Immune responses to food

Abstract

The enormous variety of antigens present in food is not ignored by the immune system. Dietary antigens are recognized as foreign, and tolerance must be induced. The regulation of both mucosal and systemic non-responsiveness to dietary antigens is therefore a basic physiological process which has drawn experimental interest for many years. Indeed, the first report on the induction of non-responsiveness by a fed antigen was published over one hundred years ago.¹ Since that time it has become clear that, in keeping with the need to maintain tolerance to dietary antigens, the oral route of antigen administration is uniquely suited to inducing antigen specific non-responsiveness. Experiments in the late 1980s highlighted the practical benefits of oral antigen administration by demonstrating that intragastric delivery of autoantigens, prior to peripheral immunization, protected against the development of autoimmunity in mice.^{2, 3} This finding was subsequently confirmed in a large variety of animal models of autoimmune, allergic, and inflammatory disease, as well as in models of transplant rejection.⁴ The generalizability of the observation that oral administration of antigen can protect against the development of antigen-induced systemic disease became the foundation for immunotherapeutic trials of orally administered antigens for several human diseases including rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, autoimmune uveitis and food allergy.⁵ However, unlike the murine models where the autoantigens were well defined and administered before disease was induced, the clinical trials attempted to modulate established tissue damage in settings in which the autoantigens were both complex and poorly characterized. It was not surprising, then, when these initial trials met with limited success. Both the murine and human studies succeeded, however, in stimulating interest in understanding the mechanisms by which orally administered antigens induce systemic nonresponsiveness to subsequent antigen challenge.

Early work by Weiner and colleagues described high and low dose oral tolerance mediated by deletion or anergy/suppression and a novel subset of TGF-β secreting “Th3” cells.^{6, 7} The doses designated as high and low were somewhat arbitrarily defined. The identification of transcription factors that specify CD4 T cell differentiation did not reveal a Th3 subset, but did show that the production of TGF-β by innate immune cells is an important fate specifying cytokine for both Th17 cells and peripherally induced Foxp3⁺ regulatory T cells (Tregs).⁸ With the discovery of Foxp3⁺ Tregs, attention switched to the role of food antigen specific Tregs induced in the context of the dietary vitamin A metabolite retinoic acid in gut draining lymph nodes. It was even suggested that oral tolerance was entirely attributable to retinoic acid.⁹ Subsequent work showed that the presence of both TGF-β and retinoic acid in the mesenteric lymph node was critical to induce Tregs with homing receptors that allowed them to migrate back to the small intestinal lamina propria and expand under the influence of IL-10.¹⁰ In recent years, interest in understanding immune responses to food has been propelled by the skyrocketing prevalence of food allergies.¹¹ In this volume we review the current understanding of the mechanisms regulating non-responsiveness to food and explore how that knowledge is informing new therapeutic approaches to prevent or treat food allergies and other pathologic responses to dietary antigens.

Miranda-Waldetario and Curotto de Lafaille begin by reviewing the historical perspective mentioned above and providing up-to-date insights on the different antigen presenting cells/cellular compartments central to the induction of food antigen specific Tregs.¹² A specific subset of RORγt⁺ expressing food antigen specific Fox3⁺ Tregs, induced primarily in the draining duodenal lymph node, is critical for tolerance to dietary antigens. Both these authors and Cheifetz and Knoop emphasize that a unique developmental window (and mucosal microenvironment) in early life is critical for inducing non-responsiveness to food.¹³ The animal model data described is in keeping with the current understanding that early life introduction of allergenic foods is essential to the induction of tolerance. When the prevalence of life-threatening peanut allergies started to climb in the U.S., the American Academic of Pediatrics (AAP) issued guidance which advised pregnant women and breast-feeding mothers to avoid peanut consumption and to withhold peanuts from their children until the age of 3.¹⁴ This turned out to be exactly the wrong advice. In the landmark Learning About Early Prevention (LEAP) study, Lack and colleagues noted that peanut allergy was much more common in children living in the U.K. than children from the same ethnic background living in Israel. They observed that children in Israel (but not the U.K.) were fed a peanut containing snack in early life. A randomized clinical trial clearly demonstrated that early introduction of peanuts reduced the risk of subsequent peanut allergy.¹⁵ The AAP guidelines were reversed in 2019 to recommend that peanut containing products be introduced to all infants by 6 months of age.¹⁶

