Mouse C4b-binding Protein in Adaptive Immunity

描述（由申请人提供）：本研究计划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，以描述人类C4BP在适应性免疫中的总体贡献。本研究的目的是基于一个中心假设，即C4BP结合B细胞上表达的CD40介导了许多重要的免疫调节生物学反应，包括对t依赖性抗原应答的免疫球蛋白类转换，以及生发中心B细胞的增殖和拯救。我们新一代的C4BP“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。这一建议的结果将显著促进对先天免疫系统和适应性免疫系统如何相互作用以提供强大免疫反应的理解。此外，这些研究还将提供基本信息，有助于更好地了解b细胞成熟和免疫球蛋白的产生，从而为自身免疫性疾病（如系统性红斑狼疮）以及IgE相关的过敏性疾病（包括特应性哮喘）的发病机制提供重要见解。为了实现提案的总体目标，提出了三个目标。目的一将评估小鼠C4BP与小鼠B细胞上表达的CD40之间的结合相互作用。目的二将检测c4bp缺陷（-/-）小鼠与野生型小鼠的淋巴细胞发育。目的三将确定与野生型小鼠相比，c4bp缺陷（-/-）小鼠对t依赖性和t非依赖性抗原的抗体反应，以及与野生型小鼠相比，c4bp缺陷（-/-）小鼠的生发中心形成。

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.