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 4

FcγRIV activation induces systemic anaphylaxis in VSV-, HSV-, and influenza A–infected mice.

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FcγRIV activation induces systemic anaphylaxis in VSV-, HSV-, and influe...
(A) Serum levels of IFN-α and IFN-β in naive and VSV-infected WT mice (1 × 108 PFU). Dotted lines indicate the LOD for each analyte. Values below the LOD were assigned a value of half the detection limit for visualization and statistical analysis. Results show pooled data from 2 independent experiments with similar results (n = 3 mice/group/experiment). (B) VSV-infected WT mice (1 × 108 PFU) were treated 24 h.p.i. with 9E9 or an isotype control (200 μg). Survival, body temperature, and clinical score were monitored over time. Results are representative of 2 independent experiments (n = 3 mice/group/experiment). (C) WT and Fcgr4−/− mice were infected i.v. with LCMV-docile (5 × 105 PFU), HSV-1 (1 × 106 PFU), or influenza A virus (1 × 106 PFU) and then treated 24 h.p.i. with 200 μg 9E9 antibody. Survival, body temperature, and clinical score were monitored over time. Results show data from 1 experiment (n = 5–6 mice/group). All data are presented as the mean ± SD. **P < 0.01 and ****P < 0.0001, by Student’s t test (A), log-rank test for survival (B and C), or 2-way ANOVA for body temperature and clinical score (B and C).