Tregs are not the only T cell subset responsive to dietary antigens. Berin and colleagues review a spectrum of aberrant immune responses to food including Th2 driven IgE-mediated food allergy, the less common non-IgE, Th2 mediated inflammation seen in eosinophilic esophagitis (EoE) and the as yet poorly understood inflammation characteristic of food protein induced enterocolitis (FPIES).¹⁷ Only two types of stimuli elicit an IgE response-helminthic parasites and allergens. Given its deleterious effects for the host in allergic disease, Rahman and Wesemann explore the fascinating question of why IgE emerged in mammals at all.¹⁸ They discuss potential evolutionary origins in protection against toxins and parasites and newer information on dietary quality control. They examine the mechanisms regulating the development of IgE secreting plasma cells, affinity and memory of the IgE response and the implications of these features for effective immunotherapy. IgE is not the only food specific Ig isotype. IgA is produced in large quantities in the gut and usually associated with responses to toxins, pathogens or commensal bacteria. Siniscalco et al. investigate the induction of food specific IgA, a largely unappreciated aspect of the immune response to food.¹⁹ They report that T cell requirements for food specific IgA differ from those of IgE. It is not yet clear whether the induction of food specific IgA represents a counter-regulatory response to the induction of IgE; data thus far do not correlate food specific IgA with antigen specific non-responsiveness.

The role of neuroimmune regulation in both homeostasis and disease is an area of intense and growing interest in the broader immunology community. Matatia et al. delve into this exciting new field with the hypothesis that dysregulated neuroimmune circuits drive allergic disease.²⁰ They review the organization of the central and peripheral nervous systems and how components of each integrate with immune cells at barrier surfaces. They suggest that sensory neurons sense allergens and directly contribute to allergic immunity. A second review reports that histamine released by mast cell degranulation induced by a localized food specific IgE response is sensed by colonic neurons to trigger the abdominal pain associated with irritable bowel syndrome.²¹

The mother–child dyad plays a critical role in immune homeostasis in early life. The next set of reviews examines this interaction from the perspective of the newborn's response to food. Breast milk is the ideal infant food in its provision of nutrients important for infant growth and protection. Immune cells and proteins in breast milk support the nascent infant immune system.²² Oyoshi and colleagues emphasize the protection afforded by the transfer of maternal antibodies.²³ Data from a neonatal mouse model reveal that detergent containing products can promote sensitization to food in mice with mutations in skin barrier genes which are also exposed to environmental allergens. Maternal supplementation with α-tocopherol (vitamin E) can block this response in genetically susceptible neonates.²⁴

It is clear that gene–environment interactions contribute to the pathogenesis of food allergy. Frischmeyer-Guerrerio et al. explore how immunologic and genetic factors intersect to elicit allergic responses to food, with particular emphasis on the role of TGF-β in driving atopy in both patients with Loeys-Dietz syndrome and a murine model of this disease.²⁵ Nocerino et al. review current approaches to disease modification in cow's milk allergy, one of the most common (and earliest onset) pediatric food allergies.²⁶ Monogenic disorders can also reveal novel insights into the immunoregulatory pathways that control tolerance to dietary antigens in both food allergy and celiac disease.²⁷ Light and Nagler provide evidence in support of the hypothesis that 21st century lifestyle factors have, collectively, resulted in a loss of diversity in the commensal microbiome and the depletion of allergy protective intestinal bacteria. They propose that, in addition to food antigen specific Tregs, a bacteria-induced barrier protective response is required to induce tolerance to food and prevent food allergy. They describe the microbiome and its metabolites and examine novel microbiome-modulating approaches to prevent or treat allergic responses to food.²⁸ We close with a synthesis from Chatila and colleagues which describes a central role for host–microbe interactions in early life as a series of mucosal immune checkpoints that regulate the induction of oral tolerance, and its abrogation in food allergy.²⁹

CRN is a co-founder of ClostraBio, Inc.