Primary Biliary Cirrhosis

M Eric Gershwin, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, California, USA

Ian R Mackay, Centre for Molecular Biology and Medicine, Monash University, Clayton, Victoria, Australia

Primary biliary cirrhosis (PBC) is an enigmatic chronic liver disease characterized by progressive inflammatory obliteration of the intrahepatic bile ducts. Clinical features and laboratory studies of the disease include data suggesting an underlying immunologic basis for pathology. These features include a marked predominance of female patients, the presence of a variety of autoantibodies, circulating immune complexes, complement activation, defects in immunoglobulin class switching, T cell regulatory dysfunction, predominance of T cells in the hepatic periductular infiltrates, and an increased association with scleroderma and the sicca complex. The autoantibodies found in PBC include antibodies to thyroid antigens, nuclear antigens, thymocyto-toxic autoantibodies, and mitochondrial-specific antibodies.

There are striking B lymphocyte abnormalities in PBC, including high levels of serum immunoglobulins, with an immunoglobulin G3 (IgG3) subclass restriction and a range of autoantibodies including, as noted above, those to mitochondrial antigens and occasionally antibodies to centromeric antigen and other undefined nuclear antigens. There is also increased serum complement consumption. The association with disease is closer for mitochondrial antibody and PBC than for any other autoimmune process; while PBC may occur in the absence of mitochondria-specific antibodies, such cases are most exceptional. Also, there are T lymphocyte immuno-regulatory abnormalities that involve both CD4 and CD8" cells. In brief, the number of CD4+ and CD8+ cells in blood are decreased and various functional assays show deficiencies affecting both subsets of T cells. Histologically, biliary ductules in the liver are surrounded and penetrated by infiltrating T lymphocytes, mostly of the CD8 phenotype. Granu-lomata are prominent in the periductular infiltrates which is unusual for autoimmune pathology. The bile duct epithelium normally expresses only major histocompatibility complex (MHC) class I molecules but, in PBC, MHC class II molecules are also expressed in biliary epithelial cells, possibly under the influence of cytokines released by activated T cells. Such expression may be relevant to the autoimmune pathogenesis of PBC, since biliary epithelial cells which express MHC class II molecules could act in an inducer capacity as antigen-presenting cells for CD4 ' helper T cells. The inducer processes and the peptide molecule(s) that stimulate T cells have yet to be identified and functional data are needed to substantiate the immunohistochemical evidence for the cytodestructive effects of CD8 + T cells.

The clinical signs of disease include features that are consistent with chronic intrahepatic biliary obstruction including itching, jaundice, steatorrhea and osteomalacia. This classic presentation is now being replaced by early or asymptomatic disease recognized by the occurrences of liver functional abnormalities on autoanalyzer screening of serum. The treatment of patients is primarily directed at reducing itching as well as dietary replacement for malabsorption and osteomalacia. Treatment with corticosteroids and/or immunosuppressive agents has generally been unimpressive, perhaps because these were usually given only in advanced disease. Ursodeoxycholic acid (UDCA) is of established benefit according to the results of recent trials and there have been optimistic reports on the use of methotrexate. The results of liver transplantation for advanced disease are excellent.

The hallmark of PBC is the presence of high-titer mitochondrial autoantibodies in patients' sera. Such reactivity has been demonstrated using standard immunofluorescent assays, ELISA, complement fixation and inhibition of enzymic activity. Mitochond-ria-specific antibodies recognize major mitochondrial inner membrane proteins of approximately 74, 56, 52, 48 kDa and 36 kDa (Table 1). These four mitochondrial autoantigens have been identified as being protein X and the acyltransferases (E2) of three related 2-oxo acid dehydrogenase complexes: the pyruvate dehydrogenase complex (PDO. the branched-chain oxo acid dehydrogenase complex (BCOADH), and the oxoglutamate dehydrogenase complex (OGDC). The identification was established using either expressed polypeptides from DNA clones or purified enzyme preparations. Moreover, the mitochondrial autoantibodies of patients specifically inhibit the function in vitro of these enzymes.

