Type I IFN–dependent FcγRIV signaling in murine monocytes promotes lethal anaphylaxis during viral infections
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
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
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Research Article Autoimmunity Immunology Infectious disease

Type I IFN–dependent FcγRIV signaling in murine monocytes promotes lethal anaphylaxis during viral infections

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

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Figure 8

FcγRIV post-infection crosslinking triggers PAF production, leading to mortality in infected mice.

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FcγRIV post-infection crosslinking triggers PAF production, leading to m...
(A) Serum PAF levels in naive WT mice and LCMV-infected WT and Fcgr4–/– mice (1 × 106 PFU) 20 minutes after i.p. 9E9 (200 μg) or isotype control treatment, 24 h.p.i. Data were pooled from 2 experiments (n = 2–4 mice/group/experiment). (B) Serum PAF levels in LCMV-infected mice (1 × 106 PFU) 20 minutes after i.p. 9E9 (200 μg) or isotype control treatment. Some mice received MC-21 (CCR2-depleting antibody, 35 μg) or an isotype control antibody. Data were pooled from 2 independent experiments (or 1 experiment for isotype-treated animals) with similar results (n = 2–3 mice/group/experiment). (C) Serum PAF levels in LCMV-infected (1 × 106 PFU) WT and Ifnar1–/– mice, which were treated with either 9E9 (200 μg) or an isotype control 24 h.p.i. Data were pooled from 2 independent experiments with similar results (n = 2–3 mice/group/experiment). (D) Kaplan-Meier survival curves, body temperature, and clinical score (Supplemental Table 1) were used to compare LCMV-infected (1 × 106 PFU) WT mice treated with 200 μg 9E9 antibody 24 h.p.i. One group received an additional treatment with a PAF-R blocker (WEB2086) (100 μg) 20 minutes before the 9E9 treatment. Data were pooled from 2 experiments (n = 3–4 mice/group/experiment). All data are presented as the mean ± SD. *P < 0.05, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (A– C) or log-rank test for survival or 2-way ANOVA for body temperature and clinical score (D).