COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses^1,2,3,4,5,6. Although pathological innate immune activation is well-documented in severe disease¹, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling⁷ to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.

COVID-19 表现出多种临床表型，其特征是宿主免疫反应夸大和误导^1,2,3,4,5,6 。尽管病理性先天免疫激活在严重疾病中已有充分记录¹ ，但自身抗体对疾病进展的影响尚不明确。在这里，我们使用一种称为快速细胞外抗原分析⁷的高通量自身抗体发现技术来筛查 194 名 SARS-CoV-2 感染者，其中包括 172 名 COVID-19 患者和 22 名患有轻症或无症状感染的医护人员，针对 2,770 种细胞外和分泌蛋白（外蛋白组成员）的自身抗体。我们发现，与未感染者相比，COVID-19 患者的自身抗体反应性显着增加，并且针对免疫调节蛋白（包括细胞因子、趋化因子、补体成分和细胞表面蛋白）的自身抗体的流行率很高。我们确定这些自身抗体通过抑制免疫受体信号传导和改变外周免疫细胞组成来扰乱免疫功能并损害病毒学控制，并发现这些自身抗体的小鼠替代物会增加 SARS-CoV-2 感染小鼠模型中疾病的严重程度。我们对组织相关抗原的自身抗体的分析揭示了与特定临床特征的关联。我们的研究结果表明，外蛋白组导向的自身抗体在 COVID-19 中具有病理作用，对免疫功能以及与临床结果的关联具有多种影响。