Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by neutralizing IFN-I autoantibody-containing plasmas from aged individuals with HIV-1 and from individuals with severe COVID-19. These faces overlap with IFN-I regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, and neutralizing plasmas efficiently block the interaction of IFN-I with both receptor subunits in vitro. In contrast, non-neutralizing autoantibody-containing plasmas limit the interaction of IFN-I with only one receptor subunit and display relatively low IFN-I-binding avidities, thus likely hindering neutralizing function. Iterative engineering of signaling-inert mutant IFN-Is (simIFN-Is) retaining dominant autoantibody targets created potent decoys that prevent IFN-I neutralization by autoantibody-containing plasmas and that restore IFN-I-mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting IFN-I autoantibodies from plasmas, leaving antiviral antibodies unaffected. Our study reveals mechanisms of action for IFN-I autoantibodies and demonstrates a proof-of-concept strategy to alleviate pathogenic effects.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2025-03-20
DOI
https://doi.org/10.1084/jem.20242039
Citations
13
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
Field-Weighted Citation Impact
17.68

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article

Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

Benjamin G. Hale, Enos Bernasconi, Dunja Nicca, Niklaus Daniel Labhardt et al.
13 citations
The Journal of Experimental Medicine
Monoclonal and Polyclonal Antibodies Research
17.68
article

Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

Benjamin G. Hale, Enos Bernasconi, Dunja Nicca, Niklaus Daniel Labhardt, Olivia Keiser, Angela Ciuffi, Sonja Fernbach, Paraskevas Filippidis, Heiner C. Bucher, Hans Hellmuth Hirsch, Hansjakob Furrer, Sabine Yerly, Johannes Nemeth, Karoline Aebi‐Popp, Karoline Leuzinger, Maja Weisser, Gilles Wandeler, Irène A. Abela, Helen Kovari, David Jackson‐Perry, Ferran Roche‐Campo, Anna Hachfeld, P Paioni, Matthieu Perreau, Barbara Hasse, Philip Tarr, Karin J. Metzner, Silvio D. Brugger, Luisa Salazar‐Vizcaya, Thomas Klimkait, D Haerry, Alexandra Calmy, Huldrych F. Günthard, Alexandra Trkola, Christian R. Kahlert, Michael Huber, Esther Sauras-Colón, Laurent Kaiser, Matthias Cavassini, Kevin Groen, Pedro David Wendel‐Garcia, Roger D. Kouyos, Roberto F. Speck, Julia Notter, Matthias Egger, Jan Fehr, Marylène Lejeune, Giuseppe Pantaleo, Katharina Kusejko, Dominique L. Braun, Andri Rauch, Jacques Fellay, A Anagnostopoulos, Roger Kuratli, Nicolas Müller, Patrick Schmid, Begogna Martinez de Tejada, Luisa Elzi, G Dollenmaier, Matthias Hoffmann, Christoph A. Fux, Manuel Battegay, Catja Marzolini, M Stöckle, Irène Hösli, Willy I. Staiger, Jannik Enkelmann
article en
13 citations

Abstract

Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by neutralizing IFN-I autoantibody-containing plasmas from aged individuals with HIV-1 and from individuals with severe COVID-19. These faces overlap with IFN-I regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, and neutralizing plasmas efficiently block the interaction of IFN-I with both receptor subunits in vitro. In contrast, non-neutralizing autoantibody-containing plasmas limit the interaction of IFN-I with only one receptor subunit and display relatively low IFN-I-binding avidities, thus likely hindering neutralizing function. Iterative engineering of signaling-inert mutant IFN-Is (simIFN-Is) retaining dominant autoantibody targets created potent decoys that prevent IFN-I neutralization by autoantibody-containing plasmas and that restore IFN-I-mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting IFN-I autoantibodies from plasmas, leaving antiviral antibodies unaffected. Our study reveals mechanisms of action for IFN-I autoantibodies and demonstrates a proof-of-concept strategy to alleviate pathogenic effects.

The Journal of Experimental MedicineVol. 222(6)
University of Bern (CH), University of Zurich (CH), University Hospital of Bern (CH), University Hospital of Zurich (CH), Institut de Recerca Biomèdica Catalunya Sud (ES), Institute of Virology of the Slovak Academy of Sciences (SK), University of Lausanne (CH)
National Science Foundation, Novartis Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Novartis Stiftung für Medizinisch-Biologische Forschung, Université de Genève, Universität Zürich
Good health and well-being
Openalex Percentile: Top 1%
Monoclonal and Polyclonal Antibodies Research
17.68
DOIOpen Access PDFOpenAlex
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