CD8 T cells mediate direct biliary ductule damage in nonobese diabetic autoimmune biliary disease

Guo Xiang Yang, Yuehong Wu, Hiroki Tsukamoto, Patrick S Leung, Zhe Xiong Lian, Daniel B. Rainbow, Kara M. Hunter, Gerard A. Morris, Paul A. Lyons, Laurence B. Peterson, Linda S. Wicker, M. Eric Gershwin, William M. Ridgway

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33 Scopus citations

Abstract

We previously described the NOD.c3c4 mouse, which is protected from type 1 diabetes (T1D) because of protective alleles at multiple insulin-dependent diabetes (Idd) genes, but develops autoimmune biliary disease (ABD) resembling primary biliary cirrhosis (PBC). In this paper, we characterize the NOD.ABD strain, which is genetically related to the NOD.c3c4 strain but develops both ABD and T1D. Histologically, NOD.ABD biliary disease is indistinguishable from that in NOD.c3c4 mice. The frequency of effector memory (CD44 +CD62L-) and central memory (CD44+CD62L +) CD8 T cells is significantly increased in the intrahepatic lymphocyte fraction of NOD.ABD mice, and NOD.ABD CD8 T cells produce more IFN-γ and TNF-α, compared with controls. NOD.ABD splenocytes can transfer ABD and T1D to NOD.c3c4 scid mice, but only T1D to NOD scid mice, suggesting that the genetic origin of the target organ and/or its innate immune cells is critical to disease pathogenesis. The disease transfer model, importantly, shows that biliary duct damage (characteristic of PBC) and inflammation precede biliary epithelial cell proliferation. Unlike T1D where both CD4 and CD8 T cells are required for disease transfer, purified NOD.ABD CD8 T cells can transfer liver inflammation into NOD.c3c4 scid recipients, and disease transfer is ameliorated by cotransferring T regulatory cells. Unlike NOD.c3c4 mice, NOD.ABD mice do not develop anti-nuclear or anti-Smith autoantibodies; however, NOD.ABD mice do develop the antipyruvate dehydrogenase Abs typical of human PBC. The NOD.ABD strain is a model of immune dysregulation affecting two organ systems, most likely by mechanisms that do not completely coincide.

Original languageEnglish (US)
Pages (from-to)1259-1267
Number of pages9
JournalJournal of Immunology
Volume186
Issue number2
DOIs
StatePublished - Jan 15 2011

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ASJC Scopus subject areas

  • Immunology

Cite this

Yang, G. X., Wu, Y., Tsukamoto, H., Leung, P. S., Lian, Z. X., Rainbow, D. B., Hunter, K. M., Morris, G. A., Lyons, P. A., Peterson, L. B., Wicker, L. S., Gershwin, M. E., & Ridgway, W. M. (2011). CD8 T cells mediate direct biliary ductule damage in nonobese diabetic autoimmune biliary disease. Journal of Immunology, 186(2), 1259-1267. https://doi.org/10.4049/jimmunol.1001597