Functional and Phenotypic Studies of Eosinophilic Granulocytes in Patients with Eosinophilic Esophagitis

Abstract

Eosinophilic Esophagitis (EoE) is a chronic inflammatory disorder of unknown etiology, in which the esophagus is infiltrated by eosinophils and T cells. Topical corticosteroids are one of the treatment options for patients with EoE. The function of eosinophils in EoE is unknown, here we hypothesize that eosinophils serve as immunoregulatory cells. The eosinophils in the blood of untreated adult patients with EoE have a distinct phenotype. The aims of this thesis were to explore whether the eosinophilic phenotype of untreated patients with EoE can be reverted to the healthy phenotype by topical corticosteroid treatment, and to examine whether blood eosinophils from children with EoE have a distinct phenotype, different from that of healthy children. Moreover, we tested the hypothesis that eosinophils, similar to regulatory T cells, can diminish T cell proliferation and express FOXP3. The role of the eosinophilic protein galectin-10 in mediating immunosuppression was also investigated. This thesis demonstrates that the EoE phenotype of blood eosinophils is not restored by topical corticosteroid treatment, except with respect to CD18. We also show that eosinophils from patients with EoE have an immunoregulatory phenotype, i.e., increased levels of FOXP3 and galectin-10. Moreover, eosinophils from healthy subjects and patients with EoE are able to suppress T cell proliferation in vitro, in part via galectin-10. We show that eosinophils exposed to activated T cells release galectin-10 via DNA nets and appear to transfer this protein to T cells through synapses. Two subsets of eosinophils emerge after co-culturing. Finally, we demonstrate that the blood eosinophils of children with EoE have a distinct phenotype, different from that of healthy children and that of adults with EoE. Importantly, we reveal marked age-related differences regarding the molecular patterns displayed by the blood eosinophils of healthy donors. Our finding that eosinophils from patients with EoE have upregulated immunoregulatory molecules could indicate that the function of eosinophils in EoE is to reduce a T cell-mediated inflammation in the esophagus.