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 6

Inflammatory monocytes are essential mediators of anaphylaxis upon viral infection.

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Inflammatory monocytes are essential mediators of anaphylaxis upon viral...
(A) WT mice were infected with LCMV (1 × 106 PFU) and treated with 9E9 (20 μg) or isotype 24 h.p.i. One group received RB6-8C5 (200 μg) 2 h.p.i. Survival, body temperature, and clinical score were monitored over time. Data were pooled from 2 experiments (n = 3 mice/group/experiment). (B) WT mice infected with LCMV (1 × 106 PFU) were treated 24 h.p.i. with 9E9 (20 μg) or an isotype control. CCR2+ inflammatory monocytes were depleted with MC-21 antibody (35 μg) 2 h.p.i. Survival, body temperature, and clinical score were monitored over time. Data were pooled from 3 experiments (n = 2–3 mice/group/experiment). (C) LCMV-infected WT mice received PSA (anti-BSA IgG 1,000 μg + BSA 300 μg) 24 h.p.i., Some mice received MC-21 antibody. Survival, body temperature, and clinical score were monitored over time. Data were pooled from 2 experiments (n = 3 mice/group/experiment). (D) Ifnar1fl/fl Cx3cr1-CreERtg/+ mice and littermate controls were treated with tamoxifen to induce Cre recombination, infected with LCMV (1 × 106 PFU), and then treated 24 h.p.i. with 9E9 (20 μg) or an isotype control. Survival, body temperature, and clinical score were monitored over time. Data represent 1 experiment (n = 3–4 mice/group). (E) gMFI and frequencies of FcγRIV on inflammatory monocytes from the blood of mice in D, 1 hour before antibody or isotype control treatment. Data represent 1 experiment (n = 6–8 mice/group). All data are presented as the mean ± SD. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by log-rank test (survival) (A–D), 2-way ANOVA (clinical score and temperature) (A–D), or Student’s t test (E).