Mouse and human neutrophils induce anaphylaxis
Friederike Jönsson, … , Marc Daëron, Pierre Bruhns
Friederike Jönsson, … , Marc Daëron, Pierre Bruhns
Published March 23, 2011
Citation Information: J Clin Invest. 2011;121(4):1484-1496. https://doi.org/10.1172/JCI45232.
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Research Article

Mouse and human neutrophils induce anaphylaxis

Abstract

Anaphylaxis is a life-threatening hyperacute immediate hypersensitivity reaction. Classically, it depends on IgE, FcεRI, mast cells, and histamine. However, anaphylaxis can also be induced by IgG antibodies, and an IgG1-induced passive type of systemic anaphylaxis has been reported to depend on basophils. In addition, it was found that neither mast cells nor basophils were required in mouse models of active systemic anaphylaxis. Therefore, we investigated what antibodies, receptors, and cells are involved in active systemic anaphylaxis in mice. We found that IgG antibodies, FcγRIIIA and FcγRIV, platelet-activating factor, neutrophils, and, to a lesser extent, basophils were involved. Neutrophil activation could be monitored in vivo during anaphylaxis. Neutrophil depletion inhibited active, and also passive, systemic anaphylaxis. Importantly, mouse and human neutrophils each restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis in mice and suggesting that neutrophils can contribute to anaphylaxis in humans. Our results therefore reveal an unexpected role for IgG, IgG receptors, and neutrophils in anaphylaxis in mice. These molecules and cells could be potential new targets for the development of anaphylaxis therapeutics if the same mechanism is responsible for anaphylaxis in humans.

Authors

Friederike Jönsson, David A. Mancardi, Yoshihiro Kita, Hajime Karasuyama, Bruno Iannascoli, Nico Van Rooijen, Takao Shimizu, Marc Daëron, Pierre Bruhns

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Figure 1

Neutrophils mediate FcγRIV-dependent active anaphylaxis.

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Neutrophils mediate FcγRIV-dependent active anaphylaxis. Indicated mice ...
Indicated mice were immunized and challenged with BSA. Central temperatures and survival rates were monitored. (A) ASA in WT (n = 4), FcγRIIIA–/– (n = 5), and FcεRI/II–/– (n = 4) mice. (B) ASA in WT (n = 9) and 5KO mice (n = 7). (C) ASA in 5KO mice injected with anti-FcγRIV mAbs (n = 10) or isotype control (n = 11) before BSA challenge. (D) Representative expression of FcγRIV on mouse blood and peritoneal cells: B cells (CD19+), T cells (CD4+), monocytes (mono.) (CD11b+Gr1–), neutrophils (neutro.) (CD11b+Gr1+), basophils (baso.) (IgE+DX5+), eosinophils (eosino.) (Gr1+SiglecF+), macrophages (macro.) (CD11b+Gr1–), and mast cells (IgE+CD117+). (E and F) ASA in 5KO mice injected with (E) PBS liposomes (lipo.) (n = 7) or clodronate liposomes (n = 8), (F) anti-Gr1 mAbs (n = 8) or isotype (iso.) control (n = 9) before BSA challenge. Data are a compilation of 2 experiments. Note that both PBS and clodronate liposome injections inhibited ASA-associated mortality. (G) Immunized 5KO mice were injected with anti-Gr1 mAbs or isotype control on day 0, challenged with BSA on day +1, retroorbitally bled on days +2 and +6, but otherwise left untouched until rechallenged with BSA on day +7. Upper panel: representative density plots of blood leukocytes stained as indicated. Percentages of Gr1hiCD11bhi cells (neutrophils) are indicated. Lower panel: ASA in immunized 5KO mice at day +7 after depletion (Iso, n = 3; anti-Gr1, n = 4). (A–C and E–G) Data are represented as mean ± SEM. (A–F) Data are representative from at least 2 independent experiments (A, 2; B, 5; C, 4; D, 3; E, 2; and F, 4 experiments). ***P < 0.001. X’s represent mortality in the 100% experimental group.