Institut Pasteur, Department of Immunology, Unit of Antibodies in Therapy and Pathology, Paris, France.
INSERM U1222, Paris, France.
Sci Immunol. 2018 Apr 13;3(22). doi: 10.1126/sciimmunol.aan5997.
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.
血小板是血管完整性的关键调节因子；然而，它们在过敏反应中的作用（一种危及生命的全身性过敏反应，其特征是血管完整性丧失和血管渗漏）尚不清楚。过敏反应是由针对通常无害抗原的抗体引发的不适当细胞反应的结果，导致大量介质释放和迅速发生的器官功能障碍。人血小板表达免疫球蛋白 G（IgG）抗体的受体，并且可以释放有效的介质，但其在过敏反应中的作用在以前的小鼠模型中尚未得到解决，可能是因为小鼠血小板上不表达 IgG 受体。我们研究了在人 IgG 受体表达的小鼠模型和一组患有药物诱导过敏反应的患者中，血小板对 IgG 依赖性过敏反应的贡献。仅当它们表达人 IgG 受体 FcγRIIA/CD32A 时，血小板计数才会在过敏反应诱导后立即且显著下降。血小板耗竭可减轻过敏反应，而血小板增多症则大大加重其严重程度。FcγRIIA 表达的血小板在体内可被 IgG 免疫复合物直接激活，足以恢复对耐药小鼠过敏反应的易感性。激活的血小板释放的 5-羟色胺有助于过敏反应的严重程度。来自一组患有药物诱导过敏反应的患者的数据表明，血小板激活与过敏反应的严重程度相关，并伴有循环血小板数量减少。我们的发现确定了血小板在 IgG 依赖性过敏反应中的关键作用，并为设计针对血小板的靶向策略以减轻过敏反应的严重程度提供了依据。
