Regulation of the B-Cell Development and Differentiation

描述（由申请人提供）：免疫反应的多样性和特异性由B淋巴细胞和T淋巴细胞上的抗原结合受体体现。增殖扩张和程序性消除活化或自身反应性细胞之间的平衡也受到这些抗原受体的严格调节。免疫球蛋白D （IgD）和IgM是人类和小鼠绝大多数外周B细胞上表达的两种主要抗原受体同型。虽然许多证据表明IgM在驱动b细胞发育中很重要，但IgD的作用仍不清楚，IgM和IgD在调节体液免疫反应中的作用也不清楚。最近，我们证明了IgM和IgD在淋巴稳态和胸腺依赖的体液免疫反应中具有不同的作用。这些新发现支持了一个模型，在该模型中，通过delta或mu重链的信号事件差异调节B细胞的发育和分化。该项目将利用IgM缺陷和IgD缺陷小鼠模型，解决关于IgM和IgD受体在B细胞发育过程中如何差异调节细胞存活/生长和细胞死亡的机制的几个关键问题。实验还将研究IgM或IgD缺失时的免疫反应。进一步的研究将探讨在IgM +/-杂合子中表达多个重链的B细胞的V(D)J重排和功能。这些研究将阐明IgM和IgD抗原受体的不同功能特征，阐明b细胞稳态和b细胞免疫的机制，从而更好地了解免疫缺陷和自身免疫性疾病的分子和细胞基础。

DESCRIPTION (provided by applicant): The diversity and specificity of an immune response is embodied by the antigen-binding receptors on both B and T lymphocytes. The balance between proliferative expansion and programmed elimination of activated or autoreactive cells is also tightly regulated by these antigen receptors. Immunoglobulin D (IgD) and IgM are the two major antigen receptor isotypes expressed on the vast majority of peripheral B cells in humans and mice. While much evidence indicates that IgM is important in driving B-cell development, the contribution of IgD remains unclear, as are the roles of IgM and IgD in regulating humoral immune responses. Recently, we demonstrated that IgM and IgD have distinct roles in lymphoid homeostasis and in thymus-dependent humoral immune responses. These novel findings support a model in which signaling events through delta or mu heavy chain differentially regulate B cell development and differentiation. This project will address several critical questions about the mechanisms how IgM and IgD receptors differentially condition cell survival/growth and cell death during B cell development using both IgM-deficient and IgD deficient mouse models. Experiments will also investigate immune responses when either IgM or IgD is absent. Additional studies will probe the V(D)J rearrangements and functions of B cells expressing multiple heavy chains in IgM +/- heterozygotes. The proposed studies will elucidate distinct functional features of IgM and IgD antigen receptors and illuminate mechanisms of B-cell homeostasis and B-cell immunity, which may lead to better understanding the molecular and cellular basis of immunodeficiency and autoimmune disorders.