ABSTRACT
We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.
Subject(s)
Eosinophilic Esophagitis/chemically induced , Eosinophilic Esophagitis/metabolism , Esophagus/metabolism , Inflammation Mediators/metabolism , Interleukin-33/metabolism , Adaptive Immunity , Adolescent , Animals , Aspergillus fumigatus/pathogenicity , Biopsy , Case-Control Studies , Cell Proliferation , Chemokine CCL26 , Chemokines, CC/metabolism , Child , Child, Preschool , Disease Models, Animal , Endothelial Cells/immunology , Endothelial Cells/metabolism , Eosinophilic Esophagitis/genetics , Eosinophilic Esophagitis/immunology , Eosinophilic Esophagitis/microbiology , Eosinophilic Esophagitis/pathology , Esophagus/immunology , Esophagus/microbiology , Esophagus/pathology , Humans , Immune Tolerance , Immunity, Innate , Interleukin-13/deficiency , Interleukin-13/genetics , Interleukin-33/genetics , Macrophages/immunology , Macrophages/metabolism , Mice, Inbred BALB C , Mice, Knockout , Phenotype , RNA, Messenger/metabolism , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Time Factors , Up-RegulationABSTRACT
BACKGROUND: In spring 2002, WONCA Europe, the European Society of General Practice/Family Medicine and its Network organizations reached consensus on a 'new' European definition of general practice. Subsequently, the European General Practice Research Workshop (EGPRW) started working on a European General Practice Research Agenda. This topic was addressed during the 2002 EGPRW autumn meeting. OBJECTIVE: Our aim was to explore the views of European general practice researchers on needs and priorities as well as barriers for general practice research in Europe. METHODS: In seven discussion groups, 43 general practice researchers from 18 European countries had to answer the following questions. (i) What major topics should be included in a research agenda for general practice in your country? (ii) What are the barriers to adequate implementation of general practice research in your country? Group answers were listed and subsequently categorized by two authors. RESULTS: Research on 'clinical issues' (common diseases, chronic diseases, etc.), including diagnostic strategies, was considered to be the core content of general practice research, with primary care-based morbidity registration essential for surveillance of disease, clinical research and teaching in general practice. There was also consensus on the need for research on education and teaching. 'Insufficient funding opportunities' was perceived to be the major barrier to the development of general practice research. CONCLUSIONS: These findings could be used as a basis for national checklists of 'content of' and 'conditions for' general practice research. European general practice research training programmes should be developed further.
