C REACTIVE PROTEIN IN HOST DEFENSE

描述（改编自申请人摘要）：C反应蛋白 转基因（CRPtg）小鼠产生急性期人CRP反应， 对抗致命的肺炎球菌感染 的长远目标 建议的研究是确定这种CRP依赖性宿主的机制 防御功能。 我们的工作假设是：1）CRP有助于 通过结合病原体进行免疫前宿主防御，从而靶向它们， 通过补体激活和Fc受体（FcR）介导的清除 吞噬作用 2)CRP激活补体导致C3沉积 细菌上的片段，导致增强的保护性抗体反应。 一 类似的作用是由CRP包被的抗原与FcR结合介导的， 抗原呈递细胞 3)这些事件取决于快速诱导的 CRP基因，与其经尿道调节的水平成比例， 组成型表达 将使用CRPtg小鼠对这些假设进行检验 以及它们的杂交体在补体蛋白C3和 因子B，在FcR的1H-链中，和在白细胞介素-6中。 的程度 保护免受肺炎球菌、脑膜炎球菌和沙门氏菌感染， 将测定血清CRP和肺中存在的CRP。 模型 胸腺依赖性和非依赖性抗原将用于研究 CRP对抗细菌抗体反应的影响。 最后， 性激素、地塞米松、生长激素和补体蛋白 CR基因调控中的片段进行研究。 这些研究将 增加对宿主固有防御机制及其 与获得性免疫的相互作用。

DESCRIPTION (Adapted from applicant's abstract): C-Reactive Protein transgenic (CRPtg) mice mount acute phase human CRP responses, which protect against lethal infection with pneumococci. The long term objective of the proposed research is to define the mechanisms for this CRP-dependent host defense function. Our working hypotheses are: 1) CRP contributes to pre-immune host defense by binding to pathogens, thus targeting them for clearance via complement activation and Fc receptor (FcR)-mediated phagocytosis. 2) Activation of complement by CRP leads to deposition of C3 fragments on bacteria, leading to enhanced protective antibody responses. A similar effect is mediated by CRP-coated antigens binding to FcR on antigen-presenting cells. 3) These events depend on rapid induction of the CRP gene, in proportion to the levels of its hormonally-regulated constitutive expression. These hypotheses will be tested using CRPtg mice and their hybrids genetically deficient in the complement proteins C3 and factor B, in the ^H-chain of FcR, and in interleukin-6. The extent of protection from pneumococci, meningococci, and salmonellae, effected by serum CRP and CRP present in the lungs, will be determined. Model thymus-dependent and -independent antigens will be used to investigate the effects of CRP on the anti-bacterial antibody response. Finally the role of sex hormones, dexamethasone, growth hormone, and complement protein fragments in CR gene regulation will be investigated. These studies will increase the understanding of innate host defense mechanisms and their interaction with acquired immunity.