The human biliary epithelial cell plasma membrane antigen in primary biliary cirrhosis: Pyruvate dehydrogenase X?

Joplin, RE; Wallace, L L; Jg, Lindsay; Palmer, JM; Yeaman, SJ; Neuberger, J

doi:10.1053/gast.1997.v113.pm9352878

Cited by 29 publications

(19 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The recent suggestion that the protein aberrantly expressed on the surface of biliary epithelia from patients with PBC may be PDC-E3BP rather than PDC-E2 provided the first evidence that the initial breakdown of tolerance might in fact be to PDC-E3BP. 10 Our findings, that preabsorption with rE2 removed all subsequent activity in ELISA against rE3BP, but not vice versa, would be compatible with the original breakdown of tolerance being to E3BP with subsequent epitope spreading to E2. The important issue of the target and driving force for the initial breakdown of tolerance remains, however, to be clarified.…”

Section: Discussionsupporting

confidence: 70%

Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis

Palmer

Jones

Quinn³

et al. 1999

Hepatology

View full text Add to dashboard Cite

Autoantibodies to the pyruvate dehydrogenase complex (PDC) are present in the serum of more than 95% of patients with primary biliary cirrhosis (PBC), the major epitope being the inner lipoyl domain of the E2 component. Immunoblotting suggests a similar prevalence of antibodies to a tightly associated lipoic acid-containing protein, E3 binding protein (E3BP). Attempts to resolve E3BP from E2 have been unsuccessful, restricting study of the nature and significance of antibody responses to the individual proteins. In particular, it is unclear (1) whether there is true cross-reactivity between E3BP and E2 and, if so, which is the originating response and (2) whether autoantibodies preferentially bind a lipoylated epitope on E3BP as is the case with PDC-E2. In this study, complementary DNAs encoding rE2, full-length rE3BP, its single lipoyl domain (rLip), and core domain (rE3BPCore) were cloned, and the proteins were expressed in Escherichia coli. Sera from 47 PBC patients were studied by immunoblotting and enzymelinked immunosorbent assay (ELISA) against rE2, rE3BP, rE3BPCore, and both unlipoylated (U) and lipoylated (L) rLip. All sera were reactive by ELISA to some degree with all recombinant proteins except rE3BPCore, to which only 6 of 47 showed any reactivity. Significant correlations (P F .0001) were observed when comparing absorbance values for rE3BP with both rLip (U) (r ‫؍‬ 0.793) and (L) (r ‫؍‬ 0.963). The mean absorbance for rLip (U, 0.26 ؎ 0.05) was, however, significantly lower than the absorbance for rLip (L) (0.78 ؎ 0.12; P F .0001). After probing by immunoblotting and elution of antibodies from rE2 and rE3BP, subsequent reprobing against the components in whole PDC revealed true cross-reactivity. In summary, the response to E3BP is primarily directed against the lipoylated domain of the protein. It still remains unclear, however, whether the initial breakdown of tolerance is to E2 or E3BP. (HEPATOLOGY 1999;30:21-26.)Primary biliary cirrhosis (PBC) is characterized by the presence of serum autoantibodies reactive with mitochondrial self-antigens identified as the members of the 2-oxoacid dehydrogenase family of multienzyme complexes. 1 Studies identifying the dominant autoantigen as the pyruvate dehydrogenase complex (PDC) showed that 95% of PBC patients had serum antibodies reactive with both the well-characterized dihydrolipoamide acetyltransferase (E2) and the less well-characterized protein X (more recently renamed the E3 binding protein [E3BP]) components of PDC. 2 Mammalian PDC-E2 and E3BP have been shown to be structurally similar, with E2 having two tandemly repeated amino-terminal lipoyl domains 3,4 and E3BP a single lipoyl domain, 5-7 the lipoic acid moieties being covalently linked through specific lysine residues.The almost universal association between the presence of autoantibodies specific for PDC-E2 and PDC-E3BP and the development of the histological lesions of PBC strongly suggests that the instigating breakdown of self-tolerance in this disease is against one or both of these antige...

