IL-2 receptor α-/- mice and the development of primary biliary cirrhosis

Kanji Wakabayashi, Zhe Xiong Lian, Yuki Moritoki, Ruth Y. Lan, Koichi Tsuneyama, Ya Hui Chuang, Guo Xiang Yang, William Ridgway, Yoshiyuki Ueno, Aftab A. Ansari, Ross L. Coppel, Ian R. Mackay, M. Eric Gershwin

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1240-1249
Number of pages10
JournalHepatology
Volume44
Issue number5
DOIs
StatePublished - Nov 2006

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Biliary Liver Cirrhosis
Interleukin-2 Receptors
Liver
Serum
Interleukin-12 Subunit p40
Cytokines
Antibody Specificity
Autoantigens
Regulatory T-Lymphocytes
Natural History
Autoimmunity
Immunoglobulin A
Interleukin-2
Spleen
Immunoglobulin G
Staining and Labeling
Inflammation
T-Lymphocytes
Antibodies

ASJC Scopus subject areas

  • Hepatology

Cite this

Wakabayashi, K., Lian, Z. X., Moritoki, Y., Lan, R. Y., Tsuneyama, K., Chuang, Y. H., ... Gershwin, M. E. (2006). IL-2 receptor α-/- mice and the development of primary biliary cirrhosis. Hepatology, 44(5), 1240-1249. https://doi.org/10.1002/hep.21385

IL-2 receptor α-/- mice and the development of primary biliary cirrhosis. / Wakabayashi, Kanji; Lian, Zhe Xiong; Moritoki, Yuki; Lan, Ruth Y.; Tsuneyama, Koichi; Chuang, Ya Hui; Yang, Guo Xiang; Ridgway, William; Ueno, Yoshiyuki; Ansari, Aftab A.; Coppel, Ross L.; Mackay, Ian R.; Gershwin, M. Eric.

In: Hepatology, Vol. 44, No. 5, 11.2006, p. 1240-1249.

Research output: Contribution to journalArticle

Wakabayashi, K, Lian, ZX, Moritoki, Y, Lan, RY, Tsuneyama, K, Chuang, YH, Yang, GX, Ridgway, W, Ueno, Y, Ansari, AA, Coppel, RL, Mackay, IR & Gershwin, ME 2006, 'IL-2 receptor α-/- mice and the development of primary biliary cirrhosis', Hepatology, vol. 44, no. 5, pp. 1240-1249. https://doi.org/10.1002/hep.21385
Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH et al. IL-2 receptor α-/- mice and the development of primary biliary cirrhosis. Hepatology. 2006 Nov;44(5):1240-1249. https://doi.org/10.1002/hep.21385
Wakabayashi, Kanji ; Lian, Zhe Xiong ; Moritoki, Yuki ; Lan, Ruth Y. ; Tsuneyama, Koichi ; Chuang, Ya Hui ; Yang, Guo Xiang ; Ridgway, William ; Ueno, Yoshiyuki ; Ansari, Aftab A. ; Coppel, Ross L. ; Mackay, Ian R. ; Gershwin, M. Eric. / IL-2 receptor α-/- mice and the development of primary biliary cirrhosis. In: Hepatology. 2006 ; Vol. 44, No. 5. pp. 1240-1249.
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AU - Lian, Zhe Xiong

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AU - Lan, Ruth Y.

AU - Tsuneyama, Koichi

AU - Chuang, Ya Hui

AU - Yang, Guo Xiang

AU - Ridgway, William

AU - Ueno, Yoshiyuki

AU - Ansari, Aftab A.

AU - Coppel, Ross L.

AU - Mackay, Ian R.

AU - Gershwin, M. Eric

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AB - 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.

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