Les IgG, leurs récepteurs et les neutrophiles : acteurs de la réaction anaphylactique ?

Abstract

Anaphylaxis is a systemic hyperacute allergic reaction that develops within minutes following antigen/allergen exposure in humans. Animal models of passive anaphylaxis proposed that anaphylaxis is an IgE-dependent, FcɛRI-dependent, mast cell-dependent, histamine-dependent reaction. Anaphylaxis, however, can be induced by IgG antibodies. For example, IgG1-induced passive systemic anaphylaxis depends on the activating IgG receptor FcγRIIIA and, perhaps, on basophils. Surprisingly, active systemic anaphylaxis in mice required neither IgE, nor FcɛRI, nor mast cells or basophils. We showed recently that active systemic anaphylaxis involves IgG antibodies, activating IgG receptors FcγRIIIA and FcγRIV, platelet-activating factor (PAF), neutrophils and, to a lower extent, basophils. Neutrophil depletion inhibited active, but also passive, systemic anaphylaxis. Importantly, human neutrophils restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis and that IgG receptors on human neutrophils may be responsible for anaphylaxis induction. In humans, neutrophils, like mast cells, basophils and eosinophils, do not express FcγRIIIA or FcγRIV, but the activating IgG receptor FcγRIIA. We therefore extended our investigation to the role of human FcγRIIA in systemic anaphylaxis by generating novel FcγRIIA-transgenic mice. We found that in these mice FcγRIIA was sufficient to trigger both active and passive systemic anaphylaxis. We identified monocyte/macrophages and neutrophils to be responsible for FcγRIIA-dependent passive systemic anaphylaxis. Supporting these findings, human monocytes and neutrophils produced anaphylactogenic mediators following FcγRIIA engagement. Our results therefore unravel an unexpected role of IgG, IgG receptors and neutrophils in anaphylaxis and suggest that neutrophils (and monocytes) activated by IgG-induced aggregation of FcγRIIA can contribute to human anaphylaxis.