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 7

SARS-CoV-2 infection drives conserved upregulation of activatory FcγRs on inflammatory monocytes.

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SARS-CoV-2 infection drives conserved upregulation of activatory FcγRs o...
(A) Representative dot plots and corresponding percentages showing CD14 and CD16 expression in gated monocytes, categorized into 4 populations (gated from CD11b+CD8–CD56–, not shown) isolated from peripheral blood of healthy controls (n = 37) and patients with COVID-19 (n = 64). (B) Normalized expression of FCGR3A in cells annotated as classical monocytes comparing healthy controls (mean = 0.042, SD = 0.610), patients with mild-to-moderate COVID-19 (mean = 0.214, SD = 1.364), and patients with severe COVID-19 (mean = 0.219, SD = 1.340). The dataset was obtained from publicly available scRNA-Seq data on classical monocytes (32) and analyzed. (C) Frequency of CD14+FCGR3A+ classical monocytes in healthy controls, patients with mild-to-moderate COVID-19, and patients with severe COVID-19. The dataset was obtained from publicly available scRNA-Seq of classical monocytes (32) and analyzed. All data are presented as the mean ± SD. ***P < 0.001 and ****P < 0.0001, by Student’s t test (A), Kruskal-Wallis test with post hoc pairwise Wilcoxon rank-sum tests (B), or χ2 test with post hoc pairwise Fisher’s exact test (C).