Immune activation in the intestinal mucosa before the onset of colitis in G alpha i2-deficient mice

G-protein subunit G alpha i2-deficient mice spontaneously develop an inflam matory bowel disease that clinically and histopathologically resembles ulce rative colitis in humans. The aim of this study was to determine whether im munological changes precede the development of colitis in G alpha i2-defici ent mice. Therefore, G alpha i2-deficient mice with no clinical or histopat hological signs of colitis were compared with G alpha i2-deficient mice wit h established colitis and wild-type animals, concerning immunological param eters. Healthy G alpha i2-deficient mice displayed an increased frequency o f CD4(+) T cells and a decreased frequency of CD19(+) B lymphocytes in the intestinal mucosa compared with control mice. The CD4(+) population was cha racterized by a memory phenotype, i.e. increased expression of CD44 and dec reased expression of CD45RB and CD62L, as well as increased expression of t he mucosal homing receptors integrins alpha 4 beta 7 and alpha E beta 7. Pr oduction of pro-inflammatory cytokines, interleukin (IL)-1 beta and interfe ron (IFN)-gamma, were increased in G alpha i2-deficient mice before clinica l signs of disease were evident. In addition, total immunoglobulin (Ig)G an d IgA levels in large intestinal secretions were increased significantly co mpared with wild-type mice, and antibodies specific for the normal intestin al flora in large intestinal secretions were present in G alpha i2-deficien t mice several weeks before the onset of colitis. In contrast, antibodies a gainst tropomyosin, a putative autoantigen in human ulcerative colitis, wer e not found in G alpha i2-deficient mice before the onset of colitis, altho ugh they were present in animals with established disease. In conclusion, a ctivation of the intestinal immune system precedes histopathological and cl inical signs of inflammation in G alpha i2-deficient mice, suggesting that immune abnormalities play an important role in the induction of colitis.