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IL‐2 receptor α −/− mice and the development of primary biliary cirrhosis
Author(s) -
Wakabayashi Kanji,
Lian ZheXiong,
Moritoki Yuki,
Lan Ruth Y.,
Tsuneyama Koichi,
Chuang YaHui,
Yang GuoXiang,
Ridgway William,
Ueno Yoshiyuki,
Ansari Aftab A.,
Coppel Ross L.,
Mackay Ian R.,
Gershwin M. Eric
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21385
Subject(s) - primary biliary cirrhosis , immunology , cytokine , autoimmunity , cd8 , il 2 receptor , biology , biliary cirrhosis , medicine , antibody , t cell , pathology , immune system , autoimmune disease
Recently, we identified a child born with a genetic deficiency of IL‐2 receptor α (IL‐2Rα, 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‐2Rα/CD25 deficient (IL‐2Rα −/− ) 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‐2Rα −/− , 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‐γ, TNF‐α, IL‐2 and IL‐12p40. Of importance is the finding that the IL‐2Rα −/− 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‐2Rα −/− 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. (H EPATOLOGY 2006;44:1240–1249.)