效率低下， 扩大或维持这一重要的B细胞亚群。目标2 阐述CD19在外源基因识别和激活中的作用 抗原。将确定CD19是否起信号转导部分的作用 CD19/CD21/CD81复合体，已知与表面有协同作用 免疫球蛋白在共识别调理(含C3d)异体中的作用 抗原。免疫接种将伴随着流式细胞仪和 免疫组织化学技术检测B细胞分化、迁移 和生存。目标3将描述CD19作为成员的双重角色 CD19/CD21/CD81复合体，也是 BCR。这将通过CD19零突变的互补来实现 带有编码修饰的CD19分子的转基因 与BCR或CD19/CD21/CD81复合体结合。这种遗传方法将评估 CD19在这些关键信号功能中的相对作用 影响B细胞分化和抗体产生的复合体。

DESCRIPTION (Adapted from the Investigator's Abstract): Antigen receptor-mediated signaling is the key determinant governing B lymphocyte activation, differentiation or death. Molecules that modulate signals through the B cell receptor (BCR) can thus be instrumental in determining B cell fate. Much attention has been given to intracellular intermediates acting downstream of the BCR. This proposal addresses the biological role of the B cell "co-receptor" CD19 which, in the appropriate context, can augment BCR-mediated B cell activation and proliferation. The investigator has found that CD19--deficient mice are impaired in B cell lymphopoiesis and in responding to T cell-dependent antigens, and he proposes to determine the molecular basis for these defects in the context of CD19 association with the BCR and the CD19/CD21 (complement receptor 2)/CD81 complexes. In Aim 1 the role of CD19 in early B cell development will be examined, focusing on developmental checkpoints regulated by pre-BCR or BCR signaling. This involves a comparative analysis of CD19-/- and wildtype mice, which will be refined by the use of pre-BCR mutant mice and immunoglobulin transgenic mice bred onto the CD19 null background. As CD19-/- mice exhibit a severe reduction in B-1 (formerly ly-1) B cells, in Aim 1b they will determine whether this deficiency is mainly attributed to inefficient generation, expansion or maintenance of this important subpopulation of B cells. Aim 2 addresses the role of CD19 in the recognition of and activation by foreign antigen. It will be determined whether CD19 acts as the signaling moiety of the CD19/CD21/CD81 complex, which is known to synergize with surface immunoglobulin in the co-recognition of opsonized (C3d-bearing) foreign antigen. Immunizations will be accompanied by flow cytometric and immunohistochemical techniques to assess B cell differentiation, migration and survival. Aim 3 will delineate the dual roles of CD19 as both a member of the CD19/CD21/CD81 complex and also as an elementary component of the BCR. This will be accomplished by complementation of the CD19 null mutation with transgenes encoding modified CD19 molecules which associate exclusively with the BCR or CD19/CD21/CD81 complexes. This genetic approach will assess the relative contribution of CD19 to the function of these crucial signaling complexes in effecting B cell differentiation and antibody production.