title: Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(-/-) mice.
abstract: Interleukin-2 (IL-2) receptor alpha knockout (IL-2Ralpha(-/-)) mice have a deficiency of CD25 and a corresponding functional defect in T regulatory cells (Tregs). These mice spontaneously develop portal inflammation with biliary ductular damage and colitis with features similar to human inflammatory bowel disease with T cell infiltrates in both the liver and colon. In humans, inflammatory bowel disease may be accompanied by primary sclerosing cholangitis (PSC), but seldom primary biliary cirrhosis (PBC). We hypothesized that the effector mechanism responsible for T cell infiltrates would differ for colon versus liver. To address this thesis, we developed three colonies of double-knockout mice including IL-2Ralpha(-/-) CD4(-/-), IL-2Ralpha(-/-) CD8(-/-), and IL-2Ralpha(-/-) T cell receptor (TCR)-beta(-/-). Tissue immunopathology, body weight, and serum levels of cytokines, immunoglobulins, and anti-mitochondrial antibodies (AMA) were assayed at 3 months of age. Relative to IL-2Ralpha(-/-) mice, IL-2Ralpha(-/-) CD4(-/-) mice had increased biliary ductular damage but reduced inflammation in the colon. In contrast, IL-2Ralpha(-/-) CD8(-/-) mice had increased colon inflammation but markedly attenuated biliary ductular damage. Both IL-2Ralpha(-/-) CD4(-/-) and IL-2Ralpha(-/-) CD8(-/-) mice demonstrated elevated serum levels of tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), interleukin-12p40 (IL-12p40), and interleukin-2 (IL-2) compared with C57BL/6J controls, but only IL-2Ralpha(-/-) CD8(-/-) mice had increased serum levels of immunoglobulin A (IgA), AMA and interleukin-17 (IL-17). Finally, and of importance, IL-2Ralpha(-/-) TCR-beta(-/-) mice had abrogation of liver and colon pathological conditions and lacked AMA. In conclusion, on loss of Treg function in mice, CD8 T cells mediate biliary ductular damage whereas CD4 T cells mediate induction of colon-specific autoimmunity.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
authors.forename: Willy
authors.initials: W
authors.lastname: Hsu
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moritoki
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Ian
authors.initials: I
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology; D016827:CD8 Antigens / Q000235:genetics / Q000502:physiology; D002761:Cholangitis / Q000276:immunology / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000473:pathology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency*; D007421:Intestine, Small / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D016693:Receptors, Antigen, T-Cell, alpha-beta