IgG subclasses determine pathways of anaphylaxis in mice

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 1; pp. 269 - 280.e7
• Main Authors: Beutier, Héloïse, PharmD, Gillis, Caitlin M., BSci, Iannascoli, Bruno, BTS, Godon, Ophélie, MSc, England, Patrick, PhD, Sibilano, Riccardo, PhD, Reber, Laurent L., PhD, Galli, Stephen J., MD, Cragg, Mark S., PhD, Van Rooijen, Nico, PhD, Mancardi, David A., PhD, Bruhns, Pierre, PhD, Jönsson, Friederike, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2017; Elsevier Limited; Elsevier
• Subjects: Allergies; Allergy and Immunology; Anaphylaxis; Anaphylaxis - immunology; Animals; Antibodies, Monoclonal - immunology; basophil; Colleges & universities; Female; Haptens - immunology; histamine; Histamine - immunology; Human subjects; IgG; IgG Fc receptor; Immunoglobulin E - immunology; Immunoglobulin G - immunology; Immunoglobulins; Immunology; Life Sciences; macrophage; Mice, Inbred C57BL; Mice, Transgenic; monocyte; mouse model; Myeloid Cells - immunology; neutrophil; Neutrophils; platelet-activating factor; Protein Subunits - immunology; Receptors, IgG - genetics; Receptors, IgG - immunology; Rodents; Serum Albumin, Bovine - immunology; California; Fluorescein isothiocyanate; Mast cell protease 1; Association rate; histamine; RU; Gfi1; IgG; Neonatal IgG receptor; platelet-activating factor; basophil; neutrophil; mMCP-1; Growth factor independence 1; FITC; Anaphylaxis; TNP; FcRn; C57Bl/6 wild-type; Dissociation equilibrium constant; Trinitrophenyl; TRIM21; WT; PSA; Tripartite motif-containing protein 21; mouse model; Affinity constant; macrophage; Resonance units; K off; IgG Fc receptor; K A; K D; PAF; K on; Passive systemic anaphylaxis; monocyte; Dissociation rate; FcγR; KA; KD; Koff; Kon
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.03.028

Background Animal models have demonstrated that allergen-specific IgG confers sensitivity to systemic anaphylaxis that relies on IgG Fc receptors (FcγRs). Mouse IgG2a and IgG2b bind activating FcγRI, FcγRIII, and FcγRIV and inhibitory FcγRIIB; mouse IgG1 binds only FcγRIII and FcγRIIB. Although these interactions are of strikingly different affinities, these 3 IgG subclasses have been shown to enable induction of systemic anaphylaxis. Objective We sought to determine which pathways control the induction of IgG1 -, IgG2a -, and IgG2b -dependent passive systemic anaphylaxis. Methods Mice were sensitized with IgG1 , IgG2a , or IgG2b anti-trinitrophenyl mAbs and challenged with trinitrophenyl-BSA intravenously to induce systemic anaphylaxis that was monitored by using rectal temperature. Anaphylaxis was evaluated in mice deficient for FcγRs injected with mediator antagonists or in which basophils, monocytes/macrophages, or neutrophils had been depleted. FcγR expression was evaluated on these cells before and after anaphylaxis. Results Activating FcγRIII is the receptor primarily responsible for all 3 models of anaphylaxis, and subsequent downregulation of this receptor was observed. These models differentially relied on histamine release and the contribution of mast cells, basophils, macrophages, and neutrophils. Strikingly, basophil contribution and histamine predominance in mice with IgG1 - and IgG2b -induced anaphylaxis correlated with the ability of inhibitory FcγRIIB to negatively regulate these models of anaphylaxis. Conclusion We propose that the differential expression of inhibitory FcγRIIB on myeloid cells and its differential binding of IgG subclasses controls the contributions of mast cells, basophils, neutrophils, and macrophages to IgG subclass–dependent anaphylaxis. Collectively, our results unravel novel complexities in the involvement and regulation of cell populations in IgG-dependent reactions in vivo.