Division of Infection and Immunity and Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London NW3 2PP, UK; Centre for Rheumatology, Division of Medicine, University College London, London WC1E 6JF, UK.
Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Cell Rep Med. 2023 Jan 17;4(1):100894. doi: 10.1016/j.xcrm.2022.100894.
Systemic lupus erythematosus (SLE) is characterized by increased expression of type I interferon (IFN)-regulated genes in 50%-75% of patients. We report that out of 501 patients with SLE analyzed, 73 (14%) present autoantibodies against IFNα (anti-IFN-Abs). The presence of neutralizing-anti-IFN-Abs in 4.2% of patients inversely correlates with low circulating IFNα protein levels, inhibition of IFN-I downstream gene signatures, and inactive global disease score. Hallmarks of SLE pathogenesis, including increased immature, double-negative plasmablast B cell populations and reduction in regulatory B cell (Breg) frequencies, were normalized in patients with neutralizing anti-IFN-Abs compared with other patient groups. Immunoglobulin G (IgG) purified from sera of patients with SLE with neutralizing anti-IFN-Abs impedes CpGC-driven IFNα-dependent differentiation of B cells into immature B cells and plasmablasts, thus recapitulating the neutralizing effect of anti-IFN-Abs on B cell differentiation in vitro. Our findings highlight a role for neutralizing anti-IFN-Abs in controlling SLE pathogenesis and support the use of IFN-targeting therapies in patients with SLE lacking neutralizing-anti-IFN-Abs.
系统性红斑狼疮（SLE）的特征是 50%-75%的患者中存在 I 型干扰素（IFN）调节基因的表达增加。我们报告称，在分析的 501 名 SLE 患者中，有 73 名（14%）存在针对 IFNα 的自身抗体（抗 IFN-Abs）。在 4.2%的患者中存在中和性抗 IFN-Abs，与循环 IFNα 蛋白水平低、IFN-I 下游基因特征抑制和无活动的全球疾病评分呈负相关。与其他患者群体相比，SLE 发病机制的特征标志物，包括增加的未成熟、双阴性浆母细胞群体和调节性 B 细胞（Breg）频率降低，在具有中和性抗 IFN-Abs 的患者中得到了正常化。从中性化抗 IFN-Abs 的 SLE 患者血清中纯化的 IgG 可阻止 CpGC 驱动的 B 细胞向未成熟 B 细胞和浆母细胞的 IFNα 依赖性分化，从而在体外再现抗 IFN-Abs 对 B 细胞分化的中和作用。我们的发现强调了中和性抗 IFN-Abs 在控制 SLE 发病机制中的作用，并支持在缺乏中和性抗 IFN-Abs 的 SLE 患者中使用 IFN 靶向治疗。
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