Primary biliary cirrhosis is characterized by IgG3 antibodies cross-reactive with the major mitochondrial autoepitope and its Lactobacillus mimic

Abstract

The serological hallmark of primary biliary cirrhosis (PBC) is the presence of pyruvate dehydrogenase complex E2 subunit (PDC-E2) antimitochondrial antibodies (AMAs). Anti-PDC-E2 antibodies cross-react specifically with mycobacterial hsp65, and we have demonstrated that the motif SxGDL[ILV]AE shared by PDC-E2 212-226 and hsp's is a cross-reactive target. Having found that this same motif is present only in ␤-galactosidase of Lactobacillus delbrueckii (BGAL LACDE), we hypothesized that this homology would also lead to crossreactivity. The mimics were tested via ELISA for reactivity and competitive cross-reactivity using sera from 100 AMA-positive and 23 AMA-negative PBC patients and 190 controls. An Escherichia coli (ECOLI) PDC-E2 mimic that has been pathogenetically linked to PBC but lacks this motif has been also tested. Anti-BGAL 266-280 LACDE antibodies were restricted to AMA-positive patients (54 of 95, 57%) and belonged to immunoglobulin (Ig) G3. Of the 190 controls, 22 (12%; P < .001) had anti-BGAL 266-280 antibodies, mainly of the IgG4 subclass. ECOLI PDC-E2 reactivity was virtually absent. BGAL 266-280 /PDC-E2 212-226 reactivity of the IgG3 isotype was found in 52 (52%) AMA-positive PBC patients but in only 1 of the controls (P < .001). LACDE BGAL 266-280 /PDC-E2 212-226 reactivity was due to crossreactivity as confirmed via competition ELISA. Antibody affinity for BGAL 266-280 was greater than for PDC-E2 mimics. Preincubation of a multireactive serum with BGAL 266-280 reduced the inhibition of enzymatic activity by 40%, while marginal effect (12%) or no effect (2%) was observed in human or ECOLI PDC-E2 mimics. In conclusion, IgG3 antibodies to BGAL LACDE cross-react with the major mitochondrial autoepitope and are characteristic of PBC.

Differential epitope mapping of antibodies to PDC-E2 in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation and primary biliary cirrhosis

“…Results were compared with the reactivity found in 12 PBC serum samples known to be positive for anti-PDC-E2 by Western blot (1:1000 dilution). In accordance with previous reports, PBC samples were predominantly IgG3 positive ( Figure 5), 20,21 a feature shared by MGUS samples. In striking contrast, the antibody response detected after DLI was predominantly of the IgG1 and IgG2 isotypes.…”

“…30 Moreover, the antibody response in hemato-oncologic patients was directed exclusively against PDC-E2 with no reactivity toward OGDC or BCOADC, the other immunogenic reactants identified in PBC. Differences were also confirmed analyzing the involved IgG subclasses, confirming the previously described prevalence of IgG3 in PBC 20,21 and prevalently detecting IgG1 and IgG2 in patients after DLI arguing in favor of a potentially T-cell-dependent immunoglobulin production. 31,32 Most importantly, the absence of detectable liver disease in all of the examined patients over time furthermore distinguishes the population, although a delayed onset of a potential liver disease cannot be excluded considering the presence of AMAs for years in otherwise asymptomatic patients who eventually develop PBC.…”

Molecular mechanisms of cholangiopathy in primary biliary cirrhosis

“…[53][54][55][56][57][58][59] Although it is a matter of controversy whether these microorganisms are directly or indirectly causative pathogens of PBC or not, infectious agents may increase the susceptibility for apoptosis in biliary epithelial cells.…”

The Role ofE. coliInfection in the Pathogenesis of Primary Biliary Cirrhosis

“…The first finding in support of this view was that of a striking overlap of the immunodominant B-and T-(both CD4 and CD8) cell epitope on PDC-E2 [16,18,47,49,50,63]. This region is located within the inner lipoyl-binding domain of the subunit, spanning amino acid 212-231 (PDC-E2 212−231 ).…”