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• 99 % of patients are mitochodrial antibody-positive.
• Diminished suppressor cell-function.
• Increased serum concentrations of polyeric and monomeric IgM.
• Inability to convert from IgM to IgG antibody synthesis.
• Complement-activating serum factor - possibly immune complexes.
• Granulomatous infiltrate of intrahepatic biliary tree

• Primary biliary cirrhosis (PBC) is an enigmatic chronic liver disease characterized by progressive inflammatory obliteration of the intrahepatic bile ducts: the chronic granulomatous inflammatory process results in destruction of the intrahepatic biliary tree.
• These patients also exhibit lesions of the salivary, lacrimal, and pancreatic glands, scleroderma, rheumatoid arthritis, and thyroid disease.
• The disease occurs commonly in middle-aged women, who present with symptoms of cholestasis. Liver function tests show an elevated alkaline phosphatase, often with normal transminases and bilirubin. The most prominent symptom is pruritus. The rate of progression of the disease is slow, and jaundice occurs late. Many patients remain anicteric for 10-20 years. Once jaundice develops, life expectancy is considerably reduced.
• 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, thymocytotoxic autoantibodies, and anti-mitochondrial antibodies (AMA).

• While PBC has been styled as a 'model' autoimmune disease, it does not fully qualify as one. In its favor, there are striking B lymphocyte abnormalities, including high levels of serum immunoglobulins, with an IgG3 subclass reaction and a range of autoantibodies including, as noted above, those to mitochondrial antigens and occasionally to centromeric antigen and other undefined nuclear antigens. There is also increased serum complement. The association with disease is closer for antibody and PBC than for any other autoimmune process; while PBC may occur in the absence such cases are most exceptional. Also, there are T lymphocyte immunoregulatory 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. The abnormalities described relate only to nonantigen specific suppressor cells and may be secondary events. Histologically, biliary ductules in the liver are surrounded and penetrated by infiltrating T lymphocytes, mostly of the CD8 phenotype, and granulomatoma are sometimes seen in the periductular infiltrates. 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 lymphokines including interferon-g (IFN-g) 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 molecules) 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 hallmark of PBC is the presence of high-titer mitochondrial autoantibodies in patients' sera. Such reactivity has been demonstrated using standard immunofluorescent assays, enzyme-linked immunosorbent assay (ELISA), and complement fixation techniques. There has been considerable effort to determine the biochemical nature of the mitochondrial molecules being recognized, and these studies have clearly demonstrated that mitochondrial antigens can be distinguished on the basis of molecular weight (mol. wt.). AMA recognize four major mitochondrial inner membrane proteins of approximately 74, 56, 52, and 48 kDa. Recent data have identified these four mitochondrial autoantigens as being protein X and the acyltransferases (E2) of three related 2-oxo-acid dehydrogenase complexes: the pyruvate dehydrogenase complex (PDC), the branched-chain oxo-acid dehydrogenase complex (BCOADH), and the oxo-glutarate dehydrogenase complex (OGDC) (Table 1). The identification was established using either expressed polypeptides from CDNA 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 TRNA synthetase in polymyositis sera are able to inhibit TRNA aminoacylation and it has also been reported that synthesis of 28S and 18S RNA is inhibited by RNA polymerase 1 specific antibodies in scleroderma sera. In SLE sera, autoantibodies specific for Sm and UL-RNP, which are both components of small nuclear ribonucleoproteins, inhibit splicing of early RNA sequences, and autoantibodies to proliferating cell nuclear antigen inhibit DNA replication. Also, autoantibodies to the La (SS-B) nucleoprotein antigen, present in primary Sjögren's 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 themes 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 aggregates 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.
• 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. Thus far, cloned T cell lines specific for mitochondrial autoantigens have yet to be reported. 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 lipoic acid binding sites and therefore perhaps shared epitopes. Hence, a single common epitope could generate CD4+ T cells to provide help for B cell responses for each of the E2 subunits of the 2-OADH enzymes.
• There are other theoretical considerations that has applied to the understanding of the etiology and immunological responses in primary biliary cirrhosis. First, there is scanty data on specific etiology, i.e. environments toxin, or infection. It remains plausible that the mitochondrial autoantigens are cross-reactive with a highly conserved component of an infectious agent. Second, it will be important to take into account the expression of autoantigens on the biliary epithelial tissue. Thus far, there has been no evidence that these rnitochondrial enzymes are expressed on cell membranes. Third, 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. Fourth, 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.
• The advent of cloned genes for disease-relevant autoantigens represents a decided advance in the understanding of autoimmunity. A practical outcome is the availability of unlimited quantities of autoantigens for use in diagnostic immunoassays. More distinctly, the production of peptides relevant to T cell recognition will raise the possibility of experimentally manipulating and re-establishing tolerance. Finally, independent of autoimmunity, cloned genes represent an important tool and probe for studies on cell biology. Of interest is the fact that one of the autoantigens in PBC (OGDC) is produced by the same gene that is deficient in a human pediatric disorder, maple syrup urine disease. There appears to be no relevance of this to PBC, but it illustrates the applicability of cloned cellular proteins to the understanding of diverse clinical problems involving particular organelles.
• What initiates primary biliary cirrhosis is unknown. The clinical signs of disease include features that are consistent with chronic intrahepatic biliary obstruction including itching, jaundice, steatorrhea, and osteomalacia. The treatment of patients is primarily directed at reducing itching as well as dietary replacement for malabsorption and osteomalacia.

• Penicillamine, a copper-chelating and anti-inflammatory compound, has been shown to produce biochemical improvement, but whether it influence on survival is controversial.
• Treatment with corticosteroids and/or immunosuppressive agents has generally been unsatisfactory -Cyclosporine produces changes in the T cell subsets and a marked improvement in the liver biochemistry - but there have been some recent optimistic reports on the use of methotrexate.
• Impressive results have been obtained following liver transplantation for advanced disease.

1. Cliniquement

Initialement apparaissent un prurit et une asthénie, puis un ictère très progressif (après 6 mois d'évolution)

A l'examen, il existe: une hépatomégalie, une splénomégalie, une xanthomatose (cutanée ou tubéreuse), des manifestations extra-hépatiques (des arthralgies, une dermatomyosite, un phénomène de Raynaud, un syndrome de Sjögren, une thyroïdite, une glomérulonéphrite)

2. Biologiquement

Il existe une augmentation de la bilirubine, des phosphatases alcalines (2 à 5 fois la normale), des gamma GT (5 à 10 fois la normale), sélective des IgM, du cholestérol (4 à 5 g/l). Présence à 99 % d'anticorps anti-mitochondries

3. Morphologiquement

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