Intestinal Uptake and Tolerance to Food Antigens

Abstract

Food allergy is a growing concern due to its increasing world-wide incidence. Strict avoidance of allergens is a passive treatment strategy. Since the mechanisms responsible for the occurrence and development of food allergy have not yet been fully elucidated, effective individualized treatment options are lacking. In this review, we summarize the pathways through which food antigens enter the intestine and review the proposed mechanisms describing how the intestine acquires and tolerates food antigens. When oral tolerance is not established, food allergy occurs. In addition, we also discuss the contribution of commensal bacteria of the gut in shaping tolerance to food antigens in the intestinal tract. Finally, we propose that elucidating the mechanisms of intestinal uptake and tolerance of food antigens will provide additional clues for potential treatment options for food allergy.

Keywords: food allergy; food antigens; gut microbiota; intestinal barrier; intestinal immune system; oral tolerance; paracellular pathway; transcellular pathway.

Figure 1

Food antigens cross the intestinal epithelium to induce tolerance or provoke allergy. (1) Small molecules such as electrolytes and water enter the sub-epithelium via paracellular pathways. (2) Degradation of tight junctions increases the permeability of the paracellular pathway, which leads to non-selective and uncontrolled entry of macromolecules into the intestinal sub-epithelium and contributes to the sensitization process of food allergies. (3) Small molecules such as amino acids and glucose that are transported across the epithelium by apical brush boundary transporters such as SLCs on enterocytes. (4) M cells sample food antigens, and then present them to dendritic cells. (5) Goblet cells form goblet-cell-associated antigen passage (GAP) to enclose luminal antigens (food antigens and microbial antigens) in internal sack-like vesicles, and then transport them across entire cells to dendritic cells. (6) In food allergy mouse models, secretory epithelial cells function as conduits to allow the transport of food antigens through the epithelium of the small intestine and induce a food-induced anaphylactic reaction. (7) CX3CR1⁺ macrophages rely on CX3CR1 expression to form dendrites to efficiently sample antigens from the intestinal lumen without disrupting the tight junctions between the cells. CX3CR1⁺ macrophages transfer antigens they captured to CD103⁺ DC. (A) When food antigens enter the intestinal sub-epithelium through above pathways, they are acquired and processed by dendritic cells. Then DCs migrate to MLNs where they present the processed food antigens and induce tolerance or food allergy. To induce oral tolerance, DCs secrete interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and indoleamine 2,3-dioxygenase (IDO) to induce Tregs and promote their production of IL-10 and TGF-β to maintain tolerance. (B) In the case of allergy, oral antigens and adjuvants stimulate the expression of IL-33 in intestinal epithelial cells, which in turn upregulates the expression of the costimulatory molecule-OX40L on DCs. OX40L expression upregulates DCs to promote the TH2 response in the MLN and leads to more severe food allergies.