These observations relating autoantigens to functional sites of proteins are of interest in that they are consistent with an emerging trend seen in a number of other autoimmune diseases. Autoantibodies to RNA synthetase in polymyositis sera are able to inhibit RNA aminoacylation and it has also been reported that synthesis of 28S and 18S RNA is inhibited by RNA polymerase I-specific antibodies in

Table 1 Molecular weights and functions of the mitochondrial autoantigens in PBC


Molecular weight (kDa)

Pyruvate dehydrogenase (PDH) 74

E2 acetyltransferase

Protein X 56

Branched-chain 2-oxo acid dehydrogenase 52

(BCOADH) E1 a and ยก3 E2 acyltransferase Oxoglutamate dehydrogenase E2 48



Transfers acetyl group from E1 to coenzyme A (CoA)

Transfers acyl group from E1 to CoA Transfers succinyl group from E1 to CoA

scleroderma sera. In systemic lupus erythematosus (SLE) sera, autoantibodies specific for Sm and Ul-RNP, which are both components of small nuclear ribonucleoproteins (snRNP), inhibit splicing of early RNA sequences, and autoantibodies to proliferating cell nuclear antigen (PCNA) inhibit DNA replication. Additionally, autoantibodies to the La (SS-B) nucleo-protein antigen, present in primary Sjogren syndrome, interfere with the transcription of small RNA molecules. The significance of these findings in terms of disease expression has yet to be determined, but two schemes are prominent. First, as for the mitochondrial antigens of PBC, many of the described autoantigens are intracellular enzymes and exist not as single proteins but as components of large complexes, and, second, the autoantibodies directed against these subcellular molecules appear to be directed against functional sites or domains, since they interfere with cellular function in assay systems in vitro. The capacity of PBC serum to abrogate the catalytic activity of the PDC enzyme is most impressive and is the basis of a diagnostic assay. Other assays, including the use of a hybrid recombinant protein that contains all the major epitopes of PDC-E2, BCOADH-E2 and OGDC-E2, are now also available.

Although there have been significant advances based on cloning, antigen definition and epitope mapping, there has been relatively little insight into the relevance of T cell reactivity in patients. The identification of T cell reactivity will be critical. The characterization of T cell reactivity in other autoimmune diseases has likewise been difficult because of the low frequency of antigen-specific T cell activity in peripheral blood. Moreover, even when liver tissue is studied, the frequency of antigen-specific T cells may be low because of the irrelevant inflammatory response. All of the identified mitochondrial autoantigens contain lipoate-binding sites and therefore perhaps shared epitopes. Hence, a single common epitope could generate CD4" cells to provide help for the oxo-cross-reactive B cell responses for each of the E2 subunits of the 2-OADH enzymes.

There are other theoretical considerations that should be applied to the understanding of the etiology and immunological responses in primary biliary cirrhosis. First, there is scanty data on specific etiology, i.e. environmental insult, toxin or infection. It remains plausible that the mitochondrial autoantigens are cross-reactive with a microbial antigen, but this is yet to be identified with a highly conserved component of an infectious agent. Second, PBC is often viewed as a ductal disease as lesions have been reported in other epithelial glandular tissues, i.e. salivary glands and pancreatic ducts. Third, mitochondrial autoantigens are synthesized in the cytoplasm and then transported into the mitochondria; therefore, mutations in leader sequence, or defects in breakdown, could lead to altered metabolism and expression on cell membranes. Finally, there are intriguing data that suggest that there is expression of either PDC-E2 or a cross-reacting molecule on the surface of biliary epithelial cells in patients with PBC but not controls. These data, if they reflect a primary not secondary feature of disease, would explain the specific targeting of biliary cells. The molecular basis of this molecule is still unresolved.

See also: Autoantigens; Autoimmune diseases. Further reading

Coppel RL and Gershwin MF. (1995) Primary biliary cirrhosis: The molecule and the mimie. Immunological Reviews 144: 17-29. Gershwin ME and Mackay 1R (1991) Primary biliary cirrhosis: paradigm or paradox for autoimmunity. Gastroenterology 100: 822-833. Gershwin ME and Mackay IR (1995) New knowledge in primary biliary cirrhosis. Hospital Practice 30: 29-36.

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