IL-13 Overexpression Predisposes to Anaphylaxis Following Antigen Sensitization

Abstract

Anaphylaxis represents an extreme form of allergic reaction. This acute-phase component of allergy and asthma is triggered by allergen-induced degranulation of mast cells following the cross-linking of cell surface-bound, allergen-specific IgE, resulting in the liberation of inflammatory mediators and the development of bronchoconstriction. We used IL-13 transgenic mice to investigate the role of this Th2 cell-derived cytokine in the onset of allergic disease. Strikingly, IL-13-transgenic mice were highly predisposed to fatal anaphylaxis following Ag sensitization. This response correlated with substantially elevated levels of circulating Ag-specific IgE, mast cell degranulation, and histamine release. Furthermore, allergen exposure also induced phenotypic changes typical of asthma, including pulmonary fibrosis, goblet cell hyperplasia, elevated Th2 cytokines, eosinophilia, and airways occluded by mucus and Charcot-Leyden crystals. Expression of IL-4 was not required for the induction of IgE-mediated responses. These data represent the first characterization of a functional role for IL-13-induced IgE in the generation of immediate hypersensitivity reactions and highlight the importance of IL-13 in the development of the symptoms of atopy. The systemic regulation of this response makes these mice an important resource for studying atopic responses.

An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen

“…Conversely, reduced levels of IgE have been reported in IL-13-deficient mice, suggesting that IgE levels are responsive to both an increase and a decrease in the expression of IL-13 (27). Moreover, the role of IL-13 in the development of anaphylactic symptoms is well-documented (28,29). Sensitization of mice in which IL-13 is overexpressed in lymphoid cells results in the enhanced production of FIGURE 8.…”

“…Individual serum samples (five mice per group) were measured and are expressed as the geometric means Ϯ SEM. Ag-specific IgE and the rapid induction of fatal anaphylaxis (28). In asthma models, IL-13 has also been shown to be particularly important for the induction of the bronchial constriction and the smooth muscle cell contraction that characterizes the airway symptoms of an allergic response (30).…”

Helminth Infection Protects Mice from Anaphylaxis via IL-10-Producing B Cells

“…Unexpectedly, despite IL-13 transgenic mice being predisposed to anaphylaxis caused by schistosome eggs (10), these mice had no anaphylactic symptoms during acute or chronic S. mansoni infection. Therefore, in this study we evaluated whether schistosome infection renders mice less susceptible to anaphylaxis using an experimental murine model of systemic anaphylaxis.…”

“…We have previously shown that mice that overexpress IL-13 develop anaphylaxis after sensitization and re-exposure to Schistosoma mansoni eggs (10). Anaphylaxis is an acute, life-threatening, allergic reaction that can cause fatalities after exposure to allergenic Ags in sensitized atopic individuals.…”

“…Classically, anaphylaxis was considered to involve allergen cross-linking of IgE bound to its high affinity receptor, Fc⑀R1, on mast cells, initiating an intracellular signal transduction cascade that culminates in cell degranulation and the release of potent systemic mediators, including histamine and platelet-activating factor (PAF), 3 which can induce acute bronchoconstriction, tachycardia, hypotension, vascular leakage, and ultimately death (11). In earlier studies, schistosome egg sensitization induced all of these characteristic features in IL-13 transgenic mice, with injection of S. mansoni eggs inducing a rapid and highly elevated production of Th2 cytokines and Ag-specific IgE, with subsequent exposure to eggs inducing fatal anaphylaxis with attendant mast cell degranulation and histamine release (10). However, IgE does not account for all anaphylactic pathways because mice deficient in IgE can develop systemic anaphylaxis (12).…”