Naxin Tu

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

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&ggr;RIIA, hFc&ggr;RIIIA, and hFc&ggr;RIIIB) and inhibitory (hFc&ggr;RIIB) hFc&ggr;R genes, has been inserted into the equivalent murine locus, corresponding to a locus swap. Objective: We sought to determine the capabilities of hFc&ggr;Rs to induce systemic anaphylaxis and identify the cell types and mediators involved. Methods: hFc&ggr;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&ggr;R locus swap engendered hFc&ggr;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&ggr;R expression on specific myeloid cells. The contribution of hFc&ggr;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&ggr;R locus‐switched mice represent an unprecedented model of cognate hFc&ggr;R expression. Importantly, IgG‐related anaphylaxis proceeds within a native context of activating and inhibitory hFc&ggr;Rs, indicating that, despite robust hFc&ggr;RIIB expression, activating signals can dominate to initiate a severe anaphylactic reaction.