The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404 In a large immunological and genomics study of COVID-19 patients, autoantibodies to type 1 interferons correlated with outcomes. INTRODUCTION Interindividual clinical variability is vast in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranging from silent infection to rapid death. Three risk factors for life-threatening coronavirus disease 2019 (COVID-19) pneumonia have been identified—being male, being elderly, or having other medical conditions—but these risk factors cannot explain why critical disease remains relatively rare in any given epidemiological group. Given the rising toll of the COVID-19 pandemic in terms of morbidity and mortality, understanding the causes and mechanisms of life-threatening COVID-19 is crucial. RATIONALE B cell autoimmune infectious phenocopies of three inborn errors of cytokine immunity exist, in which neutralizing autoantibodies (auto-Abs) against interferon-γ (IFN-γ) (mycobacterial disease), interleukin-6 (IL-6) (staphylococcal disease), and IL-17A and IL-17F (mucocutaneous candidiasis) mimic the clinical phenotypes of germline mutations of the genes that encode the corresponding cytokines or receptors. Human inborn errors of type I IFNs underlie severe viral respiratory diseases. Neutralizing auto-Abs against type I IFNs, which have been found in patients with a few underlying noninfectious conditions, have not been unequivocally shown to underlie severe viral infections. While searching for inborn errors of type I IFN immunity in patients with life-threatening COVID-19 pneumonia, we also tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19. We searched for auto-Abs against type I IFNs in 987 patients hospitalized for life-threatening COVID-19 pneumonia, 663 asymptomatic or mildly affected individuals infected with SARS-CoV-2, and 1227 healthy controls from whom samples were collected before the COVID-19 pandemic. RESULTS At least 101 of 987 patients (10.2%) with life-threatening COVID-19 pneumonia had neutralizing immunoglobulin G (IgG) auto-Abs against IFN-ω (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three individual type I IFNs. These auto-Abs neutralize high concentrations of the corresponding type I IFNs, including their ability to block SARS-CoV-2 infection in vitro. Moreover, all of the patients tested had low or undetectable serum IFN-α levels during acute disease. These auto-Abs were present before infection in the patients tested and were absent from 663 individuals with asymptomatic or mild SARS-CoV-2 infection (P < 10−16). They were present in only 4 of 1227 (0.33%) healthy individuals (P < 10−16) before the pandemic. The patients with auto-Abs were 25 to 87 years old (half were over 65) and of various ancestries. Notably, 95 of the 101 patients with auto-Abs were men (94%). CONCLUSION A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. These findings provide a first explanation for the excess of men among patients with life-threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-β). Neutralizing auto-Abs to type I IFNs underlie life-threatening COVID-19 pneumonia. We tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19 by impairing the binding of type I IFNs to their receptor and the activation of the downstream responsive pathway. Neutralizing auto-Abs are represented in red, and type I IFNs are represented in blue. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. ISGs, IFN-stimulated genes; TLR, Toll-like receptor; IFNAR, IFN-α/β receptor; pSTAT, phosphorylated signal transducers and activators of transcription; IRF, interferon regulatory factor. Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

中文翻译：

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危及生命的 COVID-19 患者体内抗 I 型干扰素的自身抗体


