K. Wakabayashi, Z-X. Lian, and Y Moritoki contributed equally to this study.
Liver Biology and Pathobiology
IL-2 receptor α−/− mice and the development of primary biliary cirrhosis†
Article first published online: 20 OCT 2006
Copyright © 2006 American Association for the Study of Liver Diseases
Volume 44, Issue 5, pages 1240–1249, November 2006
How to Cite
Wakabayashi, K., Lian, Z.-X., Moritoki, Y., Lan, R. Y., Tsuneyama, K., Chuang, Y.-H., Yang, G.-X., Ridgway, W., Ueno, Y., Ansari, A. A., Coppel, R. L., Mackay, I. R. and Gershwin, M. E. (2006), IL-2 receptor α−/− mice and the development of primary biliary cirrhosis. Hepatology, 44: 1240–1249. doi: 10.1002/hep.21385
Potential conflict of interest: Nothing to report.
- Issue published online: 20 OCT 2006
- Article first published online: 20 OCT 2006
- Manuscript Accepted: 8 AUG 2006
- Manuscript Received: 7 JUN 2006
- National Institutes of Health. Grant Number: DK39588
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. (HEPATOLOGY 2006;44:1240–1249.)