show abstract

Section: Discussionsupporting

confidence: 70%

Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis

Palmer

Jones

Quinn³

et al. 1999

Hepatology

View full text Add to dashboard Cite

show abstract

“…After 7 days in culture, we found that normal BEC incubated with PBC lymph nodes demonstrated increased PDC-E2 by immunoblot as well as AMA immunostaining of plasma membrane (Fig. 3), the phenotypic manifestation of PBC (8,22,23). The PBC lymph node treated BEC had a Ͼ2-fold increase in AMA index (the ratio of PDC-E2 in treated and untreated BEC), but little change was observed in BEC incubated with liver disease control and normal donor lymph nodes (P ϭ 0.001, Table 2 Group a).…”

Section: Induction Of the Pbc Phenotype In Vitro By Betaretrovirusmentioning

confidence: 89%

Does a betaretrovirus infection trigger primary biliary cirrhosis?

Shen

Guo

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

217

246

View full text Add to dashboard Cite

Patients with primary biliary cirrhosis develop progressive ductopenia associated with the production of antimitochondrial antibodies that react with a protein aberrantly expressed on biliary epithelial cells and peri-hepatic lymph nodes. Although no specific microbe has been identified, it is thought that an infectious agent triggers this autoimmune liver disease in genetically predisposed individuals. Previous serologic studies have provided evidence to suggest a viral association with primary biliary cirrhosis. Here we describe the identification of viral particles in biliary epithelium by electron microscopy and the cloning of exogenous retroviral nucleotide sequences from patients with primary biliary cirrhosis. The putative agent is referred to as the human betaretrovirus because it shares close homology with the murine mammary tumor virus and a human retrovirus cloned from breast cancer tissue. In vivo, we have found that the majority of patients with primary biliary cirrhosis have both RT-PCR and immunohistochemistry evidence of human betaretrovirus infection in lymph nodes. Moreover, the viral proteins colocalize to cells demonstrating aberrant autoantigen expression. In vitro, we have found that lymph node homogenates from patients with primary biliary cirrhosis can induce autoantigen expression in normal biliary epithelial cells in coculture. Normal biliary epithelial cells also develop the phenotypic manifestation of primary biliary cirrhosis when cocultivated in serial passage with supernatants containing the human betaretrovirus or the murine mammary tumor virus, providing a model to test Koch's postulates in vitro.

show abstract

“…14 Furthermore, five anti-PDC-E2 combinatorial antibodies derived from a patient with PBC all produced identical "mitochondrial" staining patterns on Hep-2 cells but produced different staining patterns in biliary epithelial cells in liver sections derived from a patient with PBC, 15 and there are differences in the electrophoretic mobility between PDC-E2 and AMA reactive antigen isolated from the plasma membrane of biliary epithelial cells derived from the liver of patients with PBC. 16 It could be argued that aberrant expression of this AMA reactive material by biliary epithelium arises as a consequence of the inflammatory process. Yet intuitively it seems much more plausible that aberrant antigen expression by the biliary epithelium results in immune activation towards a previously functionally sequestered antigen.…”

Section: Activation Of the Naïve T Cell Response To Autoantigens In Pbcmentioning

confidence: 99%

Primary biliary cirrhosis: seeking the silent partner of autoimmunity

Sutton

Neuberger²

2002

Gut

View full text Add to dashboard Cite

The human biliary epithelial cell plasma membrane antigen in primary biliary cirrhosis: Pyruvate dehydrogenase X?

Cited by 29 publications

References 0 publications

Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis

Characterization of the autoantibody responses to recombinant E3 binding protein (protein X) of pyruvate dehydrogenase in primary biliary cirrhosis

Does a betaretrovirus infection trigger primary biliary cirrhosis?

Primary biliary cirrhosis: seeking the silent partner of autoimmunity

Contact Info

Product

Resources

About