Mucosal immunology of food allergy

Abstract

Food allergies are increasing in prevalence at a higher rate than can be explained by genetic factors, suggesting a role for as yet unidentified environmental factors. In this review, we summarize the state of knowledge about the healthy immune response to antigens in the diet and the basis of immune deviation that results in immunoglobulin E (IgE) sensitization and allergic reactivity to foods. The intestinal epithelium forms the interface between the external environment and the mucosal immune system, and emerging data suggest that the interaction between intestinal epithelial cells and mucosal dendritic cells is of particular importance in determining the outcome of immune responses to dietary antigens. Exposure to food allergens through non-oral routes, in particular through the skin, is increasingly recognized as a potentially important factor in the increasing rate of food allergy. There are many open questions on the role of environmental factors, such as dietary factors and microbiota, in the development of food allergy, but data suggest that both have an important modulatory effect on the mucosal immune system. Finally, we discuss recent developments in our understanding of immune mechanisms of clinical manifestations of food allergy. New experimental tools, particularly in the field of genomics and the microbiome, are likely to shed light on factors responsible for the growing clinical problem of food allergy.

Figure 1. Mechanism of oral tolerance induction

Antigens are captured in the lamina propria and Peyer's patch and carried to the mesenteric lymph node (MLN) by CD103⁺ DCs. DCs induce gut-homing (α4β7⁺) iTregs by a mechanism dependent on TGF-β, retinoic acid (RA), indoleamine-2,3-dioxygenase (IDO), and 4-1BB. DCs induce gut-homing IgA-secreting plasma cells also through RA-dependent mechanisms. Gut-homing iTregs are expanded in the lamina propria by IL-10-expressing CX₃CR1⁺ macrophages. These iTregs can then suppress systemic immune responses, including allergic sensitization, in an antigen-specific manner.

Figure 2. Impact of environmental factors on allergic sensitization

Green arrows indicate factors either known or suggested to promote allergic sensitization, red arrows indicate factors suppressive to allergic sensitization (known or suggested). Experimental adjuvant can induce allergic sensitization through IL-33 release from epithelial cells, driving Th2 responses via OX40L on DCs. In skin, damage and decreased barrier can function as physiologic adjuvants driving this process. Dietary factors including Vitamin D, Vitamin A, aryl hydrocarbon receptor (AHR) ligands, and folate are thought to promote regulatory responses or suppress inflammatory responses, while high fat diet (HFD) promotes inflammatory responses. The gut microbiota or its constituents can suppress aspects of the allergic immune response, directly or through the induction of Tregs.

Figure 3. Mechanisms of systemic and local manifestations of food allergy

Mast cells are central to both local and systemic manifestations of food allergy. Antigen disseminated systemically can trigger distal reactions (urticaria, bronchospasm) through histamine and platelet activating factor (PAF) dependent mechanisms. Gastrointestinal manifestations of food allergy in mice are dependent on repeated exposure to the food allergen that drives an allergic inflammation and mastocytosis that is necessary for the local symptoms. PAF and serotonin mediate the local acute response (diarrhea) to allergen exposure.