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World J Gastroenterol. Jun 7, 2008; 14(21): 3328-3337
Published online Jun 7, 2008. doi: 10.3748/wjg.14.3328
Etiopathogenesis of primary biliary cirrhosis
Ana Lleo, Pietro Invernizzi, Ian R Mackay, Harry Prince, Ren-Qian Zhong, M Eric Gershwin
Ana Lleo, Pietro Invernizzi, Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Milan 20142, Italy
Ana Lleo, Pietro Invernizzi, M Eric Gershwin, Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA 95616, United States
Ian R Mackay, Department of Biochemistry & Molecular Biology, Monash University, Clayton Victoria 3800, Australia
Harry Prince, Focus Diagnostics, 5785 Corporate Avenue, Cypress, CA 90630, United States
Ren-Qian Zhong, Laboratory Diagnostics of Changzheng Hospital, Second Military Medical University and Clinical Immunology Center of PLA, Shanghai 200003, China
Correspondence to: M Eric Gershwin, MD, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Genome and Biomedical Sciences Facility, 451 E Health Sciences Drive, suite 6510, Davis, CA 95616, United States.
Telephone: +1-530-7522884
Fax: +1-530-7524669
Received: March 19, 2008
Revised: March 28, 2008
Accepted: April 4, 2008
Published online: June 7, 2008

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure. The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies (AMA). These reflect the presence of autoreactive T and B cells to the culprit antigens, the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes, chiefly pyruvate dehydrogenase (PDC-E2). The disease results from a combination of genetic and environmental risk factors. Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins. Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing, after a long latency, the emergence of clinical disease. Initiating mimotopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or, alternatively, environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic. A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells. In the effector phase the biliary ductular cell, by reason of its proclivity to express the antigen PDC-E2 in the course of apoptosis, undergoes a multilineage immune attack comprised of CD4+ and CD8+ T cells and antibody. In this article, we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data, new developments and theories, and nominate directions for future research.

Keywords: Autoantibodies, Autoreactive T cells, 2-oxoacid dehydrogenase, Biliary epithelial cells, Primary biliary cirrhosis