An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis

Friederike Jönsson (1) , Luc de Chaisemartin (2, 3) , Vanessa Granger (2, 3) , Aurélie Gouel-Chéron (1, 3) , Caitlin Gillis (1) , Qianqian Zhu (1, 2) , Fadia Dib (3) , Pascale Nicaise-Roland (3) , Christelle Ganneau (4) , Maria Hurtado-Nedelec (3) , Catherine Paugam-Burtz (5, 6) , Skander Necib (5, 6) , Hawa Keita-Meyer (7, 8) , Matthieu Le Dorze (9) , Bernard Cholley (10) , Olivier Langeron (11, 12) , Laurent Jacob (13) , Benoît Plaud (13) , Marc Fischler (14) , Caroline Sauvan (3) , Marie-Therese Guinnepain (14) , Philippe Montravers (3, 15) , Michel Aubier (3, 15) , Sylvie Bay (4) , Catherine Neukirch (3, 15) , Florence Tubach (16) , Dan Longrois (3) , Sylvie Chollet-Martin (3, 2) , Pierre Bruhns (1)

1 Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology
2 Inflammation, Chimiokines et Immunopathologie [Châtenay-Malabry]
3 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
4 Chimie des Biomolécules - Chemistry of Biomolecules
5 Hôpital Beaujon
6 UPD7 - Université Paris Diderot - Paris 7
7 Hôpital Louis Mourier - AP-HP [Colombes]
8 REMES - Recherche Clinique ville-hôpital, Méthodologies et Société
9 Hôpital Lariboisière-Fernand-Widal [APHP]
10 HEGP - Hôpital Européen Georges Pompidou [APHP]
11 CHU Pitié-Salpêtrière [AP-HP]
12 Histopathologie humaine et Modèles animaux
13 Hôpital Saint-Louis
14 Hôpital Foch [Suresnes]
15 Lab Excellence Inflamex
16 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique

Anaphylaxis is a systemic acute hypersensitivity reaction that is considered to depend on allergen-specific immunoglobulin E (IgE) antibodies and histamine release by mast cells and basophils. Nevertheless, allergen-specific IgG antibodies have been proposed to contribute when the allergen is an abundant circulating large molecule, e.g., after infusions of therapeutic antibodies or dextran. Data from animal models demonstrate a pathway involving platelet-activating factor (PAF) release by monocytes/macrophages and neutrophils activated via their Fc gamma receptors (FcγRs). We hypothesized that such a pathway may also apply to small drugs and could be responsible for non-IgE-mediated anaphylaxis and influence anaphylaxis severity in humans. We prospectively conducted a multicentric study of 86 patients with suspected anaphylaxis to neuromuscular-blocking agents (NMBAs) during general anesthesia and 86 matched controls. We found that concentrations of anti-NMBA IgG and markers of FcγR activation, PAF release, and neutrophil activation correlated with anaphylaxis severity. Neutrophils underwent degranulation and NETosis early after anaphylaxis onset, and plasma-purified anti-NMBA IgG triggered neutrophil activation ex vivo in the presence of NMBA. Neutrophil activation could also be observed in patients lacking evidence of classical IgE-dependent anaphylaxis. This study supports the existence of an IgG-neutrophil pathway in human NMBA-induced anaphylaxis, which may aggravate anaphylaxis in combination with the IgE pathway or underlie anaphylaxis in the absence of specific IgE. These results reconcile clinical and experimental data on the role of antibody classes in anaphylaxis and could inform diagnostic approaches to NMBA-induced acute hypersensitivity reactions.

Domains: Life Sciences [q-bio]; Immunology; Allergology

Friederike Jönsson, Luc de Chaisemartin, Vanessa Granger, Aurélie Gouel-Chéron, Caitlin Gillis, et al.. An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis. Science Translational Medicine, 2019, 11 (500), pp.eaat1479. ⟨10.1126/scitranslmed.aat1479⟩. ⟨pasteur-02294649⟩