Cellular & Molecular Defects in Human B Cell Development

几十年来，很明显，对明确定义的人类遗传病的研究，是阐明正常生理事件的有力工具。这在原发免疫缺陷性疾病中最为明显。对特定免疫缺陷状态的表征导致了免疫学的显著进步，促进了对这些疾病的更多了解，并引发了新的 诊断技术和有针对性的治疗。对人类原代B细胞缺陷的研究使人们对B细胞发育的特定阶段有了更深入的了解。对B细胞谱系的承诺在淋巴发生的早期就发生了，在免疫球蛋白重链基因中有选择的基因重排；这些重排启动了抗原识别的过程，这是适应性免疫的标志。B细胞的进一步成熟的特征是 扩增，分化，运输到周围淋巴结的特定隔室，选择合适的抗原受体，产生B细胞记忆，最后是粘膜部位的种群。 伴随着B细胞群体的扩张，需要删除自我反应性克隆。所有这些事件都是相互交织在一起的，但这些相互作用的性质还没有完全被理解。该计划项目赠款的总体假设是，选定的遗传、细胞和微环境影响对正常的B细胞发育至关重要，这些过程中的任何一个过程中的缺陷都可能导致免疫缺陷。这个项目选择了B细胞免疫的四个特定阶段进行研究， 项目1：V(D)J介导的免疫缺陷的机制；项目2：研究B细胞记忆的阻断；项目：肠粘膜中IgA产生的调节和功能；项目4：原发免疫缺陷中B细胞耐受性的丧失。正常保护性免疫的发展对于理解疫苗接种、疾病预防、移植和自身免疫是必不可少的；然而，这些免疫反应是如何发展和控制的，需要进一步阐明。在西奈山，我们的初级免疫缺陷计划中有一个独特而宝贵的资源；这允许 仔细研究人类B细胞生物学的选定阶段，这是本计划项目拨款的主题。

It has been apparent for decades that the study of well defined human genetic disease, is a powerful tool in the elucidation of normal physiologic events. This Is most evident in the case of the primary immune deficiency diseases. Characterization of specific immune deficiency states has led to remarkable advances in immunology, catalyzing greater understanding of these diseases, and sparking the development of novel diagnostic techniques and targeted treatments. Studies of primary human B cell defects have led to an appreciation of specific stages of B cell development. Commitment to the B cell lineage occurs early In lymphogenesls with selected gene rearrangements in Ig heavy chain genes; these initiate the process of antigen recognition, a hall mark of adaptive immunity. Further maturation of B cells Is characterized by expansion, differentiation, trafficking to specific compartments in peripheral lymph nodes, selection of appropriate antigen receptors, the generation of B cell memory and finally population of mucosal sites. Coupled with the expansion of B cell populations, Is the requirement for deletion of self-reactive clones. All of these events are intertwined, but the nature of these interactions are Incompletely understood. The overall hypothesis of this Program Project Grant is that selected genetic, cellular and micro-environmental influences are critical to normal B cell development and that defects in any of these processes can result in Immune deficiency. This Program Project selects four specific stages of B cell immunity to Investigate, Project 1: Mechanisms of V(D)J Mediated Immunodeficiencies; Project 2: Investigating blocks to B cell memory; Projects: Regulation and function of IgA production in the intestinal mucosa; Project 4: Loss of B cell tolerance in primary immune deficiency. The development of normal protective immunity is essential for understanding vaccination, disease prevention, transplantation, and autoimmunity; yet how these immune responses are developed and controlled, require further elucidation. At Mount Sinai we have a unique and valuable resource in our Primary Immune Deficiency Program; this allows for careful study of selected stages of human B cell bioiogy, the subject of this Program Project Grant.