Liver Autoimmunity Triggered by Microbial Activation of Natural Killer T Cells

Jochen Mattner, Paul B. Savage, Patrick S Leung, Sabine S. Oertelt, Vivien Wang, Omita Trivedi, Seth T. Scanlon, Krishna Pendem, Luc Teyton, John Hart, William M. Ridgway, Linda S. Wicker, M. Eric Gershwin, Albert Bendelac

Research output: Contribution to journalArticle

168 Scopus citations

Abstract

Humans with primary biliary cirrhosis (PBC), a disease characterized by the destruction of small bile ducts, exhibit signature autoantibodies against mitochondrial Pyruvate Dehydrogenase Complex E2 (PDC-E2) that crossreact onto the homologous enzyme of Novosphingobium aromaticivorans, an ubiquitous alphaproteobacterium. Here, we show that infection of mice with N. aromaticivorans induced signature antibodies against microbial PDC-E2 and its mitochondrial counterpart but also triggered chronic T cell-mediated autoimmunity against small bile ducts. Disease induction required NKT cells, which specifically respond to N. aromaticivorans cell wall α-glycuronosylceramides presented by CD1d molecules. Combined with the natural liver tropism of NKT cells, the accumulation of N. aromaticivorans in the liver likely explains the liver specificity of destructive responses. Once established, liver disease could be adoptively transferred by T cells independently of NKT cells and microbes, illustrating the importance of early microbial activation of NKT cells in the initiation of autonomous, organ-specific autoimmunity.

Original languageEnglish (US)
Pages (from-to)304-315
Number of pages12
JournalCell Host and Microbe
Volume3
Issue number5
DOIs
StatePublished - May 15 2008

Keywords

  • CELLIMMUNO
  • HUMDISEASE
  • MICROBIO

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Cancer Research
  • Molecular Biology

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    Mattner, J., Savage, P. B., Leung, P. S., Oertelt, S. S., Wang, V., Trivedi, O., Scanlon, S. T., Pendem, K., Teyton, L., Hart, J., Ridgway, W. M., Wicker, L. S., Gershwin, M. E., & Bendelac, A. (2008). Liver Autoimmunity Triggered by Microbial Activation of Natural Killer T Cells. Cell Host and Microbe, 3(5), 304-315. https://doi.org/10.1016/j.chom.2008.03.009