Cellular origin and characterization of autoantibodies against type I IFNs in COVID-19 and APS-1
Year: 2026
Type: article
Study design: Observational Study
Abstract: Autoantibodies against type I IFNs can severely compromise antiviral defense, yet the mechanisms underlying their development remain elusive. Using high-throughput autoantigen profiling, we observed that a subgroup of severe COVID-19 patients exhibited strong binding to multiple type I IFNs. Integrated single-cell RNA and B cell receptor (BCR) sequencing with functional analysis identified B cell subsets/states enriched for IFN-α2-binding and -neutralizing antibodies in COVID-19. These findings were compared with those from patients with autoimmune polyendocrine syndrome type I, a rare genetic disease characterized by defective immune tolerance and persistent type I IFN autoimmunity. Competition surface plasmon resonance and AlphaFold 3 structural modeling identified three major functional epitope groups and seven predicted structural subclasses among neutralizing antibodies. Our results indicate that IFN-α2 autoreactivity is present in both naive and antigen-experienced B cell compartments, whereas functional IFN-neutralizing antibodies are predominantly associated with memory and atypical B cells, consistent with defective tolerance and affinity maturation-mediated selection of autoreactive B cell clones.
DOI: 10.1084/jem.20260268
Authors: Rui Sun, Siyu Lin, Luca Simonelli, Benedikt Strunz, Anish Behere, Mattia Pedotti, Tian Xu, Fanglei Zuo, Likun Du, Hui Wan, Sara Lestani, Leire de Campos-Mata, Stelios Vlachiotis, Dorottya Kalmár, Karolinska KI/K COVID-19 Study Group, Anders Sönnerborg, Dorota Religa, Susanna Brighenti, Benedict J. Chambers, Martin Cornillet, Angelica Cuapio, Malin Flodström-Tullberg, Nicole Marquardt, Jagadeeswara Rao Muvva, Anna Norrby-Teglund, Johan K. Sandberg, David Wullimann, Isabel Diaz Lozano, Kristoffer Strålin, Soo Aleman, Hans-Gustaf Ljunggren, Antonio Piralla, Fausto Baldanti, Olle Kämpe, Sophie Bensing, Lennart Hammarström, Nils Landegren, Zexian Zeng, Niklas K. Björkström, Luca Varani, Harold Marcotte, Qiang Pan-Hammarström
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Awards: Creation of a COVID-19 Immune Atlas to rapidly repurpose available drugs targeting signaling and metabolism of immune cells, Mucosal immunity against SARS-CoV-2 – an unexplored field, Regulation of immunoglobulin gene diversification: with relevance for primary immunodeficiency and lymphoid malignancies, G734294072, Multispecific antibodies against infectious diseases
OpenAlex ID: W7225139524