Type I IFN-dependent FcγRIV signaling in murine monocytes promotes lethal anaphylaxis during viral infections
Elwy A, Abdelrahman H, Specht J, Ewert GM, Friebus-Kardash J, Dhiman S, Falkenstein J, Christ TC, Wiebeck E, Shamoon A, Leimkühler NB, Gramberg T, Ruß A, Kalinke U, Kuang F, Sutter K, Kopf M, Mack M, Hansen W, Nimmerjahn F, Lang KS (2026)
Publication Type: Journal article
Publication year: 2026
Journal
Book Volume: 136
Journal Issue: 4
DOI: 10.1172/JCI192371
Abstract
Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by FcγRIV, the homolog of human FcγRIIIa. FcγRIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of FcγRIV on inflammatory monocytes, an effect absent in type I IFN receptor-deficient (Ifnar1-deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, FcγRIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type I IFN-dependent (IFN-I-dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fcγ receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.
Authors with CRIS profile
Thomas Gramberg
Professur für Antivirale Angeborene Immunität
Alina Ruß
Institute of Clinical and Molecular Virology
Falk Nimmerjahn
Lehrstuhl für Genetik
Involved external institutions
Universitätsklinikum Essen
Germany (DE)
Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich
Switzerland (CH)
Universitätsklinikum Regensburg
Germany (DE)
Zentrum für Experimentelle und Klinische Infektionsforschung GmbH (TWINCORE)
Germany (DE)
Germany (DE)
Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich
Switzerland (CH)
Universitätsklinikum Regensburg
Germany (DE)
Zentrum für Experimentelle und Klinische Infektionsforschung GmbH (TWINCORE)
Germany (DE)
How to cite
APA:
Elwy, A., Abdelrahman, H., Specht, J., Ewert, G.M., Friebus-Kardash, J., Dhiman, S.,... Lang, K.S. (2026). Type I IFN-dependent FcγRIV signaling in murine monocytes promotes lethal anaphylaxis during viral infections. Journal of Clinical Investigation, 136(4). https://doi.org/10.1172/JCI192371
MLA:
Elwy, Abdelrahman, et al. "Type I IFN-dependent FcγRIV signaling in murine monocytes promotes lethal anaphylaxis during viral infections." Journal of Clinical Investigation 136.4 (2026).
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