严重 COVID-19 的遗传学基础免疫系统很复杂，涉及许多基因，包括编码称为干扰素 (IFN) 的细胞因子的基因。缺乏特定干扰素的个体可能更容易感染传染病。此外，自身抗体系统会抑制干扰素反应，以防止病原体引起的炎症造成的损害。现在有两项研究探讨了遗传学通过该系统的组成部分影响 2019 年严重冠状病毒病 (COVID-19) 风险的可能性（参见 Beck 和 Aksentijevich 的观点）。问：张等人。使用候选基因方法，确定了患有严重 COVID-19 的患者，这些患者在涉及 I 型和 III 型 IFN 免疫调节的基因中存在突变。他们发现这些基因在患者体内富集，并得出结论：遗传学可能决定感染的临床过程。巴斯塔德等人。在大约 10% 的重症 COVID-19 肺炎患者中发现了具有高滴度的针对 I 型 IFN-α2 和 IFN-ω 的中和自身抗体的个体。在无症状或表型较轻的感染者或健康个体中都没有发现这些自身抗体。这些研究共同确定了一种方法，可用于识别危及生命的 COVID-19 风险最高的个体。科学，本期第 14 页。 eabd4570，p。 eabd4585;另见 p. 404 在一项针对 COVID-19 患者的大型免疫学和基因组学研究中，1 型干扰素自身抗体与结果相关。简介 感染严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的人之间的临床变异很大，从无症状感染到快速死亡。 已确定危及生命的 2019 冠状病毒病 (COVID-19) 肺炎的三个危险因素——男性、老年人或患有其他疾病——但这些危险因素无法解释为什么危重疾病在任何特定流行病学群体中仍然相对罕见。鉴于 COVID-19 大流行的发病率和死亡率不断上升，了解危及生命的 COVID-19 的原因和机制至关重要。基本原理 存在细胞因子免疫的三种先天性错误的 B 细胞自身免疫感染表型，其中针对干扰素 γ (IFN-γ)（分枝杆菌疾病）、白细胞介素 6 (IL-6)（葡萄球菌疾病）的中和自身抗体（自身抗体） 、IL-17A 和 IL-17F（粘膜皮肤念珠菌病）模拟编码相应细胞因子或受体的基因种系突变的临床表型。人类 I 型干扰素的先天性缺陷是严重病毒性呼吸道疾病的根源。针对 I 型干扰素的中和自身抗体已在患有一些潜在非感染性疾病的患者中发现，但尚未明确表明是严重病毒感染的基础。在寻找危及生命的 COVID-19 肺炎患者的 I 型 IFN 免疫先天性缺陷时，我们还测试了这样的假设：中和针对 I 型 IFN 的自身抗体可能是关键的 COVID-19 的基础。我们在 987 名因危及生命的 COVID-19 肺炎而住院的患者、663 名感染 SARS-CoV-2 的无症状或轻度感染者以及 1227 名健康对照者中搜索了针对 I 型干扰素的自身抗体，这些健康对照者是在 COVID-19 疫情之前采集样本的。 19 流行病。结果 987 名患者中至少有 101 名（10.2%）患有危及生命的 COVID-19 肺炎的患者在治疗时具有针对 IFN-ω（13 名患者）、针对 13 种类型的 IFN-α (36) 或针对两者 (52) 的中和免疫球蛋白 G (IgG) 自身抗体。出现危重疾病；少数还具有针对其他三种 I 型干扰素的自身抗体。这些自身抗体可中和高浓度的相应 I 型干扰素，包括它们在体外阻断 SARS-CoV-2 感染的能力。此外，所有接受测试的患者在急性疾病期间血清 IFN-α 水平较低或检测不到。这些自身抗体在受测试的患者感染前就存在，但在 663 名无症状或轻度 SARS-CoV-2 感染者中不存在 (P < 10−16)。在大流行之前，它们仅存在于 1227 名健康个体中的 4 名 (0.33%) (P < 10−16) 中。携带自身抗体的患者年龄在 25 岁至 87 岁之间（一半超过 65 岁）并且具有不同的血统。值得注意的是，101 名自身抗体患者中有 95 名是男性（94%）。结论 I 型 IFN 免疫先天性缺陷的 AB 细胞自身免疫表型导致至少 2.6% 的女性和 12.5% 的男性出现危及生命的 COVID-19 肺炎。在这些患者中，适应性自身免疫损害先天和内在的抗病毒免疫。这些发现首次解释了危及生命的 COVID-19 患者中男性过多以及随着年龄的增长风险增加的原因。它们还提供了一种方法来识别有可能患上危及生命的 COVID-19 的个人，并确保他们参加疫苗试验。最后，它们为预防和治疗铺平了道路，包括血浆置换、浆母细胞耗竭和非自身抗体（例如 IFN-β）靶向的重组 I 型干扰素。中和 I 型 IFN 的自身抗体是危及生命的 COVID-19 肺炎的基础。 我们测试了这样的假设：中和 I 型 IFN 的自身抗体可能通过损害 I 型 IFN 与其受体的结合以及下游响应途径的激活而成为关键的 COVID-19 的基础。中和自身抗体以红色表示，I 型干扰素以蓝色表示。在这些患者中，适应性自身免疫损害先天和内在的抗病毒免疫。 ISGs，干扰素刺激基因； TLR，Toll 样受体； IFNAR、IFN-α/β受体； pSTAT，磷酸化信号转导子和转录激活子； IRF，干扰素调节因子。严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染过程中的个体间临床差异很大。我们报告，987 名危及生命的 2019 年冠状病毒病 (COVID-19) 肺炎患者中，至少有 101 名患者体内存在抗干扰素 ω (IFN-ω) 的中和免疫球蛋白 G (IgG) 自身抗体 (auto-Abs)（13 名患者），危重疾病发作时使用 13 种 IFN-α (36)，或同时对抗两种 (52)；少数还具有针对其他三种 I 型干扰素的自身抗体。自身抗体可以中和相应的 I 型干扰素在体外阻断 SARS-CoV-2 感染的能力。在 663 名无症状或轻度 SARS-CoV-2 感染者中未发现这些自身抗体，并且在 1227 名健康人中仅 4 人存在这些自身抗体。携带自身抗体的患者年龄在 25 岁至 87 岁之间，101 名患者中有 95 名是男性。 I 型 IFN 免疫先天性缺陷的 AB 细胞自身免疫表型导致至少 2.6% 的女性和 12.5% 的男性危及生命的 COVID-19 肺炎。