IgE promotes type 2 innate lymphoid cells in murine food allergy.

BACKGROUND: Mast cells serve an important sentinel function at mucosal barriers and have been implicated as key early inducers of type 2 immune responses in food allergy. The generation of Th2 and IgE following food allergen ingestion is inhibited in the absence of mast cells. Group 2 innate lymphoid cells are also thought to play an important early role in nascent allergic responses. OBJECTIVE: To test whether IgE-mediated mast cell activation promotes intestinal ILC2 responses following ingestion of food allergens and whether ILC2 amplify food allergy. METHODS: Two different mouse models of food allergy, one using intraperitoneally ovalbumin (OVA)-primed BALB/c animals and the other using enterally peanut-sensitized inherently atopic IL4raF709 mice, were applied to test the contributions of IgE antibodies and mast cells to ILC2 responses. The effect of ILC2 on mast cell activation and on anaphylaxis was tested. RESULTS: ILC2 responses were significantly impaired in both models of food allergy in Igh7-/- mice harbouring a targeted deletion of the gene encoding IgE. A similar reduction in food allergen-induced ILC2 was observed in mast cell-deficient Il4raF709 KitW-sh mice, and this was partially corrected by reconstituting these animals using cultured bone marrow mast cells. Mast cells activated ILC2 for IL-13 production in an IL-4Rα-dependent manner. Activated ILC2 amplified systemic anaphylaxis by increasing target tissue sensitivity to mast cell mediators. CONCLUSIONS AND CLINICAL RELEVANCE: These findings support an important role for IgE-activated mast cells in driving intestinal ILC2 expansion in food allergy and reveal that ILC2, in turn, can enhance responsiveness to the mediators of anaphylaxis produced by mast cells. Strategies designed to inhibit IgE signalling or mast cell activation are likely to inhibit both type 2 immunity and immediate hypersensitivity in food allergy.

A CCL chemokine-derived peptide (CDIP-2) exerts anti-inflammatory activity via CCR1, CCR2 and CCR3 chemokine receptors: Implications as a potential therapeutic treatment of asthma.

Allergic asthma is a chronic inflammatory disease characterized by the accumulation of eosinophils, Th2 cells and mononuclear cells in the airways, leading to changes in lung architecture and subsequently reduced respiratory function. We have previously demonstrated that CDIP-2, a chemokine derived peptide, reduced in vitro chemotaxis and decreased cellular infiltration in a murine model of allergic airway inflammation. However, the mechanisms involved in this process have not been identified yet. Now, we found that CDIP-2 reduces chemokine-mediated functions via interactions with CCR1, CCR2 and CCR3. Moreover, using bone marrow-derived eosinophils, we demonstrated that CDIP-2 modifies the calcium fluxes induced by CCL11 and down-modulated CCR3 expression. Finally, CDIP-2 treatment in a murine model of OVA-induced allergic airway inflammation reduced leukocyte recruitment and decreases production of cytokines. These data suggest that chemokine-derived peptides represent new therapeutic tools to generate more effective antiinflammatory drugs.

Super-oxidized solution inhibits IgE-antigen-induced degranulation and cytokine release in mast cells.

Activation of the high affinity IgE receptor (Fc epsilonRI) through IgE-antigen complexes induces mast cell degranulation, synthesis of lipid mediators and cytokine production. These effects are involved in Type I hypersensitivity reactions and controlling them has been the main objective of many anti-allergic therapies. Here we report that pretreatment of murine bone marrow derived mast cells (BMMC) with super-oxidized solution (SOS) inhibits Fc epsilonRI dependent-beta hexosaminidase and cytokine release. This effect is exerted without altering total protein tyrosine phosphorylation, MAPK activation, cytokine mRNA accumulation or calcium mobilization after Fc epsilonRI triggering. Our data suggest that this neutral pH-SOS acts like a mast cell-membrane stabilizer inhibiting the cell machinery for granule secretion without altering the signal transduction pathways induced by IgE-antigen receptor crosslinking.