Food allergy has increased at an alarming rate over the past two decades, with children bearing a disproportionate burden of disease. Clinical symptoms range from mild reactions to severe, life-threatening anaphylaxis, and effective FDA-approved treatment options remain limited — food avoidance remains the only reliably safe strategy. A better understanding of the immune mechanisms and signaling pathways underlying food allergy is therefore essential to permit development of effective and safe therapies.

Over the last 15 years, our team has made several seminal contributions unveiling a critical role for the IL-9/IL-9R axis in gastrointestinal (GI) mast cell (MC) density and its role in predisposition and severity of food allergy. A current gap in knowledge is the cellular origin of IL-9 and the GI tissue-specific signals that stimulate its induction and drive GI MC expansion.

In preliminary studies using IL-9eGFP reporter mice, we identified three IL-9-producing cell populations within the GI tract of food-allergic mice: FcεRI+ common myeloid progenitors (CMPs), innate lymphoid cell type 2 (ILC2), and CD4+ Th2 cells. Strikingly, FcεRI+ CMPs emerged as the dominant source of IL-9 in the GI tract, and their abundance correlated with food allergy severity. We also identified CD34+ IL-9+ and CD4+ IL-9+ cells in duodenal biopsy samples from peanut-allergic individuals, supporting the translational relevance of these findings.

We hypothesize that FcεRI+ CMPs secrete IL-9 to regulate GI MC density and govern predisposition and severity of food allergy. To test this hypothesis, we are pursuing three specific aims: (1) define the requirement of FcεRI+ CMP-derived IL-9 in GI MC expansion and food allergy; (2) determine the GI-specific signals — including intestinal epithelial IL-33 — that drive IL-9 induction in FcεRI+ CMPs and their role in MC progenitor proliferation and maturation; and (3) characterize human IL-9+ FcεRI+ CMPs in peanut allergy to establish clinical relevance.

Successful completion of these studies will provide a new and substantive departure from our current understanding of the molecular mechanisms governing GI MC density in food allergy, identifying FcεRI+ CMP-derived IL-9 as a central mediator in the pathogenesis of food allergy and directing the development of new and pre-existing therapeutics for treating food allergy and anaphylaxis.

A food-induced anaphylactic reaction encompasses a variety of symptoms that can affect one or more target organs, including those of the gastrointestinal, cutaneous, respiratory, and cardiovascular systems. In human subjects compromise of either the cardiovascular or respiratory system defines a severe reaction and it is postulated that basophil- and mast cell (MC)–derived mediators, through inducing pulmonary venous vasodilatation and fluid extravasation, cause the respiratory and cardiovascular collapse that leads to the severe, life-threatening anaphylactic phenotype.

Clinical studies have reported increased levels of the cytokine IL-4, and mast cell derived mediator histamine in the sera of human patients with severe anaphylaxis suggesting a role for these molecules in the regulation of anaphylaxis severity. Consistent with this, we have previously demonstrated that IL-4 can interact with vasoactive mediators such as histamine to increase hemoconcentration and the severity of anaphylaxis. The gap in knowledge is the cellular target of these IL-4–mediated effects and the underlying IL-4 receptor α chain (IL-4Rα)–dependent signaling processes involved in the amplification of histamine-induced vascular endothelial (VE) barrier dysfunction and fluid extravasation in IgE-mediated reactions is not yet fully understood.

Employing both in vitro and in vivo model systems, we are defining the relationship between IL-4 and histamine in IgE-mediated VE leak and hypovolemic shock.

So far, we have identified that IL-4 amplifies histamine-induced hypovolemic shock in mice through VE IL-4Rα chain–dependent process. Notably, IL-4 and histamine stimulated activation of ABL1 kinase activity in VE cells and VE barrier dysfunction was inhibited by pharmacologic and genetic ablation of ABL1 activity. Importantly, using both passive and active models of food-induced anaphylaxis, we showed that blockade of ABL kinase activity using the inhibitor imatinib protected the mice from the severe IgE-mediated anaphylactic phenotype after allergen exposure.

These studies implicate an important contribution by the IL-4Rα/ABL1 signaling pathway in the VE compartment in the severity of IgE- and histamine-induced anaphylaxis.

The laboratory is currently studying the IL-4Rα chain–dependent signaling processes that alter vascular endothelial function and drive severe IgE-mediated allergic reactions.

PMID: 29157947

Translocation of dietary antigens across the SI epithelium is thought to occur through microfold cell–mediated transcytosis, transepithelial dendrites, goblet cell antigen passages (GAPs), and paracellular leak. Recent data suggests that dysregulation of the mechanisms of dietary antigen sampling and presentation at the gastrointestinal epithelium to hematopoietic compartment predisposes to aberrant adaptive immune responses.

The gastrointestinal (GI) epithelial barrier comprises a single cell layer of polarized intestinal epithelial cells (IEC) that forms a physical barrier between the gut lumen (containing food, bacteria, fungi, viruses, environmental particulates, carcinogens and toxins), and the internal systems of the body. The GI epithelial barrier acts as a selective filter, limiting the uptake of pathogens and harmful substances while permitting the absorption of critical dietary components (proteins, carbohydrates, nutrients and electrolytes) that are essential for cellular growth and survival. To regulate these critical processes the intestinal epithelium consists of a functionally diverse array of epithelial cell types (i.e. enterocytes, goblet cells (GCs), neuroendocrine cells, tuft cells, Paneth cells and microfold (M) cells), which act cooperatively to promote the development and maintenance of physical and chemical barriers, host defense and nutrient absorption.

In healthy subjects microfold cell–mediated transcytosis and GAP-mediated transcellular transport seem to be the primary route of dietary antigen sampling. These processes are thought to be important in inducing systemic immunologic non-responsiveness, termed oral tolerance. However, the contribution of these processes to food allergen translocation across the allergic intestinal epithelium and induction of a food-induced IgE-mediated reaction remained unclear.

The Hogan Lab is interested in defining the processes involved in the translocation of dietary allergens across the intestinal epithelial surface to the subepithelial immune compartment in food allergic reactions.

These studies have identified that secretory intestinal epithelial cells (GC’s, enteroendocrine cells, and Paneth cells) in the small intestine (SI) of mice with food allergy act as conduits to permit dietary allergens to transport across the intestinal epithelium to underlying allergic immune cells such as mast cells. We showed that SI intestinal secretory epithelial cell antigen passages (secretory antigen passages [SAPs]) that comprise of villi and cryptic goblet cells (GCs), enteroendocrine cells, and Paneth cells; are induced by the cytokine IL-13 in a CD38/cyclic adenosine diphosphate ribose (cADPR)–dependent manner; and are conserved in human subjects. Our in vivo analyses reveal that SAPs are integral for initial translocation of food allergens across the SI epithelium to underlying MCs, which leads to induction of a food-induced anaphylactic reaction.

The laboratory is currently studying the role of SAPs in regulating the interaction between tolerogenic induction mechanisms and tolerogenic maintenance and/or reinforcement mechanisms in sustaining unresponsiveness to food antigens through life.

PMCID: PMC6779525