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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.

Original publication

DOI

10.1016/j.chom.2008.03.009

Type

Journal article

Journal

Cell host & microbe

Publication Date

05/2008

Volume

3

Pages

304 - 315

Addresses

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

Keywords

Liver, Killer Cells, Natural, T-Lymphocyte Subsets, T-Lymphocytes, Animals, Mice, Inbred Strains, Mice, Sphingomonadaceae, Gram-Negative Bacterial Infections, Liver Cirrhosis, Biliary, Hepatitis, Autoimmune, Immunoglobulin A, Immunoglobulin G, Mitochondrial Proteins, Antigens, CD1, Antibodies, Bacterial, Autoantibodies, Dihydrolipoyllysine-Residue Acetyltransferase, Antigens, CD1d