Immunopathophysiology of food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome (FPIES) and food protein-induced proctocolitis are non-IgE-mediated gastrointestinal allergies. Our current understanding of the mechanisms of these allergies linking exposure to the typical symptoms of vomiting, hypotension, and diarrhea falls behind that of other food-induced allergic disorders. Accompanying a comprehensive review of clinical features by Nowak-Wegrzyn that also appears in this issue, Berin assesses the state of our knowledge of the immune mechanisms of FPIES (J Allergy Clin Immunol 2015; 135(5):1108-1113).

FPIES is most commonly triggered by the protein component in cow’s milk, but a host of other foods can be triggers as well. Many of the foods that trigger FPIES reactions are also IgE-mediated food allergens, such as soy, fish, wheat, and egg, but many are not common in that regard. For example, rice is the third most common cause of FPIES in US cohorts, followed by oats. The fact that a range of common foods have the potential to trigger it is in contrast to celiac disease, in which pathology is triggered by a well-defined antigen in a restricted subset of foods.

Studies have demonstrated FPIES leads to changes in the intestinal architecture in response to chronic exposure to a trigger such as milk. Avoiding milk results in normalization, and its reintroduction results in a recurrence of partial villous atrophy. While this is similar to celiac disease, the two conditions differ in pathophysiology. For example, the latter is thought to be a food antigen-triggered autoimmunity. There is a lack of evidence for an autoimmune component in FPIES, but there is an association between it and atopy. There is mast cell degranulation in common between the two, which is an important factor that requires investigation.

The facts that FPIES commonly develops in response to the first food introduced into the diet and adverse reactions can develop in response to many foods that are not typically allergenic suggests there may be a regulatory defect in patients with FPIES. The presence and phenotype of food-specific T cells in the intestinal mucosa of patients with FPIES needs to be demonstrated, as has been done with celiac patients. There is even less data to explain the immune basis of acute FPIES reactions. In one case study, milk administered via enema resulted in diarrhea and weight loss, whereas drinking the milk induced vomiting, pallor, and diarrhea in the same infant. Thus, the chronic and acute manifestations of FPIES can be triggered at different sites. Is processing of the allergen during digestion required to trigger symptoms? Much remains to be investigated about its underlying immune mechanisms.