Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis

Shinji Shimoda, Judith A Van de Water, Aftab Ansari, Minoru Nakamura, Hiromi Ishibashi, Ross L. Coppel, Jack Lake, Emmet B. Keeffe, Thomas E. Roche, M. Eric Gershwin

Research output: Contribution to journalArticlepeer-review

211 Scopus citations

Abstract

The immunodominant antimitochondrial antibody response in patients with primary biliary cirrhosis (PBC) is directed against the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Based on our earlier observations regarding peripheral blood mononuclear cell (PBMC) T cell epitopes, we reasoned that a comparative analysis of the precursor frequencies of PDC-E2 163-176-specific T cells isolated from PBMC, regional hepatic lymph nodes, and from the liver of PBC patients would provide insight regarding the role oft cells in PBC. Results showed a disease-specific 100-150-fold increase in the precursor frequency of PDC-E2 163-176-specific T cells in the hilar lymph nodes and liver when compared with PBMC from PBC patients. Interestingly, autoreactive T cells and autoantibodies from PBC patients both recognize the same dominant epitope. In addition, we demonstrated cross-reactivity of PDC- E2 peptide 163-176-specific T cell clones with PDC-E2 peptide 3649 and OGDC- E2 peptide 100-113 thereby identifying a common T cell epitope 'motif' ExETDK. The peptide 163176-specific T cell clones also reacted with purified native PDC-E2, suggesting that this epitope is not a cryptic determinant. These data provide evidence for a major role for PDC-E2 peptide 163-176 and/or peptides bearing a similar motif in the pathogenesis of PBC.

Original languageEnglish (US)
Pages (from-to)1831-1840
Number of pages10
JournalJournal of Clinical Investigation
Volume102
Issue number10
StatePublished - Nov 15 1998

Keywords

  • Autoreactive T cells
  • Epitopes
  • Liver
  • Primary biliary cirrhosis
  • Pyruvate dehydrogenase

ASJC Scopus subject areas

  • Medicine(all)

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