Division of Immunology and Rheumatology, Department of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA.
Division of HIV, Infectious Diseases & Global Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
Sci Transl Med. 2024 Nov 6;16(772):eadq1789. doi: 10.1126/scitranslmed.adq1789.
Preexisting anti-interferon-α (anti-IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti-IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti-IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti-SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti-IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti-IFN-α response. In contrast, systemic IgG1 anti-IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti-IFN-α in the immunopathology of COVID-19 and suggest that anti-IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa.
血液中预先存在的抗干扰素-α（anti-IFN-α）自身抗体与危及生命的 COVID-19 易感性相关。然而，尚不清楚气道中的抗 IFN-α 自身抗体，即感染的初始部位，是否也可以决定疾病结局。在这项研究中，我们开发了一种多参数技术 FlowBEAT，用于定量和分析来自 129 名供体的气道和血液中 20 个月的纵向样本中针对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）和抗 IFN-α 的抗体的同种型。我们发现，在超过 70%的轻症和中度 COVID-19 病例中，在感染发作后会诱导鼻 IgA1 抗 IFN-α 自身抗体，与强大的抗 SARS-CoV-2 免疫、较少的症状和有效的恢复相关。鼻抗 IFN-α 自身抗体跟随宿主 IFN-α 产生的高峰，随着疾病的恢复而减弱，揭示了 IFN-α 和抗 IFN-α 反应之间的调节平衡。相比之下，系统性 IgG1 抗 IFN-α 自身抗体出现较晚，仅在一些伴有全身炎症和症状恶化的患者中检测到。这些数据揭示了鼻抗 IFN-α 在 COVID-19 免疫病理学中的保护作用，并表明抗 IFN-α 自身抗体可能在呼吸道黏膜病毒感染后发挥稳态功能来调节宿主 IFN-α。
