Regulation of the B-Cell Development and Differentiation

超出提供的空间。免疫反应的多样性和特异性体现在B和T淋巴细胞上的抗原结合受体上。增殖扩张和程序性消除活化或自身反应细胞之间的平衡也受到这些抗原受体的严格调控。因此，了解B细胞抗原受体(BCR)对B细胞发育和分化的调控机制对于了解B细胞的正常发育和确定免疫缺陷和自身免疫性疾病的分子和细胞基础是至关重要的。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亚型。虽然许多证据表明，IgM在推动B细胞发育方面很重要，但IGD的作用尚不清楚，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B细胞室的动态平衡和胸腺依赖的体液免疫反应中具有不同的作用。这些新的发现支持一种模型，在该模型中，信号事件通过5或_重链不同地调节B细胞的发育和分化。这个项目将解决几个关键问题，即通过IgM或IgM在B细胞发育和体液免疫反应中通过IGM和IGD缺陷小鼠模型的不同信号的生物学后果和意义。具体地说，我们将检验这一假设，即IgM在外周B细胞的激活和分化中起负调节作用，而IGD起正调节作用。这些研究将阐明IgM和IGD作为抗原受体和作为分泌型免疫球蛋白的不同功能特征，并将丰富我们对B细胞抗原受体如何调节B细胞成熟和免疫I反应的理解。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. 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. Therefore, understanding the mechanisms of regulation of B-cell development and differentiation by B cell antigen receptors (BCR) is crucial for understanding normal B-cell development and for determining the molecular and cellular basis of immunodeficiency and autoimmune disorders. 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 the homeostasis of the B-cell compartment and in thymus-dependent humoral immune responses. These novel findings support a model in which signaling events through 5 or _ heavy chain differentially regulate B cell development and differentiation. This project will address several critical questions about the biological consequences and significances of the distinct signals through IgD or IgM in B-cell development and humoral immune responses using both IgM- and IgD-deficient mouse models. Specifically, we will test the hypothesis that IgM mediates a negative regulatory role while IgD acts as positive regulator in B cell activation and differentiation in the periphery. The proposed studies will illuminate distinct functional features of IgM and IgD both as antigen receptors and as secreted immunoglobulins and will enrich our understanding of how the B cell antigen receptors regulate B cell maturation and immune i responses. PERFORMANCE SITE ========================================Section End===========================================