Primary biliary cirrhosis and mitochondrial autoantigens—insights from molecular biology

Gershwin, M. Eric; Coppel, Ross L.; Mackay, Ian R.

doi:10.1002/hep.1840080128

Cited by 94 publications

(30 citation statements)

References 58 publications

(28 reference statements)

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“…The pattern of staining directed against IgA was similar to that seen with C355. 1 and LC 5, with staining throughout the cell, but heaviest at the luminal surface region (Fig. 5).…”

Section: Resultsmentioning

confidence: 95%

“…It is important to emphasize that while the seven additional murine monoclonal antibodies did not react in the region ofthe surface ofbile duct epithelial cells, they did stain mitochondria in a manner similar to PBC sera and C355. 1 (Table I). As an additional control for these observations, an antibody to pyruvate decarboxylase, a common mitochondrial enzyme, was also studied.…”

Section: Resultsmentioning

confidence: 99%

“…In B, a serial section showing the same duct preincubated with LC 5 followed by C355. 1. Note the virtual absence of staining after blocking with LC 5.…”

Section: Discussionmentioning

confidence: 99%

“…Staining could be caused by a modified form of PDC-E2 that lacks all other epitopes except that recognized by C355. 1. However, such grossly truncated products ofa longer molecule are generally highly unstable and are usually rapidly removed from the cell by ubiquitin tagging and subsequent proteolysis ( 14).…”

Section: Discussionmentioning

confidence: 99%

“…The association of PBC with high titer autoantibodies to mitochondrial antigens has long been recognized and the possible significance has been discussed ( 1,2). It has now been established that PBC sera react with a series of highly conserved intramitochondrial proteins, including the E2 subunit ofthe pyruvate dehydrogenase complex (PDC-E2), the E2 subunit of the branched chain keto acid dehydrogenase complex, the E2 subunit of the a-ketoglutarate dehydrogenase complex, the El a and E I1, subunit of the pyruvate dehydrogenase complex, and protein X (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

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Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2.

Water¹,

Turchany²,

Leung³

et al. 1993

J. Clin. Invest.

191

111

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Sera from patients with primary biliary cirrhosis (PBC) react with enzymes of the 2-oxo dehydrogenase pathways, particularly PDC-E2. These enzymes are present in all nucleated cells, yet autoimmune damage is confined to biliary epithelial cells. Using a panel of eight mouse monoclonal antibodies and a human combinatorial antibody specific for PDC-E2, we examined by indirect immunofluorescence and confocal microscopy sections of liver from patients with PBC, progressive sclerosing cholangitis, and hepatocarcinoma. The imonoclonal antibodies gave typical mitochondrial immunofluorescence on biliary epithelium and on hepatocytes from patients with either PBC, progressive sclerosing cholangitis, or hepatocarcinoma. However, one of eight mouse monoclonal antibodies (C355.1) and the human combinatorial antibody reacted with great intensity and specificity with the luminal region of biliary epithelial cells from patients with PBC. Simultaneous examination of these sections with an antiisotype reagent for human IgA revealed high IgA staining in the luminal region of biliary epithelial cells in patients with PBC. IgG and IgA antibodies to PDC-E2 were detected in the bile of patients with PBC but not normal controls. We believe that this data may be interpreted as indicating that a molecule cross-reactive with PDC-E2 is expressed at high levels in the luminal region of biliary epithelial cells in

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“…The pattern of staining directed against IgA was similar to that seen with C355. 1 and LC 5, with staining throughout the cell, but heaviest at the luminal surface region (Fig. 5).…”

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

“…In B, a serial section showing the same duct preincubated with LC 5 followed by C355. 1. Note the virtual absence of staining after blocking with LC 5.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2.

Water¹,

Turchany²,

Leung³

et al. 1993

J. Clin. Invest.

191

111

View full text Add to dashboard Cite

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The relationship of “shared epitopes” of major histocompatibility complex molecules to autoimmune disease

Mackay

Rowley

Tait

1989

Arthritis & Rheumatism

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PBC 95K, a 95‐kilodalton nuclear autoantigen in primary biliary cirrhosis

Evans

Reuben

Craft

1991

Arthritis & Rheumatism

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We have identified a novel antinuclear antibody (ANA) in the sera of patients with primary biliary cirrhosis (PBC). Sera from 22 of 50 PBC patients stained the nuclei of HEp-2 cells in a pattern of 5-20 discrete dots, on indirect immunofluorescence. Typically, the titers were higher than 1:1,280. This staining pattern was seen in only 4 of 1,240 ANA-positive samples from patients with other connective tissue diseases, and in none of the ANA-positive sera from 49 patients with other liver diseases. Sera which stained the nuclear dots bound a 95-kd polypeptide in immunoblots of HeLa nuclei and in immunoprecipitates of 35S-methioninelabeled HeLa extracts. Affinity-purified antibodies from the 95-kd protein reproduced the nuclear dot immunofluorescence staining pattern, demonstrating that this polypeptide is located in the nuclear dots. ANA of this type, therefore, occur in 44% of patients with PBC, and they appear to be specific for PBC. These antibodies bind a 95-kd protein that is discrete and is scattered throughout the nucleus. Primary biliary cirrhosis (PBC) is an autoimmune disease that primarily affects the liver, resulting in cholestasis, progressive hepatic fibrosis, and cirrhosis (1). Antiinitochondrial antibodies are a characteristic feature of PBC, occurring in more than 95% of patients (2). Although 9 different antimitochondrial antibody specificities have been identified, the most common and most specific for PBC is the anti-M2 antibody (3). The M2 antigen is composed of 4 polypeptides of the inner mitochondria1 membrane that have molecular weights of approximately 74 kd, 52 kd, 45 kd, and 39 kd (4). More recently, the M2 antigen has been shown to consist of 4 metabolic ent.ymes: pyruvate dehydrogenase, branched chain 2-oxo-acid dehydrogenase, oxo-glutarate dehydrogenase, and protein X (4). These proteins are found widely in nature. Using sera from patients with PBC as probes, the proteins have been found in all eukaryotic cells examined to date, including yeasts (5,6).In contrast, antinuclear antibodies (ANA) in patients with PBC have been less well-characterized. We have recently identified an autoantibody specificity in sera from patients with PBC that stains the nucleus in a pattern of 5-20 discrete dots, by indirect immunofluorescence. The antigenic target of these antibodies is a nuclear protein of 95 kd, which we have called PBC 95K. PATIENTS AND METHODSSera. Serum samples from 50 patients with biopsyproven primary biliary cirrhosis were screened by indirect immunofluorescence on HEp-2 cells. The diagnosis of PBC was made based on the usual clinical. biochemical, and serologic abnormalities and characteristic histopathologic

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Primary biliary cirrhosis and mitochondrial autoantigens—insights from molecular biology

Cited by 94 publications

References 58 publications

Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2.

Molecular mimicry in primary biliary cirrhosis. Evidence for biliary epithelial expression of a molecule cross-reactive with pyruvate dehydrogenase complex-E2.

The relationship of “shared epitopes” of major histocompatibility complex molecules to autoimmune disease

PBC 95K, a 95‐kilodalton nuclear autoantigen in primary biliary cirrhosis

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