Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis

Abstract

IgG-mediated anaphylaxis occurs in mice and may contribute to human reactions to infused drugs. To distinguish IgE- from putative IgG-mediated human anaphylaxis, we developed blood markers for murine anaphylaxis and evaluated their human relevance. Both IgG- and IgE-mediated anaphylaxis were characterized by decreased basophil and monocyte percentages and an increased neutrophil percentage in mouse blood. IgE- but not IgG-mediated murine anaphylaxis was accompanied by large increases in IL-4 secretion, plasma soluble IL-4 receptor-α (IL-4Rα) concentration, and T-cell membrane IL-4Rα expression. T-cell IL-4Rα expression also increased when mice that express human Fcε receptor Iα were sensitized with IgG-depleted serum from a peanut-allergic individual and challenged with peanut extract. Increased T-cell IL-4Rα expression is likely to also be a marker for human IgE-mediated anaphylaxis, because IgE-activated human basophils secrete IL-4, and IL-4 increases human T-cell IL-4Rα expression in vitro. Murine IgG- but not IgE-mediated anaphylaxis was characterized by decreased neutrophil Fcγ receptor III (FcγRIII) expression that was observed even when the antigen dose was insufficient to induce shock. Human neutrophils cultured with IgG immune complexes also lost FcγRIII. These observations suggest that decreased blood neutrophil FcγRIII expression without increased IL-4Rα expression can be used to determine whether and when IgG-mediated anaphylaxis occurs in man.

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

“…33 These reactions can lead to mortality by increased vascular permeability, respiratory arrest due to smooth muscle contraction, multi organ failure or cardiac arrest due to decreased cardiac output. 34 To better understand the underlying mechanism of toxicity in mice treated with repeat anti-PD-1 treatment, heart, lungs, liver and kidney tissues were examined by a trained pathologist Table 1. Anti-PD-1 and anti-PD-L1 induced fatal hypersensitivity reactions are specific to 4T1 tumor bearing mice.…”

“…34 Additionally, neutrophils have been identified as key players in mediating anaphylactic reactions in mice and humans. 38 To further evaluate the cause of death in mice treated with PD-1/PD-L1 blockade, we compared lungs and spleens of mice treated with anti-PD-1, anti-CTLA4 or isotype control antibody, both in non-tumor bearing and 4T1 bearing mice, for overall neutrophil and T cell content in the lungs.…”

IgE knock‐in mice suggest a role for high levels of IgE in basophil‐mediated active systemic anaphylaxis

“…However, since the discovery of anaphylaxis in IgE-deficient mice [6] and more recently studies on basophil biology, a number of publications have focused on the contribution of alternative pathways to anaphylaxis [7][8][9].…”

“…-1242 decades [3][4][5]. However, since the discovery of anaphylaxis in IgE-deficient mice [6] and more recently studies on basophil biology, a number of publications have focused on the contribution of alternative pathways to anaphylaxis [7][8][9]. It has become evident that the isotype, quantity, and quality of the sensitizing antibodies are important parameters for anaphylaxis [9].…”

“…In summary, at least two mutually nonexclusive pathways exist that employ allergen-mediated cross-linking of either receptor bound IgE and/or receptor bound IgG and lead to activation of mast cells and/or basophils leading to release of inflammatory substances, e.g. histamine or platelet activating factor [7,10].Nevertheless, experiments to examine the role of the active polyclonal antibody response in anaphylaxis are hampered by the low expression of IgE and a low frequency of IgE expressing B cells in WT mice [11,12]. In order to circumvent this problem, we generated an IgE knock-in mouse strain to study the role of IgE regulation in vivo.…”