232 NOD2 signaling critically influences sensitization to orally ingested allergens and severity of anaphylaxis

Abstract

Anaphylactic reactions to food are still increasing. As food uptake occurs in the microbial rich intestine and alterations of organ specific microbiota have been shown to be associated with allergic and autoimmune diseases, we detemined whether innate immune signals of the intestinal microbiota influences sensitization to orally ingested allergens and subsequent anaphylactic reactions. Peptidoglycan (PGN) sensed by NOD2 and TLR2, is a major cell wall component of Gram-positive and Gram-negative bacteria which are abundantly found in the intestine. To investigate the role of PGN recognition in regard to sensitization to food allergens, we sensitized C57Bl/6 (wt) and TLR2-/-x NOD2-/- mice with Ovalbumin (OVA). After challenge, TLR2-/-x NOD2-/- mice showed significantly stronger decrease of body temperature compared to wt mice. To delineate the impact of TLR2 and NOD2, TLR2-/- or NOD2-/- mice were investigated. Compared to wt mice TLR2-/- animals showed no differences in body temperature drop after challenge. In contrast NOD2-/- mice displayed a significantly stronger decrease in body temperature after challenge as wt mice. Furthermore NOD2-/- mice had significantly higher IgE levels than wt mice. To examine the underlying mechanisms we isolated mesenterial lymph nodes (mLN). After restimulation T cells from mLN of NOD2-/- displayed significantly enhanced IL-4, IL-5 and IL-13 levels demonstrating predominant induction of Th2 cells in the gastrointestinal immune system (GALT) in the absence of NOD2 signaling. Taken together these results clearly demonstrate a critically role of innate immune recognition of the intestinal microbiota by NOD2 in shaping the quality of T helper cell responses in the GALT. In the absence of NOD2 Th2 responses are induced in the GALT leading to enhanced IgE production and severe anaphylaxis. Activating NOD2 using either non-pathogenic bacteria or specific agonists could be a feasible strategy to attenuate sensitization to food allergens.