FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization.
FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization.
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DOI：
10.3389/fimmu.2022.972723
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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被动免疫抗d可预防母体对RhD的同种异体免疫，从而预防胎儿和新生儿的溶血性疾病。出乎意料的是，抗d在某些情况下失败，一些单克隆抗d制剂矛盾地增强了同种异体免疫。通过抗- d调节体液免疫的潜在机制尚不清楚。我们之前报道过，在小鼠模型中，IgG抗体亚类对红细胞（RBC）输注的同种免疫反应有差异调节；特别是IgG2c显著增强RBC同种抗体反应。最初的机制研究表明，IgG2c：红细胞免疫复合物优先被脾树突状细胞（DC）亚群消耗，这些亚群在红细胞同种异体免疫中起作用。在dc上缺失激活的fc - γ受体（fc - γ rs）（即fc - γ ri、fc - γ riii和fc - γ riv）可消除igg2c介导的增强同种免疫。由于dc表达高水平的FcγRIV，这对IgG2c亚类具有高亲和力，我们假设FcγRIV是增强同种异体免疫所必需的。为了验证这一假设，我们使用敲除小鼠和阻断抗体来操纵FcγR的表达。本文的数据表明，FcγRIV，而不是FcγRI或FcγRIII，是igg2c介导的红细胞同种抗体产生增强所必需的。此外，FcγRI单独足以清除igg2c介导的红细胞，但不能增加同种异体免疫，这表明红细胞清除可以在不诱导同种异体免疫的情况下发生。总之，这些数据，结合先前的观察结果，支持了红细胞特异性IgG2c抗体被动免疫通过FcγRIV连接脾常规dc （cdc）增加红细胞同种抗体产生的假设。这就提出了一个问题，即在免疫预防制剂中标准化抗体亚类是否可取，并建议哪些亚类可能是产生单克隆抗d治疗药物的最佳选择。
Passive immunization with anti-D can prevent maternal alloimmunization to RhD thereby preventing hemolytic disease of the fetus and newborn. Unexpectedly, anti-D fails in some cases and some monoclonal anti-D preparations paradoxically enhances alloimmunization. The underlying mechanisms modulating humoral alloimmunization by anti-D are unknown. We previously reported that IgG antibody subclasses differentially regulate alloimmunity in response to red blood cell (RBC) transfusions in a mouse model; in particular, IgG2c significantly enhanced RBC alloantibody responses. Initial mechanistic studies revealed that IgG2c:RBC immune complexes were preferentially consumed by the splenic dendritic cell (DC) subsets that play a role in RBC alloimmunization. The deletion of activating Fc-gamma receptors (FcγRs) (i.e., FcγRI, FcγRIII, and FcγRIV) on DCs abrogated IgG2c-mediated enhanced alloimmunization. Because DCs express high levels of FcγRIV, which has high affinity for the IgG2c subclass, we hypothesized that FcγRIV was required for enhanced alloimmunization. To test this hypothesis, knockout mice and blocking antibodies were used to manipulate FcγR expression. The data presented herein demonstrate that FcγRIV, but not FcγRI or FcγRIII, is required for IgG2c-mediated enhancement of RBC alloantibody production. Additionally, FcγRI is alone sufficient for IgG2c-mediated RBC clearance but not for increased alloimmunization, demonstrating that RBC clearance can occur without inducing alloimmunization. Together, these data, combined with prior observations, support the hypothesis that passive immunization with an RBC-specific IgG2c antibody increases RBC alloantibody production through FcγRIV ligation on splenic conventional DCs (cDCs). This raises the question of whether standardizing antibody subclasses in immunoprophylaxis preparations is desirable and suggests which subclasses may be optimal for generating monoclonal anti-D therapeutics.
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