Rapid migration of thymic emigrants to the colonic mucosa in ulcerative colitis patients.

Inflammatory bowel disease (IBD) is associated with imbalances of the local intestinal immune responses, with dysregulated CD4(+) T cells contributing to the chronic inflammation. Having demonstrated altered T cell maturation in the thymus in two different mouse models of colitis, we set out to investigate whether abnormalities in T cell maturation is present in patients with ulcerative colitis (UC) or Crohn's disease (CD). Specimens were obtained from peripheral blood (CD; n = 14, UC; n = 22), colon and small intestinal specimens (CD; n = 6, UC; n = 13). As controls, peripheral blood specimens were obtained from healthy volunteers, patients with adenocarcinomas (n = 18) and colonic specimens from patients with adenocarcinomas (n = 14). Recent thymic emigrants were estimated by analysis of the normalized ratio of T cell receptor excision circles (TRECs) by real-time polymerase chain reaction (PCR). The frequency of naive- and proliferating T lymphocytes and markers of extrathymic T cell maturation in the mucosa was analyzed by flow cytometry and real time-PCR. TREC levels in peripheral blood T lymphocytes were similar between IBD patients and controls. In contrast, UC patients demonstrated significantly increased levels of TRECs both in intraepithelial and lamina propria lymphocytes from the colonic mucosa compared to patients with adenocarcinomas and CD. However, markers for extrathymic T cell maturation in the mucosa were not different between controls and IBD patients. The increased TREC levels in mucosal but not peripheral blood lymphocytes in UC patients in the absence of increased extrathymic maturation in situ in the mucosa together demonstrate that recent thymic emigrants are recruited rapidly to the inflamed mucosa of these patients.

Regression of Peyer's patches in G alpha i2 deficient mice prior to colitis is associated with reduced expression of Bcl-2 and increased apoptosis.

BACKGROUND: G protein deficient (G alpha i2-/-) mice spontaneously develop an inflammatory bowel disease (IBD) closely resembling ulcerative colitis. Previous studies have demonstrated that gut T cells are hyperreactive to the endogenous microflora in most IBD models. AIMS: The aim of this study was to analyse Peyer's patches (PP), the inductive sites for gut mucosal immune responses. SUBJECTS AND METHODS: G alpha i2-/- mice, an animal model for IBD, were analysed using immunological methods with regard to phenotype and function. RESULTS: We found significantly decreased numbers of PP in G alpha i2-/- mice. Even before the onset of colitis, G alpha i2 deficient animals exhibited diminished size of PP, as judged by histology. This involution of PP was associated with strongly increased levels of apoptotic lymphocytes, associated with decreased levels of antiapoptotic intracellular protein Bcl-2. PP T lymphocytes showed highly elevated production of interferon gamma in response to the enteric flora compared with PP T cells from wild-type mice, which produced predominantly interleukin 10. CONCLUSIONS: Thus even before the onset of colitis, the PP in G alpha i2 deficient mice is a Th1 dominated milieu associated with downregulated levels of Bcl-2, resulting in increased apoptosis of lymphocytes leading to regression of PP. We speculate that this Th1 dominated microenvironment in the inductive site for mucosal immune responses contributes to the development of colitis in G alpha i2 deficient mice.