Histamine-induced RPS6 phosphorylation in dendritic cells is associated with the severity of peanut allergic reactions

The phosphorylation of the ribosomal protein S6 (RPS6) was reported to be increased in myeloid cell subsets after stimulation with peanut extract in peanut-allergic individuals or with anti-IgE antibodies in both allergic and nonallergic donors. The mechanisms driving this increase of RPS6 phosphorylation (pS6) and its clinical impacts remain to be elucidated. Therefore, we investigated the mechanism of pS6 induction in plasmacytoid DCs (pDCs) and conventional DCs (cDCs) using whole blood stimulated with peanut extract or anti-IgE antibodies. This approach included in vitro basophil depletion and the application of receptor antagonists. Clinical associations with differential pS6 were performed with data from a well-defined cohort of peanut-allergic individuals participating in the food intervention trial TINA. Our findings revealed an increase of pS6 in pDCs and cDCs via histamine receptor 2 (H2R) signaling after IgE-dependent basophil degranulation and histamine release. In adults - but not in children - pS6 in cDCs was positively associated with food allergy severity, as determined by titrated oral food challenges. The association of pS6 in cDCs with food allergy severity in an age-dependent manner suggests a possibly novel functional mechanism, which may contribute to the course of food allergy, e.g., via increased antigen presentation.