The intestinal mucosa is the largest lymphoid organ in the body, which simultaneously protects us from pathogens as well as maintains tolerance to dietary constituents and the normal intestinal flora. Dysfunctional control of local immune responses may lead to development of Inflammatory Bowel Disease(IBD) - the common name for ulcerative colitis (UC) and Crohn´s disease (CD), manifested as chronic intestinal inflammation characterized by nausea, diarrhea and severe pain. UC patients also have an increased risk of developing colorectal cancer.
G proteins are a family of GTP-binding proteins that are involved in a variety of transmembrane signaling systems. Mice homozygously deficient in the G protein αi2 subunit (Gαi2-/-) develop IBD with an immunopathology similar to that observed in ulcerative colitis patients, including development of colorectal cancer. Our previous studies on the Gαi2-/- mice have demonstrated immune changes characterized by activation of proinflammatory T helper 1 cells, changes that are present, although to a lower degree, already prior to colitis development. Gαi2-/- mice respond to dietary antigens with a Th1 dominated pro-inflammatory cytokine response in the mucosa prior to colitis, whereas Gαi2+/- mice respond with increased production of the regulatory cytokine IL-10. By bone marrow and lymphocyte transfer we have demonstrated the importance of different cell population on colitis development.
Our aim is to unravel the etiology of the immunopathology observed in this IBD model in the hope that we may be able to explain the mechanism/s causing disease. In addition, T cell ontogeny is studied in patients suffering from IBD. We are currently elucidating possible defects in thymocyte function and T cell ontogenesis in Gαi2-/- mice and IBD patients. Human T cell ontogeny is investigated by TRECS analysis of peripheral blood as well as mucosal lymphocytes. We are also elucidating possible defects in chemokine and chemokine receptor expression and signaling in e.g. the thymus of the Gαi2-/- mice, and its possible role in the pathogenesis of colitis.
Bjursten M, Willén R and Hultgren Hörnquist E. (2005) Transfer of Colitis by Gαi2-deficient T lymphocytes: Impact of Subpopulation and Tissue Origin. Inflammatory Bowel Disease, 11(11):997-1005.
Bjursten M, Bland PW, Willén R and Hultgren Hörnquist E. (2005) Long term treatment with anti- integrin α4 antibodies aggravates colitis in Gαi2-deficient mice. Eur. Journal of Immunol.35:2274-2283
Öhman L, Willén R, Hultgren O and Hultgren Hörnquist E. (2005) Bordetella pertussis vaccine enhances mucosal IL-10 production, induces apoptosis of activated Th1 cells and attenuates colitis of Gαi2-deficient mice. Clin Exp Immunol., 141, 37-46