Autoantibodies against type I IFNs in patients with life-threatening COVID-19.
Autoantibodies against type I IFNs in patients with life-threatening COVID-19.
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危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
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发表时间：
2020-10-23
期刊：
影响因子：
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通讯作者：
Casanova JL
中科院分区：
文献类型：
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作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
免疫系统是复杂的，涉及许多基因，包括那些编码被称为干扰素（ifn）的细胞因子的基因。缺乏特异性干扰素的个体更容易感染传染病。此外，自身抗体系统抑制IFN反应，以防止病原体引起的炎症损害。现在有两项研究调查了遗传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（见Beck和Aksentijevich的观点）。Q. Zhang等人使用候选基因方法确定了参与I型和III型IFN免疫调节的基因突变的严重COVID-19患者。他们在患者体内发现了这些基因的富集，并得出结论：基因可能决定了感染的临床病程。Bastard等人在约10%的COVID-19重症肺炎患者中发现了高滴度的针对I型IFN-α2和IFN-ω的中和性自身抗体。这些自身抗体在无症状或表型较轻的感染者或健康个体中均未发现。总之，这些研究确定了一种方法，可以通过这种方法识别危及生命的COVID-19风险最高的个体。《科学》，本期p., p. eabd4585；另见p.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预后相关。感染了严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的人的个体间临床差异很大，从无声感染到迅速死亡。目前已经确定了危及生命的2019冠状病毒病（COVID-19）肺炎的三个风险因素——男性、老年人或有其他疾病——但这些风险因素无法解释为什么在任何特定的流行病学群体中，重症疾病仍然相对罕见。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。存在三种先天性细胞因子免疫错误的B细胞自身免疫感染表型，其中针对干扰素-γ (IFN-γ)（分枝杆菌病）、白细胞介素-6 (IL-6)（葡萄球菌病）和IL-17A和IL-17F（粘膜皮肤念珠菌病）的中和性自身抗体（autoabs）模拟编码相应细胞因子或受体的基因的种系突变的临床表型。I型干扰素的人类先天性错误是严重的病毒性呼吸道疾病的基础。针对I型ifn的中和性自身抗体，已在一些潜在的非感染性疾病患者中发现，但尚未明确显示是严重病毒感染的基础。在寻找危及生命的COVID-19肺炎患者I型IFN免疫的先天性错误时，我们还验证了一种假设，即中和I型IFN的自身抗体可能是COVID-19关键的基础。我们在987例因危及生命的COVID-19肺炎住院的患者、663例无症状或轻度感染的SARS-CoV-2感染者以及1227名在COVID-19大流行前采集样本的健康对照中寻找针对I型IFNs的自身抗体。在987例危及生命的COVID-19肺炎患者中，至少有101例（10.2%）在危重疾病发病时具有针对IFN-ω（13例）、针对13种IFN-α（36例）或针对两种IFN-α（52例）的中和免疫球蛋白G （IgG）自身抗体；少数人也有针对其他三种I型干扰素的自动抗体。这些自身抗体可以中和高浓度的相应I型ifn，包括它们在体外阻断SARS-CoV-2感染的能力。此外，所有接受检测的患者在急性疾病期间血清IFN-α水平均较低或检测不到。663例无症状或轻度SARS-CoV-2感染患者在感染前存在这些自身抗体（P < 10−16）。在大流行之前，1227名健康个体中只有4人（0.33%）存在这种病毒（P < 10−16）。有自体抗体的患者年龄在25 - 87岁之间（其中一半超过65岁），来自不同的祖先。值得注意的是，101例自体抗体患者中有95例为男性（94%）。在至少2.6%的女性和12.5%的男性中，先天性I型IFN免疫错误的B细胞自身免疫表型导致了危及生命的COVID-19肺炎。在这些患者中，适应性自身免疫损害了先天和内在抗病毒免疫。这些发现为危及生命的COVID-19患者中男性过多以及风险随年龄增长而增加提供了第一个解释。它们还提供了一种手段，可以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、血浆母细胞耗散和非自身抗体靶向的重组I型IFN（如IFN-β）。我们测试了一种假设，即中和I型ifn的auto-Abs可能通过损害I型ifn与其受体的结合和下游反应途径的激活而成为COVID-19的基础。中和的自体抗体用红色表示，I型干扰素用蓝色表示。在这些患者中，适应性自身免疫损害了先天和内在抗病毒免疫。ISGs，干扰素刺激基因；toll样受体；IFNAR， IFN-α/β受体；pSTAT，磷酸化信号转导和转录激活因子；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变异性很大。我们报道，在987例危及生命的冠状病毒病2019 （COVID-19）肺炎患者中，至少有101例在危重疾病发病时具有针对干扰素-ω (IFN-ω)（13例）、针对13种IFN-α（36例）或针对两者（52例）的中和性免疫球蛋白G （IgG）自身抗体（auto-Abs）；少数人也有针对其他三种I型干扰素的自动抗体。在体外，自体抗体可中和相应I型干扰素阻断SARS-CoV-2感染的能力。663名无症状或轻度SARS-CoV-2感染的个体中未发现这些自身抗体，1227名健康个体中只有4人存在这些抗体。自体抗体患者年龄在25 - 87岁之间，101例患者中有95例为男性。在至少2.6%的女性和12.5%的男性中，先天性I型IFN免疫错误的B细胞自身免疫表型导致了危及生命的COVID-19肺炎。
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. , p. eabd4585; see also p. In a large immunological and genomics study of COVID-19 patients, autoantibodies to type 1 interferons correlated with outcomes. 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. 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. 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%). 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). 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.
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DOI：
10.1093/bioinformatics/8.3.275
发表时间：
1992-06-01
期刊：
COMPUTER APPLICATIONS IN THE BIOSCIENCES
影响因子：
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作者：
JONES, DT;TAYLOR, WR;THORNTON, JM
通讯作者：
THORNTON, JM
影响因子：
9.5
作者：
Katoh K;Rozewicki J;Yamada KD
通讯作者：
Yamada KD
影响因子：
16.8
作者：
Hoffmann HH;Schneider WM;Rice CM
通讯作者：
Rice CM
影响因子：
13.3
作者：
Mathian, Alexis;Mouries-Martin, Suzanne;Amoura, Zahir
通讯作者：
Amoura, Zahir
影响因子：
11.8
作者：
Döffinger, R;Helbert, MR;Kumararatne, DS
通讯作者：
Kumararatne, DS