title: IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis.
abstract: Recently, we identified a child born with a genetic deficiency of IL-2 receptor alpha (IL-2Ralpha, CD25) expression who had several clinical manifestations of primary biliary cirrhosis (PBC). In addition, there has been suggestive evidence in both patients with PBC and their first-degree relatives that a deficiency of regulatory T cells (Tregs) is an integral component for susceptibility to PBC. Based on these observations, we generated IL-2Ralpha/CD25 deficient (IL-2Ralpha(-/-)) mice and wild-type littermate controls and followed them longitudinally for the natural history of liver immunopathology and appearance of antimitochondrial antibodies (AMAs). The analyses included immunohistochemical staining of liver and portal tract infiltrates as well as FACS profiles of lymphoid subpopulations in liver and spleen. In addition, serum cytokine profiles were quantitated. Importantly, IL-2Ralpha(-/-), but not littermate controls, develop portal inflammation and biliary ductular damage similar to human patients with PBC. CD4(+) and CD8(+) T cells predominate among portal cell infiltrates and sera reflect a Th1 cytokine bias with increased levels of IFN-gamma, TNF-alpha, IL-2 and IL-12p40. Of importance is the finding that the IL-2Ralpha(-/-) mice not only develop significantly increased serum levels of IgG and IgA, but they also develop AMAs with specificity for PDC-E2, which maps to the inner lipoyl domain of the autoantigen, all characteristics which are hallmarks of human PBC. In conclusion, the IL-2Ralpha(-/-) mice should facilitate studies of the early events in PBC and especially the tantalizing connection between Treg deficiency and autoimmunity specifically directed to mitochondrially located PDC-E2 and subsequent biliary ductular cell damage.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
authors.forename: Kanji
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moritoki
authors.forename: Ruth Y
authors.initials: RY
authors.lastname: Lan
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chuang
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: William
authors.initials: W
authors.lastname: Ridgway
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007136:Immunoglobulins / Q000097:blood*; D053645:Interleukin-2 Receptor alpha Subunit / Q000172:deficiency* / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000209:etiology* / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology*; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; D053645:Interleukin-2 Receptor alpha Subunit