Fig. 1.

Overview of direct and indirect pro-allergenic immune responses to anti-ulcer drugs (AUD). a, f With regards to oral allergens, the gastric pH elevation by AUDs, most dominantly by proton-pump inhibitors (PPI) and H2 receptor antagonists (H2RA), leads to reduced pepsin activation and impaired food antigen degradation, enabling persistence of ingested epitopes and their uptake in the intestines^{14–16,23,24}. This leads to formation of antigen-specifc IgE and promotion of a Th2 type dominated immune milieu resulting in eosinophilic inflammation and allergic symptoms^14,15,24. b–e With regards to directly AUD-associated innate and adjuvant immune effects, PPIs can (b) induce AhR-mediated mast cell activation synergizing with IgE-FcɛRI signaling and resulting in mediator release³⁰ and enhanced CD63 expression via the S1P pathway; both mechanisms result in allergic symptoms manifestation; (c) H2RAs stimulate the release of Th2 cytokines from both monocyte and Th2 cells leading to a B-cell isotype switch resulting in IgG1 (mice) and IgE production (humans, mice)³¹; (d) Further, H2RAs promote an increase in Th2 cytokine releasing iNKT cells³², particularly when co-exposed to lipid antigens, and increase in CD1d+ DCs via TLR2 activation; (e) Sucralfate, an aluminum compound, can induce IL-4 release from DCs along with IL-5^33,34 and caspase-dependent IL-1β secretion⁴³ from monocytes promoting an isotype switch in B-cells into IgE production; f The resulting disturbance of gut microbiota composition^35,37,45 additionally supports a pro-allergic Th2 milieu and enhances allergic symptoms