<br>Fcgr2b 和 Fcgr3 是软骨抗体诱导关节炎的主要遗传因素，超越编码补体 C5 的 Hc 的影响,European Journal of Immunology

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Fcgr2b 和 Fcgr3 是软骨抗体诱导关节炎的主要遗传因素，超越编码补体 C5 的 Hc 的影响
European Journal of Immunology ( IF 4.5 ) Pub Date : 2024-02-05 , DOI: 10.1002/eji.202350659
Zhongwei Xu ₁ , Àlex Moreno-Giró _{1,

2} , Danxia Zhao ₁ , Alexander Krämer ₁ , Rajan Kumar Pandey ₁ , Bingze Xu ₁ , Susanna L Lundström ₃ , Rikard Holmdahl ₁

Affiliation

与人类类风湿性关节炎 (RA) 一样，小鼠胶原诱导性关节炎 (CIA) 不仅与 MHC II 类遗传多态性相关，而且在某种程度上与其他基因座相关，包括编码 Fc γ 受体 (FCGR) 和补体 C5 的基因。在这项研究中，我们使用软骨抗体诱导关节炎 (CAIA) 模型（其中关节炎在 12 小时内发生）来确定 FCGR 和 C5 ( Hc ) 的相对重要性。在 CAIA 中，抑制或删除 FCGR3 显着阻碍关节炎的发展，强调了该受体的关键作用。阻断 FCGR3 也会降低 FCGR4 的水平，反之亦然。当使用专门与 FCGR2B 和 FCGR3 相互作用的 IgG1 致关节炎混合物时， Fcgr2b ⁻小鼠中迅速引发关节炎症，但Fcgr3 ⁻小鼠中则不然，这表明 FCGR3 足以促进 CAIA 的发展。关于补体激活，C5 突变的Fcgr2b ⁺⁺ .Hc ^**小鼠对 CAIA 具有完全抵抗力，而Fcgr2b ⁻⁻ .Hc ^**小鼠则迅速发展为关节炎。我们得出的结论是，FCGR3 对于 CAIA 的发展至关重要且足够，特别是在由 IgG1 抗体诱导时。小鼠 FCGR3 的人类直系同源物 FCGR2A 可能与 RA 发病机制有关。 FCGR2B 缺陷导致关节炎快速进展，并克服 C5 缺陷带来的抵抗力。

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Fcgr2b and Fcgr3 are the major genetic factors for cartilage antibody-induced arthritis, overriding the effect of Hc encoding complement C5

Like rheumatoid arthritis (RA) in humans, collagen-induced arthritis (CIA) in mice is associated with not only MHC class II genetic polymorphism but also, to some extent, with other loci including genes encoding Fc gamma receptors (FCGRs) and complement C5. In this study, we used a cartilage antibody-induced arthritis (CAIA) model in which arthritis develops within a 12-h timeframe, to determine the relative importance of FCGRs and C5 (Hc). In CAIA, inhibiting or deleting FCGR3 substantially hindered arthritis development, underscoring the crucial role of this receptor. Blocking FCGR3 also reduced the levels of FCGR4, and vice versa. When employing an IgG1 arthritogenic cocktail that exclusively interacts with FCGR2B and FCGR3, joint inflammation was promptly initiated in Fcgr2b⁻⁻ mice but not in Fcgr3⁻⁻ mice, suggesting that FCGR3 is sufficient for CAIA development. Regarding complement activation, Fcgr2b⁺⁺.Hc^** mice with C5 mutated were fully resistant to CAIA, whereas Fcgr2b⁻⁻.Hc^** mice developed arthritis rapidly. We conclude that FCGR3 is essential and sufficient for CAIA development, particularly when induced by IgG1 antibodies. The human ortholog of mouse FCGR3, FCGR2A, may be associated with RA pathogenesis. FCGR2B deficiency allows for rapid arthritis progression and overrides the resistance conferred by C5 deficiency.

更新日期：2024-02-05

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