Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
J Clin Immunol. 2024 Apr 22;44(4):104. doi: 10.1007/s10875-024-01708-7.
Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs.
We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs.
Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor.
Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.
在患有危及生命的 2019 年冠状病毒病（COVID-19）的患者中已发现针对 I 型干扰素（IFN）的自身抗体（auto-abs），这表明自身抗体的存在可能是疾病严重程度的一个危险因素。因此，我们研究了自身抗 I 型 IFN 引起 COVID-19 恶化的机制。
我们评估了 123 例 COVID-19 患者的血浆以测量针对 I 型 IFNs 的自身抗体。我们对自身抗体阳性患者的外周血单核细胞进行单细胞 RNA 测序（scRNA-seq），并进行自身抗体的表位作图。
19 例严重 COVID-19 患者中有 3 例和 42 例危重症 COVID-19 患者中有 4 例存在中和针对 I 型 IFN 的自身抗体。有自身抗 I 型 IFNs 的患者无特征性的临床特征。38 例 COVID-19 患者的 scRNA-seq 显示，常规树突状细胞和经典单核细胞中的 IFN 信号转导减弱，自身抗体阳性患者的 SARS-CoV-2 特异性 BCR 库减少。此外，来自自身抗体阳性 COVID-19 患者的 IFN-α2 自身抗体识别 IFN-α2 的特征性表位，该表位与受体结合。
在 COVID-19 患者中发现的针对 I 型 IFN 的自身抗体通过阻断 I 型 IFN 与其受体的结合来抑制树突状细胞和单核细胞中的 IFN 信号转导。未能适当诱导产生针对 SARS-CoV-2 的抗体可能是 COVID-19 严重程度的一个致病因素。
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