Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization

Patrick S Leung, Ogyi Park, Koichi Tsuneyama, Mark J. Kurth, Kit Lam, Aftab A. Ansari, Ross L. Coppel, M. Eric Gershwin

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Although significant advances have been made in dissecting the effector mechanisms in autoimmunity, the major stumbling block remains defining the etiological events that precede disease. Primary biliary cirrhosis (PBC) illustrates this paradigm because of its high degree of heritability, its female predominance, and its extraordinarily specific and defined immune response and target destruction. In PBC, the major autoantigens belong to E2 components of the 2-oxo-acid dehydrogenase family of mitochondrially located enzymes that share a lipoylated peptide sequence that is the immunodominant target. Our previous work has demonstrated that synthetic mimics of the lipoate molecule such as 6-bromohexoanate demonstrate a high degree of reactivity with PBC sera prompted us to immunize groups of guinea pigs with 6-bromohexoanate conjugated to BSA. In this study, we provide serologic and immunohistochemical evidence that such immunized guinea pigs not only develop antimitochondrial autoantibody responses similar to human PBC, but also develop autoimmune cholangitis after 18 mo. Xenobiotic-immunized guinea pigs are the first induced model of PBC and suggest an etiology that has implications for the causation of other human autoimmune diseases. The data also reflect the likelihood that, in PBC, the multilineage antimitochondrial response is a pathogenic mechanism and that loss of tolerance and subsequent development of biliary lesions depends on either modification of the host mitochondrial Ag or a similar breakdown due to molecular mimicry.

Original languageEnglish (US)
Pages (from-to)2651-2657
Number of pages7
JournalJournal of Immunology
Volume179
Issue number4
StatePublished - Aug 15 2007

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Biliary Liver Cirrhosis
Xenobiotics
Immunization
Guinea Pigs
Molecular Mimicry
Keto Acids
Cholangitis
Autoimmunity
Causality
Autoantibodies
Autoimmune Diseases
Oxidoreductases
Peptides
Enzymes
Serum

ASJC Scopus subject areas

  • Immunology

Cite this

Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. / Leung, Patrick S; Park, Ogyi; Tsuneyama, Koichi; Kurth, Mark J.; Lam, Kit; Ansari, Aftab A.; Coppel, Ross L.; Gershwin, M. Eric.

In: Journal of Immunology, Vol. 179, No. 4, 15.08.2007, p. 2651-2657.

Research output: Contribution to journalArticle

Leung, PS, Park, O, Tsuneyama, K, Kurth, MJ, Lam, K, Ansari, AA, Coppel, RL & Gershwin, ME 2007, 'Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization', Journal of Immunology, vol. 179, no. 4, pp. 2651-2657.
Leung, Patrick S ; Park, Ogyi ; Tsuneyama, Koichi ; Kurth, Mark J. ; Lam, Kit ; Ansari, Aftab A. ; Coppel, Ross L. ; Gershwin, M. Eric. / Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization. In: Journal of Immunology. 2007 ; Vol. 179, No. 4. pp. 2651-2657.
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