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Anaphylaxis: Lessons from mouse models

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Studies with mouse models demonstrate 2 pathways of systemic anaphylaxis: a classic pathway mediated by IgE, FcɛRI, mast cells, histamine, and platelet-activating factor (PAF) and an alternative pathway mediated by IgG, FcγRIII, macrophages, and PAF. The former pathway requires much less antigen and antibody than the latter. This is modified, however, by IgG antibodies that prevent IgE-mediated anaphylaxis by intercepting antigen before it binds to mast cell–associated IgE. Consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but mediate systemic anaphylaxis induced by larger quantities. The importance of the alternative pathway in human subjects is unknown, but human IgG, IgG receptors, macrophages, mediators, and mediator receptors have appropriate properties to support this pathway if sufficient IgG and antigen are present. The severity of systemic anaphylaxis is increased by nitric oxide produced by the enzyme endothelial nitric oxide synthase and by the cytokines IL-4 and IL-13 and decreased by endogenous β-adrenergic stimulation and receptors that contain ITIM that bind tyrosine phosphatases. Anaphylaxis is also suppressed by other receptors and ion channels that function through distinct mechanisms. Unlike systemic anaphylaxis, intestinal anaphylaxis (allergic diarrhea) is almost totally IgE and mast cell dependent and is mediated predominantly by PAF and serotonin. Some potent food allergens, including peanuts and tree nuts, can directly enhance anaphylaxis by stimulating an anaphylactoid response through the innate immune system. Results of these studies suggest novel prophylactic agents, including nonstimulatory anti-IgE mAbs, IL-4 receptor antagonists, PAF antagonists, and agents that cross-link FcɛRI or FcγRIII to an ITIM–containing inhibitory receptor.

Section snippets

Two pathways of murine systemic anaphylaxis

Central to all studies of anaphylaxis in the mouse is the observation that systemic anaphylaxis (rapid and potentially reversible hypotension, hypothermia, decreased mobility, and scratching) can be mediated by 2 independent mechanisms.3 One, which I refer to as the classic pathway, involves mast cells sensitized by IgE antibodies bound to FcɛRI. Antigen-induced cross-linking of mast cell–associated IgE leads rapidly to mast cell degranulation with release of mediators and enzymes, such as the

Physiologic and pharmacologic modulators of systemic anaphylaxis

The most direct determinants of anaphylaxis induction and severity are the extent and rapidity of cross-linking of mast cell FcɛRI and macrophage FcγRIII. These are influenced by antigen dose, speed of antigen access to the circulation (ie, route of antigen administration), concentration of IgE and IgG antibody, antibody affinity, number and activation state of mast cells and macrophages, and density of mast cell FcɛRI and macrophage FcγRIII. Multiple additional factors, however, can act at

Mouse models of intestinal anaphylaxis

Allergen ingestion can induce the shock syndrome characterized as systemic anaphylaxis but more commonly induces gastrointestinal symptoms, such as diarrhea.1, 46, 47 Three experimental mouse models of intestinal anaphylaxis have been described: one in which mice are sensitized by ingestion of an allergen, such as peanut extract, with cholera toxin48; one in which mice are sensitized by means of intraperitoneal injection of chicken ovalbumin (OVA) with the adjuvant alum (aluminum hydroxide)49;

Passive cutaneous anaphylaxis

Although passive cutaneous anaphylaxis (PCA) is more useful as a model for probing mechanisms of anaphylaxis than a model of human allergy, it has played an historically important role in dissection of the mechanisms of anaphylaxis.57 Unlike systemic anaphylaxis in the mouse, PCA mediated by autologous antibody appears to be entirely mast cell dependent and is primarily dependent on IgE.58 PCA can also be mediated, however, by a fraction of IgG1 molecules, called anaphylactic IgG1. These IgG1

Relevance of mouse models to human anaphylaxis

The focus of this article on specifics of mouse models of anaphylaxis, including the effects of specific mouse IgG isotypes and immunoglobulin receptors, raises questions about the human relevance of these studies. The many similarities and few differences between the mouse and human immune systems that are germane to the relevance of mouse models to human anaphylaxis have been previously summarized (reproduced here as Table II).61 There are no precise homologies between mouse and human IgG

Implications for prophylaxis and treatment

Regardless of the importance of IgG-mediated anaphylaxis in human subjects, studies with mouse models have suggested several approaches that might be useful for anaphylaxis prophylaxis (Table III) but few or none that might be useful for treatment. The possible prophylactic closest to the clinic is an anti-IgE mAb that binds to an IgE epitope blocked by FcɛRI, so that it can prevent IgE binding to mast cell FcɛRI but cannot induce anaphylaxis by cross-linking IgE already bound to FcɛRI on mast

Future goals of rodent studies in anaphylaxis

Many goals for future research in this area are obvious continuations of present studies, including (1) determination of the requirements for IL-4 and IL-13 in maintaining allergen sensitization once it has been induced, (2) identification of the ligands of each mast cell– and macrophage-associated ITIM-containing receptor, (3) evaluation of the relative importance of the classic and alternative pathways of anaphylaxis in response to different allergens, (4) identification of better footprints

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    (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Supported by grants R01 AI35987, R01 AI45766, R01 AI052099, and P01 HL076383; a Veterans Administration Merit Award; and the Food Allergy and Anaphylaxis Network.

    Disclosure of potential conflict of interest: F. D. Finkelman has consulting arrangements with Abbott, Plexxikon, Peptimmune, CSI, Amgen, and Wyeth; has patent licensing arrangements with BD PharMingen and eBioscience; and has received grant support from Abbott and Plexxikon.

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