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Peer-reviewedCC BYThe Journal of experimental medicine

Cellular origin and characterization of autoantibodies against type I IFNs in COVID-19 and APS-1.

  • Rui Sun1
  • Siyu Lin2
  • Luca Simonelli3
  • Benedikt Strunz4
  • Anish Behere5
  • Mattia Pedotti3
  • Tian Xu2
  • Fanglei Zuo1
  • Likun Du1
  • Hui Wan1
  • Sara Lestani3
  • Leire de Campos-Mata1
17 more authors
  • Stelios Vlachiotis1
  • Dorottya Kalmár1
  • Karolinska KI/K COVID-19 Study Group
  • Kristoffer Strålin4,6
  • Soo Aleman4,6
  • Hans-Gustaf Ljunggren4
  • Antonio Piralla7
  • Fausto Baldanti7,8
  • Olle Kämpe9,10
  • Sophie Bensing9,10
  • Lennart Hammarström1
  • Nils Landegren5
  • Zexian Zeng2
  • Niklas K Björkström4
  • Luca Varani3
  • Harold Marcotte1
  • Qiang Pan-Hammarström1
10 affiliations
  1. 1Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
  2. 2Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University , Beijing, China.
  3. 3Institute for Research in Biomedicine, Università Della Svizzera Italiana , Bellinzona, Switzerland.
  4. 4Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  5. 5Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
  6. 6Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
  7. 7Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
  8. 8Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy.
  9. 9Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.
  10. 10Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.
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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.

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Cite

BibTeXRIS
BibTeX
@article{sun2026cellular,
  title = {{Cellular origin and characterization of autoantibodies against type I IFNs in COVID-19 and APS-1.}},
  author = {Rui Sun and Siyu Lin and Luca Simonelli and Benedikt Strunz and Anish Behere and Mattia Pedotti and Tian Xu and Fanglei Zuo and Likun Du and Hui Wan and Sara Lestani and Leire de Campos-Mata and Stelios Vlachiotis and Dorottya Kalmár and Karolinska KI/K COVID-19 Study Group and Kristoffer Strålin and Soo Aleman and Hans-Gustaf Ljunggren and Antonio Piralla and Fausto Baldanti and Olle Kämpe and Sophie Bensing and Lennart Hammarström and Nils Landegren and Zexian Zeng and Niklas K Björkström and Luca Varani and Harold Marcotte and Qiang Pan-Hammarström},
  journal = {The Journal of experimental medicine},
  year = {2026},
  month = nov,
  doi = {10.1084/jem.20260268},
  url = {https://europepmc.org/article/MED/42975591},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Cellular origin and characterization of autoantibodies against type I IFNs in COVID-19 and APS-1.
AU  - Rui Sun
AU  - Siyu Lin
AU  - Luca Simonelli
AU  - Benedikt Strunz
AU  - Anish Behere
AU  - Mattia Pedotti
AU  - Tian Xu
AU  - Fanglei Zuo
AU  - Likun Du
AU  - Hui Wan
AU  - Sara Lestani
AU  - Leire de Campos-Mata
AU  - Stelios Vlachiotis
AU  - Dorottya Kalmár
AU  - Karolinska KI/K COVID-19 Study Group
AU  - Kristoffer Strålin
AU  - Soo Aleman
AU  - Hans-Gustaf Ljunggren
AU  - Antonio Piralla
AU  - Fausto Baldanti
AU  - Olle Kämpe
AU  - Sophie Bensing
AU  - Lennart Hammarström
AU  - Nils Landegren
AU  - Zexian Zeng
AU  - Niklas K Björkström
AU  - Luca Varani
AU  - Harold Marcotte
AU  - Qiang Pan-Hammarström
PY  - 2026
DA  - 2026/11/03
JO  - The Journal of experimental medicine
DO  - 10.1084/jem.20260268
UR  - https://europepmc.org/article/MED/42975591
AB  - 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.
SN  - 0022-1007
SN  - 1540-9538
ER  -