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Cell Host Microbe. 2008 May 15;3(5):304-15. doi: 10.1016/j.chom.2008.03.009.

Liver autoimmunity triggered by microbial activation of natural killer T cells.

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  • 1Howard Hughes Medical Institute, Committee on Immunology, Department of Pathology, University of Chicago, Chicago, IL 60637, USA. jochen.mattner@cchmc.org

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 alpha-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.

Comment in

PMID:
18474357
[PubMed - indexed for MEDLINE]
PMCID:
PMC2453520
Free PMC Article

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