Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis

Shinji Shimoda, Minoru Nakamura, Hiromi Ishibashi, Akira Kawano, Takashi Kamihira, Norihiro Sakamoto, Sho Matsushita, Atsushi Tanaka, Howard J. Worman, M. Eric Gershwin, Mine Harada

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Background & Aims: The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of wellknown cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). Methods: To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. Results: For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. Conclusions: These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.

Original languageEnglish (US)
Pages (from-to)1915-1925
Number of pages11
JournalGastroenterology
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2003

ASJC Scopus subject areas

  • Gastroenterology

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    Shimoda, S., Nakamura, M., Ishibashi, H., Kawano, A., Kamihira, T., Sakamoto, N., Matsushita, S., Tanaka, A., Worman, H. J., Gershwin, M. E., & Harada, M. (2003). Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. Gastroenterology, 124(7), 1915-1925. https://doi.org/10.1016/S0016-5085(03)00387-1