Department of Neurology, Huashan Hospital Fudan University, Shanghai, China.
National Center for Neurological Disorders, Shanghai, China.
Front Immunol. 2022 Jan 26;13:746068. doi: 10.3389/fimmu.2022.746068. eCollection 2022.
Antibody-induced complement activation may cause injury of the neuromuscular junction (NMJ) and is thus considered as a primary pathogenic factor in human myasthenia gravis (MG) and animal models of experimental autoimmune myasthenia gravis (EAMG). In this study, we tested whether CRIg/FH, a targeted complement inhibitor, could attenuate NMJ injury in rat MG models. We first demonstrated that CRIg/FH could inhibit complement-dependent cytotoxicity on human rhabdomyosarcoma TE671 cells induced by MG patient-derived IgG . Furthermore, we investigated the therapeutic effect of CRIg/FH in a passive and an active EAMG rodent model. In both models, administration of CRIg/FH could significantly reduce the complement-mediated end-plate damage and suppress the development of EAMG. In the active EAMG model, we also found that CRIg/FH treatment remarkably reduced the serum concentration of autoantibodies and of the cytokines including IFN-γ, IL-2, IL-6, and IL-17, and upregulated the percentage of Treg cells in the spleen, which was further verified . Therefore, our findings indicate that CRIg/FH may hold the potential for the treatment of MG immune modulation.
抗体诱导的补体激活可能导致神经肌肉接头（NMJ）损伤，因此被认为是人类重症肌无力（MG）和实验性自身免疫性重症肌无力（EAMG）动物模型中的主要致病因素。在这项研究中，我们测试了靶向补体抑制剂 CRIg/FH 是否可以减轻大鼠 MG 模型中的 NMJ 损伤。我们首先证明，CRIg/FH 可以抑制由 MG 患者来源的 IgG 诱导的人横纹肌肉瘤 TE671 细胞的补体依赖性细胞毒性。此外，我们还研究了 CRIg/FH 在被动和主动 EAMG 啮齿动物模型中的治疗效果。在这两种模型中，CRIg/FH 的给药均可显著减少补体介导的终板损伤，并抑制 EAMG 的发展。在主动 EAMG 模型中，我们还发现 CRIg/FH 治疗可显著降低血清中自身抗体和细胞因子（包括 IFN-γ、IL-2、IL-6 和 IL-17）的浓度，并上调脾脏中 Treg 细胞的比例，这进一步得到了验证。因此，我们的研究结果表明，CRIg/FH 可能具有治疗 MG 的潜力，可用于免疫调节。
