Research ArticleALLERGY

Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis

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Science Immunology  13 Apr 2018:
Vol. 3, Issue 22, eaan5997
DOI: 10.1126/sciimmunol.aan5997

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Potent platelets

Anaphylaxis results from inappropriate immune responses to allergens. Human platelets express the IgG receptor FcγRIIA/CD32A and release inflammatory mediators in response to their engagement, but their contribution to anaphylaxis is not well understood. Beutier et al. developed mouse models that express either human FcγRIIA/CD32A alone or the full human IgG receptor complexity to understand the role of platelets in anaphylaxis. Anaphylaxis induced a marked decrease in platelet levels, but preventive platelet depletion reduced anaphylaxis severity. A clinical study of patients with drug-induced anaphylaxis revealed that a severe reaction was likewise associated with fewer circulating platelets. Activated platelets released serotonin, which contributed to anaphylaxis severity. These results reveal a critical role for platelets in IgG-mediated anaphylaxis.

Abstract

Platelets are key regulators of vascular integrity; however, their role in anaphylaxis, a life-threatening systemic allergic reaction characterized by the loss of vascular integrity and vascular leakage, remains unknown. Anaphylaxis is a consequence of inappropriate cellular responses triggered by antibodies to generally harmless antigens, resulting in a massive mediator release and rapidly occurring organ dysfunction. Human platelets express receptors for immunoglobulin G (IgG) antibodies and can release potent mediators, yet their contribution to anaphylaxis has not been previously addressed in mouse models, probably because mice do not express IgG receptors on platelets. We investigated the contribution of platelets to IgG-dependent anaphylaxis in human IgG receptor–expressing mouse models and a cohort of patients suffering from drug-induced anaphylaxis. Platelet counts dropped immediately and markedly upon anaphylaxis induction only when they expressed the human IgG receptor FcγRIIA/CD32A. Platelet depletion attenuated anaphylaxis, whereas thrombocythemia substantially worsened its severity. FcγRIIA-expressing platelets were directly activated by IgG immune complexes in vivo and were sufficient to restore susceptibility to anaphylaxis in resistant mice. Serotonin released by activated platelets contributed to anaphylaxis severity. Data from a cohort of patients suffering from drug-induced anaphylaxis indicated that platelet activation was associated with anaphylaxis severity and was accompanied by a reduction in circulating platelet numbers. Our findings identify platelets as critical players in IgG-dependent anaphylaxis and provide a rationale for the design of platelet-targeting strategies to attenuate the severity of anaphylactic reactions.

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