tetano
Editor, Senior Moderator
J Exp Med
. 2026 Nov 2;223(12):e20260268.
doi: 10.1084/jem.20260268. Epub 2026 Nov 3.
Rui Sun # 1 , Siyu Lin # 2 , Luca Simonelli # 3 , Benedikt Strunz 4 , Anish Behere 5 , Mattia Pedotti 3 , Tian Xu 2 , Fanglei Zuo 1 , Likun Du 1 , Hui Wan 1 , Sara Lestani 3 , Leire de Campos-Mata 1 , Stelios Vlachiotis 1 , Dorottya Kalmár 1 ; Karolinska KI/K COVID-19 Study Group; Kristoffer Strålin 4 6 , Soo Aleman 4 6 , Hans-Gustaf Ljunggren 4 , Antonio Piralla 7 , Fausto Baldanti 7 8 , Olle Kämpe 9 10 , Sophie Bensing 9 10 , Lennart Hammarström 1 , Nils Landegren 5 , Zexian Zeng 2 , Niklas K Björkström 4 , Luca Varani 3 , Harold Marcotte 1 , Qiang Pan-Hammarström 1
Collaborators, Affiliations Expand
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.
. 2026 Nov 2;223(12):e20260268.
doi: 10.1084/jem.20260268. Epub 2026 Nov 3.
Cellular origin and characterization of autoantibodies against type I IFNs in COVID-19 and APS-1
Rui Sun # 1 , Siyu Lin # 2 , Luca Simonelli # 3 , Benedikt Strunz 4 , Anish Behere 5 , Mattia Pedotti 3 , Tian Xu 2 , Fanglei Zuo 1 , Likun Du 1 , Hui Wan 1 , Sara Lestani 3 , Leire de Campos-Mata 1 , Stelios Vlachiotis 1 , Dorottya Kalmár 1 ; Karolinska KI/K COVID-19 Study Group; Kristoffer Strålin 4 6 , Soo Aleman 4 6 , Hans-Gustaf Ljunggren 4 , Antonio Piralla 7 , Fausto Baldanti 7 8 , Olle Kämpe 9 10 , Sophie Bensing 9 10 , Lennart Hammarström 1 , Nils Landegren 5 , Zexian Zeng 2 , Niklas K Björkström 4 , Luca Varani 3 , Harold Marcotte 1 , Qiang Pan-Hammarström 1
Collaborators, Affiliations Expand
- PMID: 42975591
- PMCID: PMC13729907
- DOI: 10.1084/jem.20260268
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.