Immunoregulatory Pathways Are Active in the Small Intestinal Mucosa of Patients with Potential Celiac Disease

OBJECTIVES: Potential celiac disease (CD) relates to subjects with a normal small intestinal mucosa who are at increased risk of developing CD as indicated by positive CD-associated serology. The objective of this study was to investigate in the small intestinal mucosa of such patients the state of immunological activation with special emphasis on immunoregulatory circuits. METHODS: Duodenal biopsies from active CD (n=48), potential CD (n=58), and control patients (n=45) were studied. RNA expression for interferon gamma(IFN gamma) and interleukin-10 (IL-10) were quantified by real-time quantitative PCR. The percentage of CD4+CD25+Foxp3+ T regulatory cells (Foxp3+Tregs) was determinated by flow cytometry and the number of Foxp3+ and IL-15+ cells by immunohistochemistry. Furthermore, we analyzed the suppressive function of CD4+CD25+ T cells, isolated from potential CD biopsy samples, as well as the effect of IL-15, on autologous peripheral blood responder CD4+CD25- T cells. RESULTS: In potential CD patients with Marsh 1 lesion, IFN gamma-RNA expression was significantly less than in active, but enhanced if compared with potential CD patients with Marsh 0 lesion and with controls (P<0.001). The number of IL-15+ cells in subjects with potential CD was increased in comparison with controls (P<0.05), but lower than active CD (P<0.01). IL-10-RNA expression was upregulated in Marsh 0 potential CD patients if compared with those with Marsh 1 lesion (P<0.01) and controls (P<0.001), whereas there were no differences with active CD. The ratio IL-10/IFN gamma reached the highest value in Marsh 0 potential CD compared with the other groups (P<0.05). The percentage of Foxp3+Tregs was also higher in potential CD compared with controls (P<0.05), although it was lower than in active CD (P<0.01). In co-culture assay, intestinal CD4+CD25+ T cells from potential CD patients exerted suppressive effects on T responder cells, and their activity was not impaired by IL-15. CONCLUSIONS: Potential CD patients show a low grade of inflammation that likely could be due to active regulatory mechanisms preventing the progression toward a mucosal damage.