C REACTIVE PROTEIN IN HOST DEFENSE

描述(摘自申请者摘要)：C-反应蛋白 转基因(CRPtg)小鼠产生急性时相人类CRP反应，从而保护 对抗肺炎球菌的致命性感染。该计划的长远目标 建议的研究是定义这种依赖于CRP的宿主的机制 防御功能。我们的工作假设是：1)C反应蛋白有助于 通过与病原体结合来进行免疫前宿主防御，从而靶向于 补体激活和Fc受体(FCR)介导的清除 吞噬作用。2)C反应蛋白激活补体导致C3沉积 细菌上的碎片，导致增强的保护性抗体反应。一个 类似的作用是由CRP包被的抗原与FCR结合所介导的。 抗原提呈细胞。3)这些事件依赖于快速诱导 C反应蛋白基因，与其受激素调节的水平成比例 构成表达。这些假说将在CRPtg小鼠身上进行验证 以及他们的杂交种在补体蛋白C3和C3方面存在遗传缺陷 B因子，在FCR的^H链中，在白细胞介素6中。其影响范围 对肺炎球菌、脑膜炎双球菌和沙门氏菌的保护作用 将测定血清C反应蛋白和肺部存在的C反应蛋白。型号 胸腺依赖和不依赖的抗原将被用于研究 C反应蛋白对抗细菌抗体应答的影响。最后一点就是 性激素、地塞米松、生长激素和补体蛋白 我们将研究CR基因调控中的片段。这些研究将 增加对寄主固有防御机制和它们的理解 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.