Immune-Mediated Mechanisms in Cofactor-Dependent Food Allergy and Anaphylaxis: Effect of Cofactors in Basophils and Mast Cells

Abstract

Cofactors may explain why in some cases food ingestion leads to anaphylaxis while in others elicits a milder reaction or tolerance. With cofactors, reactions become more severe and/or have a lower allergen threshold. Cofactors are present in up to 58% of food anaphylaxis (FAn). Exercise, NSAIDs, and alcohol are the most frequently described, although the underlying mechanisms are poorly known. Several hypotheses have suggested the influence of these cofactors on basophils and mast cells (MCs). Exercise has been suggested to enhance MC activation by increasing plasma osmolarity, redistributing blood flow, and activating adenosine and eicosanoid metabolism. NSAIDs' cofactor effect has been related with cyclooxygenase inhibition and therefore, prostaglandin E₂ (PGE₂) production. Indeed, overexpression of adenosine receptor 3 (A₃) gene has been described in NSAID-dependent FAn; A₃ activation potentiates FcϵRI-induced MC degranulation. Finally, alcohol has been related with an increase of histamine levels by inhibition of diamino oxidase (DAO) and also with and increase of extracellular adenosine by inhibition of its uptake. However, most of these mechanisms have limited evidence, and further studies are urgently needed. In conclusion, the study of the immune-related mechanisms involved in food allergic reactions enhanced by cofactors is of the utmost interest. This knowledge will help to design both tailored treatments and prophylactic strategies that, nowadays, are non-existent.

Keywords: NSAID; adenosin; basophil; cofactor; exercise; food allergy; mast cell; prostaglandin.

Figure 1

Mechanisms in cofactor-enhanced food anaphylaxis. Adenosine and eicosanoid metabolism hypothesis. The panel depicts the most frequent cofactors involved in food anaphylaxis (from top to bottom): alcohol, exercise, and non-steroidal anti-inflammatory drugs (NSAIDs). Mild reactions in the absence of a cofactor may end up in an anaphylaxis with the same amount of allergen together with the presence of a cofactor. Ado, adenosine; green arrows, increase; red arrows, decrease. *Evidence based on references (, , , , , , , , –59, 66, 67).