Institute for Systemic Inflammation Research, University of Lübeck, 23538 Lübeck, Germany.
Immunobiology. 2012 Nov;217(11):1067-79. doi: 10.1016/j.imbio.2012.07.015.
Immunoglobulin G (IgG)-mediated activation of complement and IgG Fc receptors (FcγRs) are important defense mechanisms of the innate immune system to ward off infections. However, the same mechanisms can drive severe and harmful inflammation, when IgG antibodies react with self-antigens in solution or tissues, as described for several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and immune vasculitis. More specifically, IgG immune complexes (ICs) can activate all three pathways of the complement system resulting in the generation of C3 and C5 cleavage products that can activate a panel of different complement receptors on innate and adaptive immune cells. Importantly, complement and FcγRs are often co-expressed on inflammatory immune cells such as neutrophils, monocytes, macrophages or dendritic cells and act in concert to mediate the inflammatory response in autoimmune diseases. In this context, the cross-talk between the receptor for the anaphylatoxin C5a, i.e. C5ar1 (CD88) and FcγRs is of major importance. Recent data suggest a model of bidirectional regulation, in which CD88 acts upstream of FcγRs and sets the threshold for FcγR-dependent effector responses by regulating the ratio between activating and inhibitory FcγRs. Vice versa, FcγR ligation can either amplify or block C5aR-mediated effector functions, depending on whether IgG IC aggregate activating or inhibitory FcγRs. Further, complement and FcγRs cooperate on B cells and on follicular dendritic cells to regulate the development of autoreactive B cells, their differentiation into plasma cells and, eventually, the production of autoantibodies. Here, we will give an update on recent findings regarding this complex regulatory network between complement and FcγRs, which may also regulate the inflammatory response in allergy, cancer and infection.
免疫球蛋白 G（IgG）介导的补体激活和 IgG Fc 受体（FcγRs）是先天免疫系统抵御感染的重要防御机制。然而，当 IgG 抗体与溶液或组织中的自身抗原反应时，相同的机制也会引发严重和有害的炎症，如系统性红斑狼疮、类风湿关节炎和免疫血管炎等几种自身免疫性疾病中所述。更具体地说，IgG 免疫复合物（IC）可以激活补体系统的所有三个途径，导致 C3 和 C5 裂解产物的产生，这些产物可以激活先天和适应性免疫细胞上的一系列不同的补体受体。重要的是，补体和 FcγRs 通常在炎症性免疫细胞（如中性粒细胞、单核细胞、巨噬细胞或树突状细胞）上共同表达，并协同作用以介导自身免疫性疾病中的炎症反应。在这种情况下，过敏毒素 C5a 的受体，即 C5ar1（CD88）和 FcγRs 之间的串扰非常重要。最近的数据表明了一种双向调节模型，其中 CD88 在上游作用于 FcγRs，并通过调节激活和抑制性 FcγRs 之间的比例来设定 FcγR 依赖性效应反应的阈值。反之，FcγR 交联可以根据 IgG IC 聚集激活或抑制性 FcγRs 来放大或阻断 C5aR 介导的效应功能。此外，补体和 FcγRs 在 B 细胞和滤泡树突状细胞上合作，以调节自身反应性 B 细胞的发育、其向浆细胞的分化，最终产生自身抗体。在这里，我们将更新关于补体和 FcγRs 之间这种复杂调控网络的最新发现，该网络也可能调节过敏、癌症和感染中的炎症反应。
