Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
J Immunol. 2018 Apr 15;200(8):2615-2626. doi: 10.4049/jimmunol.1700429. Epub 2018 Mar 9.
By their interaction with IgG immune complexes, FcγR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcγR-knockout mice, it has been concluded that FcγRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcγRs (FcγRI/II/III/IV mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcγRIIb-deficient mice, FcγRI/II/III/IV mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcγRs in the modulation of the adaptive immune response in vivo. We conclude that FcγRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.
通过与 IgG 免疫复合物的相互作用，FcγR 和补体将先天免疫和适应性免疫联系起来，显示出功能冗余。在补体缺陷小鼠中，IgG 的下游效应功能通常受损，适应性免疫也是如此。基于使用 FcγR 敲除小鼠的各种模型系统，已经得出结论，FcγRs 也是先天和适应性免疫的关键调节剂；然而，支持这些结论的一些模型系统存在有缺陷的实验设计。为了解决这个问题，我们生成了一种缺乏所有 FcγR（FcγRI/II/III/IV 小鼠）的新型小鼠模型。这些小鼠表现出正常的发育和淋巴样和髓样发生。尽管 IgG 效应途径受损，但对各种挑战（包括细菌感染和 IgG 免疫复合物）的适应性免疫反应并未受损。与 FcγRIIb 缺陷小鼠一样，FcγRI/II/III/IV 小鼠产生了更高的 Ab 滴度，但没有自身抗体。这些观察结果表明，激活 FcγR 在体内调节适应性免疫反应中具有冗余作用。我们得出结论，FcγR 是 IgG 效应分子的下游分子，在免疫系统的发生和维持以及适应性免疫的调节中具有有限的作用。
