Role of Human Eosinophils and T cells in EGID

Eosinophilic gastrointestinal disorders (EGIDs) of the upper GI tract are predominantly food-triggered chronic eosinophilic disorders with profoundly negative impact on quality of life. When left untreated, both eosinophilic esophagitis and eosinophilic gastroenteritis lead to progressive scarring of the affected GI tract segments. Predictive, non-invasive diagnostic testing and treatments are sorely lacking. Two types of immune cells, eosinophils and specialized T cells, have long been implicated in EGID pathogenesis, but numerous questions remain unanswered about their roles. The GI tract is the largest repository for tissue eosinophils but many other eosinophilic disorders accompanied by excessive blood eosinophilia do not present with GI symptoms. Similarly, these specialized T cells, initially attributed to EGID, are recently thought to be biomarkers in food allergy and hay fever, conditions clinically distinct from EGID. Preliminary evidence suggests there are unique blood eosinophil signatures in EGIDs that distinguish them from blood eosinophils in other eosinophilic disorders, and that specialized circulating Th2 cells in EGIDs differ from those identified in more traditional IgE-mediated atopic conditions. The central hypothesis is that these unique blood eosinophil and T lymphocyte signatures define EGID as a clinical entity distinct from other eosinophilic disorders or food-triggered diseases. The two specific aims are: 1) Definition of unique blood eosinophil signatures in EGID that distinguish it from other eosinophil-associated disorders or atopic disorders with blood eosinophilia; 2) Precise identification of the specialized Th2 cells in EGID as compared to food allergy. In collaboration with GI colleagues, well-characterized symptomatic EGID patients will be recruited to provide blood samples and assessed for the presence of food allergy by an allergist. Patients with other eosinophilic disorders or with food allergy alone will serve as controls. Next-generation RNA sequencing and high-dimensional flow cytometry on eosinophils, two cutting-edge techniques not previously possible in eosinophil investigations, will be used. Flow cytometry with intracellular cytokine staining and ex vivo cell cultures will be used to precisely define the specialized Th2 cells in EGID. Future studies will evaluate the effect of standard of care therapies on these two cell types and their signatures in EGID. This study and its findings will deepen our understanding of EGID pathogenesis, provide potential non-invasive EGID-specific diagnostic or disease activity biomarkers, and transform how one conceptualizes disease pathogenesis in other eosinophilic disorders (e.g. allergic asthma) and food-associated disorders (e.g. food allergy).