The E3BP (protein X) component of pyruvate dehydro-genase complex (PDC) is not a T-cell autoantigen in primary biliary cirrhosis (PBC)

Robe, Amanda J.; Palmer, JM; Yeaman, SJ; Jones, David

doi:10.1016/s0168-8278(00)80449-3

Cited by 3 publications

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“…A recent study, demonstrating a complete absence of T cells in the peripheral repertoires of patients with PBC who are reactive with recombinant human E3BP (in contrast to the responses seen to recombinant PDC-E2 in > 90% of the same patients) suggests that the breakdown of tolerance is principally, if not entirely, to PDC-E2. 28 Antibodies reactive with the E1 and E1 subunits (which are not crossreactive with PDC-E2 or PDC-E3BP) are seen at lower frequency (40% and 10% of patients with PBC, respectively). 29 30 Antibodies are seen to the E2 components of OGDC and BCOADC in approximately 90% and 50% of patients with PBC, respectively.…”

Section: The Autoimmune Response In Pbcmentioning

confidence: 98%

Autoantigens in primary biliary cirrhosis

Jones

2000

J Clin Pathol

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The automimmune liver disease primary biliary cirrhosis (PBC) is characterised by serum autoantibodies directed at mitochondrial and nuclear antigens (seen in most patients and a subset of patients, respectively). The antimitochondrial antibodies (AMA) characteristic of PBC are directed at members of the 2-oxoacid dehydrogenase components of multienzyme complexes; in particular, the E2 and E3 binding protein (E3BP) components of the pyruvate dehydrogenase complex (PDC). The presence of autoantibodies reactive with PDC-E2 and/or E3BP is strongly predictive of the presence of PBC. Therefore, the detection of these antibodies plays a very important role in the diagnosis of PBC. Originally demonstrated using immunofluorescence approaches, AMA can now be detected by the use of commercially available enzyme linked immunosorbent assays (ELISAs). Although the ELISA based approaches have advantages in terms of laboratory practicality, they are slightly less sensitive for the diagnosis of PBC than immunofluorescence (occasional patients with PBC show reactivity with PDC related antigens not present in the antigen preparations available for use with ELISA). Therefore, immunofluorescence should continue to be available as a complementary diagnostic test for use in occasional patients. In a subset of patients with PBC, autoantibodies are directed at increasingly well characterised nuclear antigens. Antinuclear antibody (ANA) positive patients are typically AMA negative. There are no significant diVerences in disease phenotype between AMA positive and AMA negative groups. At present, the clinical detection of ANA is mostly by Hep2 immunofluorescence, although ELISA kits for individual nuclear antigens are increasingly becoming available. (J Clin Pathol 2000;53:813-821)

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Section: The Autoimmune Response In Pbcmentioning

confidence: 98%

Autoantigens in primary biliary cirrhosis

Jones

2000

J Clin Pathol

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“…PDC reactivity is universal in PBC patient derived peripheral blood T‐cells (and absent from controls) when cocultured with PDC pulsed autologous dendritic cells [44] suggesting that apparent absence of response to PDC in primary peripheral blood mononuclear cell (PBMC) culture in some PBC patients simply reflects culture artefact. T‐cell responses appear to be principally directed against PDC‐E2 [34,40,45] although studies of T‐cell responses to the other component subunits of PDC have, to date, been limited [46]. An HLA DRB4*0101 restricted epitope spanning PDC‐E2163–176 (the lipoic acid binding site in the inner lipoyl domain) has been identified [45] and extensively characterised [47].…”

Section: Cellular Immune Responses In Pbcmentioning

confidence: 99%

The immunology of primary biliary cirrhosis: the end of the beginning?

Palmer

Kirby²,

Jones³

2002

Clinical and Experimental Immunology

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SUMMARYThe chronic liver disease primary biliary cirrhosis (PBC) is characterised by autoreactive B-cell and Tcell responses directed against mitochondrial antigens. In recent years these responses have been extensively characterised and the principal PBC associated autoantigen identified as pyruvate dehydrogenase complex (PDC). The identification of anti-PDC responses (present in over 95% of PDC patients) has given rise to important questions pertinent to our understanding of the pathogenesis of PBC. What specific role to anti-PDC responses play in target cell damage? How and why does immune tolerance break down to as highly conserved and ubiquitously expressed self-antigen as PDC? Why does breakdown in tolerance to an antigen present in all nucleated cells result in damage restricted to the intra-hepatic bile ducts? In attempting to answer these key questions we have, in this review, proposed a unifying hypothesis for the pathogenesis of PBC.Keywords animal models of disease apoptosis autoimmune disease liver cirrhosis, biliary molecular mimicry xenobiotic have been shown to be specific for the functional sites of key enzymes [11]. Further work is required to study the binding of antibodies to epitopes around the active site, including the regulatory phosphorylation sites and cofactor binding motifs. Antibodies reactive with branched chain 2-oxo acid dehydrogenase complex (BCOADC) E1a have recently been identified using highly purified human BCOADC as the antigen source [12]. The inhibitory capacity of this antibody appears not to have been tested as yet. It will be of interest to see if the auto-epitope of this enzyme also proves to be located in the catalytic domain, which also contains regulatory phosphorylation sites. The lack of detectable autoantibody reactivity to the E1 subunit of the 2-oxoglutarate dehydrogenase complex (OGDC) may be a consequence of this enzyme not being regulated by reversible phosphorylation [13].Secretory IgA anti-PDC is present in saliva [14][15][16], bile [17] and urine [18] mimicking the distribution of tissue damage in PBC and suggesting at least some mucosal targeting of the autoantibody response. These antibodies retain the PDC inhibitory activity characteristic of serum anti-PDC [10,[19][20][21].Anti-nuclear autoantibodies (ANA) are seen at a lower frequency (only being present in about a third of PBC patients) and are seen more frequently and at much higher titres in the small subgroup anti-PDC negative PBC patients [22][23][24]. Autoantibodies specific for the proteins of the nuclear pore complex (gp210, p62) may be associated with more active or severe disease [25]. This may also be true for the autoantibodies that react with proteins (Sp100 and PML) forming the antigenic targets that produce the multiple nuclear dot (MND) pattern revealed by direct immunofluorescence [23,26]. Another subset of auto antibodies previously reported to be reactive with carbonic anhydrase II [27] have more recently been described as a nonspecific marker of autoimmunity rather than being asso...

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Pathogenesis of primary biliary cirrhosis

Jones¹

2003

Journal of Hepatology

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The E3BP (protein X) component of pyruvate dehydro-genase complex (PDC) is not a T-cell autoantigen in primary biliary cirrhosis (PBC)

Cited by 3 publications

References 0 publications

Autoantigens in primary biliary cirrhosis

Autoantigens in primary biliary cirrhosis

The immunology of primary biliary cirrhosis: the end of the beginning?

Pathogenesis of primary biliary cirrhosis

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