INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France.
CNRS ERL8252, Paris, France.
Front Immunol. 2019 Apr 12;10:811. doi: 10.3389/fimmu.2019.00811. eCollection 2019.
Fc receptors (FcRs) belong to the ITAM-associated receptor family. FcRs control the humoral and innate immunity which are essential for appropriate responses to infections and prevention of chronic inflammation or auto-immune diseases. Following their crosslinking by immune complexes, FcRs play various roles such as modulation of the immune response by released cytokines or of phagocytosis. Here, we review FcR involvement in pathologies leading notably to altered intracellular signaling with functionally relevant consequences to the host, and targeting of Fc receptors as therapeutic approaches. Special emphasis will be given to some FcRs, such as the FcαRI, the FcγRIIA and the FcγRIIIA, which behave like the ancient god Janus depending on the ITAM motif to inhibit or activate immune responses depending on their targeting by monomeric/dimeric immunoglobulins or by immune complexes. This ITAM duality has been recently defined as inhibitory or activating ITAM (ITAMi or ITAMa) which are controlled by Src family kinases. Involvement of various ITAM-bearing FcRs observed during infectious or autoimmune diseases is associated with allelic variants, changes in ligand binding ability responsible for host defense perturbation. During auto-immune diseases such as rheumatoid arthritis, lupus or immune thrombocytopenia, the autoantibodies and immune complexes lead to inflammation through FcR aggregation. We will discuss the role of FcRs in autoimmune diseases, and focus on novel approaches to target FcRs for resolution of antibody-mediated autoimmunity. We will finally also discuss the down-regulation of FcR functionality as a therapeutic approach for autoimmune diseases.
Fc 受体（FcR）属于 ITAM 相关受体家族。FcR 控制体液和先天免疫，对于适当应对感染和预防慢性炎症或自身免疫性疾病至关重要。FcR 交联后，通过释放细胞因子或吞噬作用调节免疫反应。在这里，我们综述了 FcR 参与导致细胞内信号转导改变的病理过程，这些改变对宿主具有功能相关的后果，并探讨了 Fc 受体作为治疗方法的靶向作用。特别强调了一些 FcR，如 FcαRI、FcγRIIA 和 FcγRIIIA，它们的行为类似于古老的 Janus 神，取决于 ITAM 基序，通过单体/二聚体免疫球蛋白或免疫复合物靶向，抑制或激活免疫反应。这种 ITAM 双重性最近被定义为抑制性或激活性 ITAM（ITAMi 或 ITAMa），由 Src 家族激酶控制。在感染或自身免疫性疾病期间观察到的各种携带 ITAM 的 FcR 的参与与等位基因变异有关，这些变异改变了配体结合能力，导致宿主防御功能紊乱。在类风湿关节炎、狼疮或免疫性血小板减少症等自身免疫性疾病中，自身抗体和免疫复合物通过 FcR 聚集导致炎症。我们将讨论 FcR 在自身免疫性疾病中的作用，并重点讨论针对 FcR 以解决抗体介导的自身免疫的新方法。我们还将讨论下调 FcR 功能作为治疗自身免疫性疾病的一种方法。
