New clues to how food allergies trigger anaphylaxis

New research in mice reveals that food-induced anaphylaxis is driven by distinct immune pathways involving inflammatory lipids called leukotrienes. The findings, published across two separate studies, identify genetic and cellular factors that influence susceptibility to severe allergic reactions and point to the potential of the drug Zileuton to block this life-threatening response. Food allergies arise when the immune system mounts an exaggerated response to certain proteins found in foods. This reaction is typically driven by Immunoglobulin E (IgE) antibodies, which recognize dietary allergens and activates mast cells throughout the body. In severe cases, food allergen exposure leads to anaphylaxis – a life-threatening condition marked by airway constriction and cardiovascular collapse. While previous research has identified the specific mast cell signals involved in anaphylaxis caused by injected allergens in mice, the anaphylaxis-related mechanisms triggered by ingested allergens remain poorly understood. Here, across two studies in mice, researchers address this question.

In one study, Laura Hoyt and colleagues investigated why some mice develop severe allergic reactions to food when eaten, while others don't, even though both groups produce similar levels of allergy-related IgE antibodies. They found that this difference traces back to genetic variants in the enzyme DPEP1, one function of which is to break down an inflammatory molecule called leukotriene D4 (LTD4), which belongs to a group of inflammatory lipids known as cysteinyl leukotrienes (CysLTs). Mice resistant to anaphylaxis had a more active version of DPEP1, allowing them to degrade LTD4 more efficiently in the small intestine. In contrast, susceptible mice had less active DPEP1, leading to higher LTD4 levels. According to Hoyt et al., this excess LTD4 enhances the movement of allergens from the gut lumen into the tissue, triggering anaphylactic reactions.

In another study, Nathaniel Bachtel and colleagues studied how allergen exposure through the mouth or gut influences allergic reactions in mice. Bachtel et al. found that CysLTs play a critical role specifically in oral anaphylaxis but not in systemic reactions. Blocking CysLT production with the drug Zileuton reduced anaphylaxis after oral allergen exposure, yet had no effect when allergens were introduced systemically. This protective effect was linked to a particular subset of mucosal mast cells in the intestine that produce leukotrienes in response to allergens. In contrast, connective tissue mast cells, found in deeper tissues like the skin or lungs, primarily release histamine and are not involved in this leukotriene-driven pathway. According to the authors, the findings highlight that distinct mast cell populations and their chemical mediators drive different forms of allergic responses, with mucosal mast cells playing a central role in food-induced anaphylaxis.

"Because Hoyt et al. and Bachtel et al. show that Zileuton can inhibit orally induced anaphylaxis, future translational studies are warranted that examine the effectiveness of Zileuton in preventing anaphylactic food allergic reactions in humans," write Tamara Haque and Mark Kaplan in a related Perspective.