A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.

广泛的临床表现已成为严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) COVID-19 大流行的标志，尽管多种疾病结果的免疫学基础仍有待确定。我们通过高维流式细胞术对 B 细胞反应进行了详细表征，以揭示效应子和未成熟群体的显着异质性。更值得注意的是，重症患者表现出滤泡外 B 细胞活化的标志，并具有先前在自身免疫环境中描述的 B 细胞库特征。滤泡外激活与大量分泌抗体的细胞扩增和早期产生高浓度的 SARS-CoV-2 特异性中和抗体密切相关。然而，这些患者患有严重的疾病，炎症生物标志物升高，多器官衰竭和死亡。总体而言，这些发现强烈表明免疫激活在 COVID-19 患者亚群中具有致病作用。我们的研究提供了进一步的证据，表明靶向免疫调节疗法可能对特定的患者亚群有益，并且可以通过仔细的免疫分析来了解。