Mechanisms of Allergy
Pathways of anaphylaxis in the mouse,☆☆

https://doi.org/10.1067/mai.2002.123302Get rights and content

Abstract

Background: Although anaphylaxis is classically mediated by IgE, FcϵRI, mast cells, and histamine, several rodent studies suggest that an alternative pathway involving IgG, FcγRIII, macrophages and platelets, and platelet-activating factor (PAF) may be more important in the anaphylactic response to antigen challenge. Objectives: We sought to determine the relative roles of the classical and alternative pathways of anaphylaxis in a mouse model characterized by mastocytosis and a high level of antigen-specific IgE antibody. Methods: Wild-type, IgE-deficient, FcϵRI-deficient, and mast cell–deficient mice were immunized with goat anti-mouse IgD antibody, which induces mastocytosis and a large IgE and IgG anti-goat IgG response, and then challenged 14 days later with antigen (goat IgG) or rat anti-mouse IgE mAb. Specific vasoactive mediators, cell types, Ig isotypes, or Ig receptors were blocked or eliminated before challenge in some experiments. The severity of anaphylaxis was gauged by changes in body temperature, physical activity, and mortality. Results: Equal doses of antigen or anti-IgE mAb induced similar anaphylactic responses. Anti-IgE mAb-induced anaphylaxis was FcϵRI and mast cell dependent and mediated predominantly by histamine. In contrast, neither mast cells nor platelets appeared important for antigen-induced anaphylaxis, which was FcγRIII and macrophage dependent and mediated predominantly by PAF. Conclusions: Antigen-induced anaphylaxis in the mouse proceeds primarily through the IgG, FcγRIII, macrophage, and PAF pathway, even in an experimental model that is characterized by strong mast cell and IgE responses. The presence of FcγRIII on human macrophages makes it possible that the IgG, FcγRIII, macrophage, and PAF pathway also contributes to human anaphylaxis. (J Allergy Clin Immunol 2002;109:658-68.)

Section snippets

Mice

Female BALB/c mice were purchased from NCI (Frederick, Md). IgE-deficient mice (FVBN background, a gift from P. Leder, Cambridge, Mass)13 and FcϵRIα-deficient mice (BALB/c background, a gift from J.-P. Kinet, Cambridge, Mass)14 were bred in our animal facility along with the appropriate wild-type control animals. W/Wv (mast cell–deficient) mice and litter mate control mice15 were purchased from Jackson Labs (Bar Harbor, Me). All mice were age and sex matched within experiments and were used at

Anti-igE mAb– and antigen-induced anaphylaxis have similar severities, kinetics, and sensitivities

Injection of mice with GaMD stimulates large IgG and IgE anti-GIgG antibody responses.24 Challenge of GaMD-primed mice with either antigen (GIgG) or anti-IgE mAb intravenously 14 days after priming induces anaphylaxis. The severity, kinetics, and dose-response characteristics of anaphylaxis induced by injection of antigen or anti-IgE mAb were compared by evaluating decreases in mouse activity and rectal temperature for 2 hours after challenge (Fig 1, left and middle panels).

. Challenge with

Discussion

Although anaphylaxis classically involves IgE, mast cells, and FcϵRI, recent studies have demonstrated that none of these is required for the development of antigen-induced shock in previously immunized rodents. These studies also provided evidence for an alternative pathway in which IgG, non–mast cells (macrophages, granulocytes, and platelets), and FcγRIII are important.3, 4, 5, 28, 29, 34, 35, 36, 37, 38 We have examined the potential importance of each of these elements to determine whether

Acknowledgements

We thank Edward Giannini for assistance with statistical analysis and Tatyana Orekhova, Kristi Smiley, Brian Meister, and Sasha Simms for technical assistance.

References (48)

  • SH Leir et al.

    Horse gammaglobulin-induced thrombocytopenia in anaphylaxis involving sequestration and activation of platelets

    Clin Exp Allergy

    (1995)
  • B Wedi et al.

    Human HMC-1 mast cells exclusively express the FcγRII subtype of IgG receptor

    Arch Dermatol Res

    (1996)
  • D Maurer et al.

    Expression of functional high affinity immunoglobulin E receptors (FcεRI) on monocytes of atopic individuals

    J Exp Med

    (1994)
  • A Svetic et al.

    Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody

    J Immunol

    (1991)
  • FD Finkelman et al.

    Polyclonal activation of the murine immune system by a goat antibody to mouse IgD. IX. Induction of a polyclonal IgE response

    J Immunol

    (1987)
  • FD Finkelman et al.

    IgD-secreting murine plasmacytomas: identification and partial characterization of two IgD myeloma proteins

    J Immunol

    (1981)
  • HC Oettgen et al.

    Active anaphylaxis in IgE-deficient mice

    Nature

    (1994)
  • M Baniyash et al.

    Inhibition of IgE binding to mast cells and basophils by monoclonal antibodies to murine IgE

    Eur J Immunol

    (1984)
  • J. Unkeless

    Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors

    J Exp Med

    (1979)
  • RI Tepper et al.

    An eosinophil-dependent mechanism for the antitumor effect of interleukin-4

    Science

    (1992)
  • A Ujike et al.

    Modulation of immunoglobulin (Ig)E-mediated systemic anaphylaxis by low-affinity Fc receptors for IgG

    J Exp Med

    (1999)
  • J Mizgerd et al.

    Gadolinium induces macrophage apoptosis

    J Leukoc Biol

    (1996)
  • PE Stenberg et al.

    Neuraminidase-induced thrombocytopenia in mice: effects on thrombopoiesis

    J Cell Physiol

    (1991)
  • FD Finkelman et al.

    Cross-linking of membrane immunoglobulin D, in the absence of T cell help, kills mature B cells in vivo

    J Exp Med

    (1995)
  • Cited by (0)

    Supported by a Merit Award (to FDF) from the Veteran's Administration and National Institutes of Health grants RO1 AI45766, KO8 AI50006, and P60-AR-44059.

    ☆☆

    Reprint requests: Fred D. Finkelman, MD, Research Service (151), Cincinnati VAMC, 3200 Vine St, Cincinnati, OH 45220.

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