Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Gillis, Caitlin M.^1,2,3  Jonsson, Friederike^1,2  Mancardi, David A.^1,2  Tu, Naxin⁵  Beutier, Heloise^1,2,3  Van Rooijen, Nico⁴  Macdonald, Lynn E.⁵  Murphy, Andrew J.⁵  Bruhns, Pierre^1,2 

[1] Inst Pasteur, Dept Immunol, Unit Antibodies Therapy & Pathol, 25 Rue Docteur Roux, F-75015 Paris, France

[2] INSERM, U1222, Paris, France

[3] Univ Paris 06, Paris, France

[4] Vrije Univ Amsterdam Med Ctr, Dept Mol Cell Biol, Amsterdam, Netherlands

[5] Regeneron Pharmaceut, Tarrytown, NY USA

关键词: Anaphylaxis;    IgG;    knock-in mouse model;    basophil;    neutrophil;    monocyte;    macrophage;    human Fc gamma R;    platelet-activating factor;    histamine;   

DOI  :  10.1016/j.jaci.2016.06.058

来源: Elsevier

【 摘 要 】

Background: Anaphylaxis can proceed through distinct IgE- or IgG-dependent pathways, which have been investigated in various mouse models. We developed a novel mouse strain in which the human low-affinity IgG receptor locus, comprising both activating (hFc gamma RIIA, hFc gamma RIIIA, and hFc gamma RIIIB) and inhibitory (hFc gamma RIIB) hFc gamma R genes, has been inserted into the equivalent murine locus, corresponding to a locus swap. Objective: We sought to determine the capabilities of hFc gamma Rs to induce systemic anaphylaxis and identify the cell types and mediators involved. Methods: hFc gamma R expression on mouse and human cells was compared to validate the model. Passive systemic anaphylaxis was induced by injection of heat-aggregated human intravenous immunoglobulin and active systemic anaphylaxis after immunization and challenge. Anaphylaxis severity was evaluated based on hypothermia and mortality. The contribution of receptors, mediators, or cell types was assessed based on receptor blockade or depletion. Results: The human-to-mouse low-affinity Fc gamma R locus swap engendered hFc gamma RIIA/IIB/IIIA/IIIB expression in mice comparable with that seen in human subjects. Knock-in mice were susceptible to passive and active anaphylaxis, accompanied by downregulation of both activating and inhibitory hFc gamma R expression on specific myeloid cells. The contribution of hFc gamma RIIA was predominant. Depletion of neutrophils protected against hypothermia and mortality. Basophils contributed to a lesser extent. Anaphylaxis was inhibited by platelet-activating factor receptor or histamine receptor 1 blockade. Conclusion: Low-affinity Fc gamma R locus-switched mice represent an unprecedented model of cognate hFc gamma R expression. Importantly, IgG-related anaphylaxis proceeds within a native context of activating and inhibitory hFc gamma Rs, indicating that, despite robust hFc gamma RIIB expression, activating signals can dominate to initiate a severe anaphylactic reaction.

【 授权许可】

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