C-reactive protein supresses the immune system through Fc gamma receptors

描述（由申请人提供）：C反应蛋白（CRP）是一种急性期血清蛋白，在炎症反应中快速产生。大量研究表明，CRP对急性炎症、感染和自身免疫性疾病具有保护作用，但其机制尚不清楚。与CRP相互作用的细胞受体是我们鉴定的Fc γ受体（FcR）。我们已经证明了激活性和抑制性FcR与CRP相互作用对保护小鼠免受内毒素休克、自身免疫性疾病和免疫复合物介导的疾病的作用。最近的一篇论文使用过继转移系统证明，静脉注射免疫球蛋白（IVIg）可能通过调节FcR介导免疫性血小板减少性紫癜（IIP）的抑制。我们发现CRP处理的脾细胞通过与供体细胞上的FcR相互作用转移对小鼠ITP发展的抑制。我们建议研究这种抑制发生的机制。我们的假设是CRP激活的巨噬细胞通过抑制受体小鼠中FcR介导的吞噬作用来抑制免疫性ITP。我们提出抑制的转移依赖于可溶性因子，并且由于调节受体Fc γ RIIb的表达增加，靶巨噬细胞的吞噬作用降低。这一假设将通过提出的具体目标加以解决。具体目标是：1.建立CRP诱导的抑制性巨噬细胞调节靶巨噬细胞吞噬活性和FcR表达的体外系统。确定ITP体外模型中细胞-细胞接触或可溶性介质是否对吞噬作用的抑制起作用。在这项研究中，我们将确定在靶细胞中诱导抑制的机制以及哪些可溶性介质负责抑制。长期目标是确定在ITP中观察到的CRP的免疫抑制特性是否可以在人类免疫复合物介导的疾病中观察到。

DESCRIPTION (provided by applicant): C-reactive protein (CRP) is an acute phase serum protein which is produced rapidly in response to inflammation. Numerous studies have shown that CRP has protective properties in acute inflammation, infection and autoimmune dieseases however the mechanism is not understood. Cellular receptors that interact with CRP are Fc gamma receptors (FcR) which we identified. We have demonstrated the role of both activating anf inhibitory FcR interacting with CRP to protect mice frrom endotoxin shock, autoimmune disease and immune complex mediated disease. A recent paper using an adoptive transfer system demonstrated that suppression of immune thrombocytopenia purpura (IIP) was mediated by intravenous immunoglobulin (IVIg) possibly by regulating FcR. We found that CRP treated spleen cells transferred suppression of mice developing ITP through interactions with FcR on the donor cell. We propose to study the mechanism by which this suppression is taking place. Our hypothesis is that CRP-activated macrophages suppress immune ITP by inhibiting FcR-mediated phagocytosis in recipient mice. We propose that the transfer of suppression depends on a soluble factor(s) and that phagocytosis by target macrophages is decreased due to increased expression of the regulatory receptor, Fc gamma Rllb. This hypothesis will be addressed by specific aims proposed. The specfic aims are: 1. To develop an in vitro system in which CRP-induced suppressive macrophages modulate the phagocytic activity and FcR expression of target macrophages, and 2. To determine whether cell-cell contact or soluble mediators are responsible for suppression of phagocytosis in the in vitro model of ITP. In this proposed study we will identiy the mechanism by which suppression is induced in the target cell and what souble mediators are responsible for suppresion. The long term goal is to determine if the immunosuppressive properties of CRP, observed in ITP, can be oberved in human immune complex mediated diseases.