Mouse C4b-binding Protein in Adaptive Immunity

描述(申请人提供)：这项研究的目的是评估小鼠补体C4b结合蛋白(C4BP)“敲除”小鼠作为体内模型，以描绘出人类C4BP在适应性免疫中的整体贡献。这一建议的目的是基于这样一个中心假设，即表达在B细胞上的结合CD40的C4BP介导了许多在免疫调节中重要的生物反应，包括免疫球蛋白类对T依赖抗原的反应，以及生发中心B细胞的增殖和拯救。我们最新一代的C4BP“基因敲除”小鼠提供了一个独特的机会来评估C4BP作为适应性免疫的重要贡献者的生理影响。这一建议的结果将极大地促进对先天免疫系统和获得性免疫系统如何相互作用以提供强大的免疫反应的理解。此外，这些研究还将提供基本信息，有助于更好地了解B细胞的成熟和免疫球蛋白的产生，从而为系统性红斑狼疮等自身免疫性疾病以及包括特应性哮喘在内的IgE相关过敏性疾病的发病机制提供重要的见解。为了实现该提案的总体目标，提出了三个目标。目的研究小鼠C4BP与表达于小鼠B细胞上的CD40的结合作用。目的研究C4BP基因缺陷(-/-)小鼠与野生型小鼠的淋巴细胞发育情况。目的检测C4BP基因缺陷(-/-)小鼠与野生型小鼠对T依赖和T非依赖性抗原的抗体反应，以及与野生型小鼠比较生发中心的形成情况。

DESCRIPTION (provided by applicant): The objective of this research proposal is to evaluate the mouse complement C4b binding protein (C4BP) "knock-out" mouse as an in vivo model to delineate the overall contribution of human C4BP in adaptive immunity. The aims of this proposal are driven the the central hypothesis that C4BP on binding CD40 expressed on B cells mediates many important biological responses important in immune regulation, including immunoglobulin class switching in response to T-dependent antigens, and proliferation and rescue of germinal center B cells. Our recent generation of a C4BP "knock-out" mouse provides a unique opportunity to evaluate the physiological impact of C4BP as a significant contributor to adaptive immunity. The results from this proposal will significantly advance the understanding of how the innate and adaptive immune systems interact in providing a robust immune response. Moreover, these studies will also provide basic information that will facilitate a better understanding of B-cell maturation and immunoglobulin production, and thereby provide significant insights into the pathogenesis of autoimmune diseases such as systemic lupus erythematosus as well as IgE associated allergic diseases, including atopic asthma. To accomplish the overall objective of the proposal, three aims are proposed. Aim one will evaluate the binding interactions between mouse C4BP and CD40 expressed on mouse B cells. Aim two will examine lymphocyte development in C4BP-deficient (-/-) mice compared to wild-type mice. Aim three will determine the antibody response to T-dependent and T-independent antigens in C4BP-deficient (-/-) mice compared to wild-type mice, as well as to examine germinal center formation in C4BP-deficient (-/-) mice compare to wild- type mice.