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Editor's note
Open Access | 
10.1172/JCI203729
Primed to overreact: virus-induced IFN contributes to antibody-mediated anaphylaxis
Pablo Penaloza-MacMaster, Associate Editor
Address correspondence to: Pablo Penaloza-MacMaster, Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 3 Blackfan Circle, CLS 1003, Boston, Massachusetts, 02215, USA. Phone: 617.735.4450; Email: ppenaloz@bidmc.harvard.edu.
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Published February 16, 2026 - More info
J Clin Invest. 2026;136(4):e203729. https://doi.org/10.1172/JCI203729.
© 2026 Penaloza-MacMaster et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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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
Abdelrahman Elwy, Hossam Abdelrahman, Julia Specht, Gina M. Ewert, Justa Friebus-Kardash, Swati Dhiman, Julia Falkenstein, Theresa Charlotte Christ, Elisa Wiebeck, Arzoo Shamoon, Nils B. Leimkühler, Thomas Gramberg, Alina Russ, Ulrich Kalinke, Fei Kuang, Kathrin Sutter, Manfred Kopf, Matthias Mack, Wiebke Hansen, Falk Nimmerjahn, Karl S. Lang
Type I IFNs (IFN-I) are upregulated upon viral infection to restrict viral replication and orchestrate innate and adaptive immune responses. Yet, a growing body of literature has revealed that IFN-I can also have deleterious consequences, particularly when dysregulated or excessive (1–4). Clinical observations have suggested that among these consequences is an increased susceptibility to anaphylaxis during viral infections, with speculation that virus-induced IFN-I may be implicated, although the underlying mechanisms have remained unclear (5, 6).
In this issue of the JCI, Elwy, Abdelrahman, and co-authors (7) examined the effects of virus-induced IFN-I in mouse models of anaphylaxis and demonstrated that IFN-I can exacerbate antibody-mediated hypersensitivity reactions. Rather than directly mediating anaphylaxis, IFN-I induced upregulation of Fc receptors on innate immune cells, lowering the threshold for catastrophic anaphylaxis driven by antibody effector functions. Using various models of viral infection in mice, this study showed that IgG-mediated anaphylaxis was amplified during acute viral infection, driven predominantly by the Fc receptor FcγRIV, a murine homolog of human FcγRIII. Mechanistically, viral infection induced IFN-I responses, which then upregulated FcγRIV expression on inflammatory monocytes, rendering the animals more susceptible to antibody-mediated anaphylaxis. Blockade of IFN-I signaling abrogated FcγRIV upregulation and protected infected mice from anaphylaxis, establishing IFN-I as an essential upstream pathway implicated in the disease. In addition, Elwy, Abdelrahman, and co-authors showed that FcγRIV engagement on inflammatory monocytes triggered the production of platelet-activating factor (PAF), a potent vasoactive mediator responsible for lethal anaphylaxis. Pharmacologic blockade of the PAF receptor rescued the mice from anaphylaxis, highlighting a druggable downstream pathway. The authors also extended some of these findings to humans by demonstrating increased frequencies of FcγRIII-expressing monocytes in patients with COVID-19, who are known to exhibit a predisposition to allergic reactions (5, 6).
Together, these findings show that virus-induced IFN-I can act as a double-edged sword that, despite its role in coordinating antiviral defenses, can also predispose the host to lethal anaphylaxis. This work adds an important dimension to the IFN-I paradox and identifies Fc receptors and PAF as potential therapeutic targets to prevent anaphylaxis associated with viral infections.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)