Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Front Immunol. 2024 Jan 8;14:1323969. doi: 10.3389/fimmu.2023.1323969. eCollection 2023.
Lack of complement factor C1q of the classical pathway results in severely impaired primary antibody responses. This is a paradox because antibodies, especially IgM, are the most efficient activators of the classical pathway and very little specific IgM will be present at priming. A possible explanation would be that natural IgM, binding with low affinity to the antigen, may suffice to activate complement. In support of this, mice lacking secretory IgM have an impaired antibody response, which can be rescued by transfer of non-immune IgM. Moreover, passive administration of specific IgM together with antigen enhances the antibody response in a complement-dependent fashion. To test the idea, we have used a knock-in mouse strain (Cμ13) carrying a point mutation in the IgM heavy chain, rendering the IgM unable to activate complement. Mutant mice backcrossed to BALB/c or C57BL/6 background were primed and boosted with a low dose of sheep red blood cells. Confirming earlier data, no impairment in early, primary IgM- or IgG-responses were seen in either of the Cμ13 strains. However, in one of the mutant strains, late primary IgG responses were impaired. A more pronounced effect was observed after boost, when the IgG response, the number of germinal center B cells and antibody secreting cells as well as the opsonization of antigen were impaired in mutant mice. We conclude that complement activation by natural IgM cannot explain the role of C1q in primary antibody responses, but that endogenous, specific, wildtype IgM generated after immunization feedback-enhances the response to a booster dose of antigen. Importantly, this mechanism can only partially explain the role of complement in the generation of antibody responses because the IgG response was much lower in C3- or complement receptor 1 and 2-deficient mice than in Cμ13 mice.
经典途径补体因子 C1q 的缺乏会导致初级抗体反应严重受损。这是一个悖论，因为抗体，尤其是 IgM，是经典途径最有效的激活剂，而在初始阶段几乎不存在特异性 IgM。一种可能的解释是，与抗原结合亲和力低的天然 IgM 可能足以激活补体。支持这一观点的是，缺乏分泌型 IgM 的小鼠抗体反应受损，而通过转移非免疫性 IgM 可以挽救这种缺陷。此外，特异性 IgM 与抗原的被动给药以补体依赖的方式增强抗体反应。为了验证这一想法，我们使用了一种携带 IgM 重链点突变的基因敲入小鼠品系（Cμ13），使 IgM 无法激活补体。突变小鼠与 BALB/c 或 C57BL/6 背景回交后，用低剂量绵羊红细胞进行初始和加强免疫。与早期数据一致，在任何一种 Cμ13 品系中，都没有观察到早期、初级 IgM 或 IgG 反应的受损。然而，在一种突变株中，晚期初级 IgG 反应受损。在加强免疫后观察到更为明显的效应，此时突变小鼠的 IgG 反应、生发中心 B 细胞和抗体分泌细胞的数量以及抗原的调理作用受损。我们得出结论，天然 IgM 对补体的激活不能解释 C1q 在初级抗体反应中的作用，但免疫后产生的内源性、特异性、野生型 IgM 通过反馈增强了对加强剂量抗原的反应。重要的是，这种机制只能部分解释补体在抗体反应产生中的作用，因为 C3 或补体受体 1 和 2 缺陷小鼠的 IgG 反应比 Cμ13 小鼠低得多。
