Regulation of the B-Cell Development and Differentiation

描述（由申请人提供）：免疫应答的多样性和特异性由B和T淋巴细胞上的抗原结合受体体现。活化或自身反应性细胞的增殖性扩增和程序性消除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是在人和小鼠中的绝大多数外周B细胞上表达的两种主要抗原受体同种型。虽然许多证据表明IgM在驱动B细胞发育中是重要的，但IgD的贡献仍然不清楚，IgM和IgD在调节体液免疫应答中的作用也是如此。最近，我们证明了IgM和IgD在淋巴稳态和胸腺依赖性体液免疫反应中具有不同的作用。这些新的发现支持了一个模型，其中通过δ或μ重链的信号传导事件差异调节B细胞发育和分化。该项目将解决几个关键问题的机制如何IgM和IgD受体差异条件细胞存活/生长和细胞死亡在B细胞发育过程中使用IgM缺陷和IgD缺陷小鼠模型。实验还将研究当IgM或IgD不存在时的免疫应答。其他研究将探讨V（D）J重排和功能的B细胞表达多重重链的IgM +/-杂合子。拟议的研究将阐明IgM和IgD抗原受体的不同功能特征，并阐明B细胞稳态和B细胞免疫的机制，这可能会导致更好地理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.