Anaphylaxis: Mechanisms and Cytokine Regulation

A mouse model was used to study the pathogenesis of anaphylaxis and the regulation of anaphylaxis by cytokines. Mice were primed with a single i.p. injection of 0.2 ml of goat anti-mouse IgD antiserum (GαMD), which stimulates IgG and IgE antibody responses to goat IgG (GIgG), IL-4 secretion, and mastocytosis. Mice were challenged i.v. 14 days after priming with 100 μg of the relevant antigen (GIgG) or a rat IgG2a anti-mouse IgE monoclonal antibody (αE). Challenged mice were followed for 2 hours for decreased activity and decreased rectal temperature (a sign of shock). These studies demonstrate:
1) There are 2 pathways of anaphylaxis in the mouse that have similar severity and kinetics. GIgG challenge acts through an IgG-, FcγR-, macrophage-, and PAF-dependent pathway, while αE challenge acts through an IgE-, FcεRI-, mast cell-, and histamine-dependent pathway.
2) Increasing the dose of GIgG to 10 mg induces the IgE pathway, suggesting that this pathway is inhibited by blocking IgG anti-GIgG antibody.
3) Serotonin does not appear to be involved in either the IgG or IgE pathway and products of the enzyme 5-lipoxygenase exacerbate the IgG pathway but ameliorate the IgE pathway.
4) IL-4 and IL-13, injected as little as 1-2 hours prior to challenge, greatly increase the severity of anaphylaxis.
5) This effect rapidly wears off once IL-4/IL-13 is eliminated, is IL-4Rα- and Stat6-dependent, but γc- and lymphocyte-independent, is not induced by other Th2 cytokines and is inhibited through an IFN-γ-dependent mechanism if mice are pretreated with IL-12 + IL-18.
6) IL-4/IL-13 exacerbation of anaphylaxis is associated with increased responsiveness to vasoactive mediators (histamine, serotonin, PAF, LTC4), but not with increased mediator production.
7) Exacerbation probably results from increased sensitivity of vascular endothelial cells to vasoactive mediators, because it increases vascular leak induced by these mediators.