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* Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis School of Medicine, and
Department of Chemistry, University of California, Davis, CA 95616;
Department of Pathology and 21st Century Center of Excellence Program, Toyama Medical and Pharmaceutical University, Toyama, Japan;
University of California at Davis Cancer Center, Division of Hematology and Oncology, University of California at Davis, Sacramento, CA 95817;
¶ Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322; and
|| Department of Microbiology, Monash University, Clayton, Victoria, Australia
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants DK39588 and DK037003.
2 Address correspondence and reprint requests to Dr. Patrick S. C. Leung, Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis School of Medicine, 451 East Health Sciences Drive, Davis, CA 95616. E-mail address: psleung{at}ucdavis.edu
3 Abbreviations used in this paper: PBC, primary biliary cirrhosis; AMA, antimitochondrial Ab; 2-OADC-E2, E2 subunit of 2-oxo-acid dehydrogenase complex; PDC-E2, E2 subunit of pyruvate dehydrogenase complex; 6BH-BSA, 6-bromohexanoate conjugated to BSA; BCOADC-E2, E2 subunit of branched chain 2-oxo-acid dehydrogenase complex; OGDC-E2, E2 subunit of 2-oxo-glutarate dehydrogenase complex; CLA-BSA, chloroacetate-conjugated BSA; CNSDC, chronic nonsuppurative destructive cholangitis; BEC, bile duct epithelial cell.
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