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Liver autoimmunity triggered by microbial activation of natural killer T cells

Academic Article
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Overview

authors

  • Mattner, J.
  • Savage, P. B.
  • Leung, P.
  • Oertelt, S. S.
  • Wang, V.
  • Trivedi, O.
  • Scanlon, S. T.
  • Pendem, K.
  • Teyton, Luc
  • Hart, J.
  • Ridgway, W. M.
  • Wicker, L. S.
  • Gershwin, M. E.
  • Bendelac, A.

publication date

  • May 2008

journal

  • Cell Host & Microbe  Journal

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.

subject areas

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

PubMed Central ID

  • PMC2453520

International Standard Serial Number (ISSN)

  • 1931-3128

Digital Object Identifier (DOI)

  • 10.1016/j.chom.2008.03.009

PubMed ID

  • 18474357
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Additional Document Info

start page

  • 304

end page

  • 315

volume

  • 3

issue

  • 5

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