Deciphering the black box of food allergy mechanisms

Abstract

Objective To review our current understanding of immunotherapy, the immune mechanisms underlying food allergy, and the methodological advances that are furthering our understanding of the role of immune cells and other molecules in mediating food allergies. Data Sources Literature searches were performed using the following combination of terms: allergy, immunotherapy, food, and mechanisms. Data from randomized clinical studies using state-of-the-art mechanistic tools were prioritized. Study Selections Articles were selected based on their relevance to food allergy. Results Current standard of care for food allergies is avoidance of allergenic foods and the use of epinephrine in case of severe reaction during unintentional ingestion. During the last few decades, great strides have been made in understanding the cellular and molecular mechanisms underlying food allergy, and this information is spearheading the development of exciting new treatments. Conclusion Immunotherapy protocols are effective in desensitizing individuals to specific allergens; however, recurrence of allergic sensitization is common after discontinuation of therapy. Interestingly, in a subset of individuals, immunotherapy is protective against allergens even after discontinuation of immunotherapy. Whether this protection is permanent is currently unknown because of inadequate long-term follow-up data. Research on understanding the underlying mechanisms may assist in modifying protocols to improve outcome and enable sustained unresponsiveness, rather than a temporary relief against food allergies. The cellular changes brought about by immunotherapy are still a black box, but major strides in our understanding are being made at an exciting pace.

The vascular endothelial specific IL-4 receptor alpha–ABL1 kinase signaling axis regulates the severity of IgE-mediated anaphylactic reactions

“…Herein, we demonstrate that IL-4 can amplify the IgE-mediated, histamine-induced fluid extravasation through priming of the vascular endothelial compartment. Previous studies have revealed an important role for IL-4 and IL-4Rα signaling in IgE-mediated anaphylaxis; however, this was predominantly thought to be through its effect on the hematopoietic compartment driving IgE-isotype switch and the associated CD4 + Th2 and mast cell response in anaphylaxis 31, 67–69 . We show that IL-4 also acts on the non-hematopoietic compartment, namely the VE to increase the sensitivity of the VE to histamine.…”

New Perspectives in Food Allergy

“…CX3CR1+ macrophages can capture food antigens directly from the intestinal lumen by insinuating dendritic extensions between epithelial junctions (periscopic mechanism). CD103+ DCs transport the captured antigens to Peyer's patches and mesenteric lymphnodes and drive the homing of B lymphocytes secreting mucosal IgA in the gut, thus contributing to the maintenance of a specific immune tolerance [92]. IgGs, in particular, specific IgG4, can inhibit the initiation as well as the effector phases of allergic responses, thus also contributing to the acquisition of oral tolerance to food antigens [2].…”

“…Among the other cell types involved in tolerance disruption, innate lymphoid cells of type 2 (ILC2), similar to Th2 lymphocytes but lacking specificity for the antigen, and IL-9-producing cells (Th9 cells), which are mucosal mastcells capable of producing various inflammatory cytokines and capable to suppress the function of Tregcells, have been recently recognized [2,100]. All of them increase the vicious circle which leads, through an autocrine loop, to the increase in the intestinal mastcell pool [20,92,101].…”

Newly identified T cell subsets in mechanistic studies of food immunotherapy

“…Several Treg subtypes have been associated with tolerance, including Foxp3 + Tregs, IL-10-secreting Foxp3 -Tregs (also known as Tr1 cells), and TGF-β-secreting T helper 3 (Th3) cells. Further details can be found in a number of excellent reviews on the topic (46,48,(62)(63)(64)(65)(66)(67)(68).…”