Our findings comprehensively revealed the TCRβ repertoire characterization of PBC patients, and provided a TCR molecular basis to understand the mechanism of cross-recognition between human PDC-E2 and E coli PDC-E2, and the imbalance of immune tolerance in PBC.
The decreased expression of AE2 was correlated with dysregulated autophagy, abnormal expression of PDC-E2, and cellular senescence in bile duct lesions in PBC.
Recent reports indicate nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD&NASH) and primary biliary cirrhosis and primary sclerosing cholangitis (PBC&PSC) are significant of HCC.
To explore the efficacy and safety of immunosuppressive therapy for the treatment of primary biliary cirrhosis-autoimmune hepatitis (PBC-AIH) overlap syndrome accompanied by decompensated cirrhosis.
BECs express PDC-E2 on apotopes in an immunologically intact form during apoptosis, but not other epithelial cells, which could explain the tissue specificity of PBC.
Most models focus on issues of molecular mimicry between the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial autoantigen of PBC and xenobiotic cross reactive chemicals.
A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC.
The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates.
Antibody production by PBC ASCs (n = 3) was disease-specific as AMA to pyruvate dehydrogenase complex E2 subunit (PDC-E2) was detected by immunostaining, immunoblotting and ELISA.
We submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate loss of tolerance and lead to the development of PBC.
Primary biliary cirrhosis (PBC) has been often coined a model autoimmune disease based on the homogeneity amongst patients, the frequency and similarity of antimitochondrial antibodies, including the highly directed immune response to pyruvate dehydrogenase (PDC-E2).
In primary biliary cirrhosis (PBC), patients develop a multilineage response to a highly restricted peptide of the E2 component of pyruvate dehydrogenase (PDC-E2) involving autoantibody and autoreactive cluster of differentiation (CD)4(+) and CD8(+) T-cell responses.
Peptides within the catalytic site of PDC-E2 rather than the previously reported lipoyl binding peptide 167-184 may represent major immunodominant epitopes recognized by AMA in PBC.
Immune reactivity to the mpPDC-E2 antigen was significantly enhanced in PBC patients (83.7%) as compared with controls (overall frequency of 36.7%), while antibodies to the porcine PDC-E2 chain were found only in PBC patients (88%) excluding a simple cross-reactivity of PDC-related antibodies.
The serological hallmark of PBC is the presence of high-titer antimitochondrial antibodies (AMA) against the inner lipoyl domain of E2 subunits of 2-oxo-acid dehydrogenase complexes, in particular the E2 component of the pyruvate dehydrogenase complex (PDC-E2).
These samples were basically divided into two distinct groups according to the presence of ductal injury: group 1 with CLD and predominantly biliary disease (n=26: 17 cGVHD and 9 primary biliary cirrhosis [PBC]) and group 2 with CLD and predominantly parenchymal liver disease (n=56: 20 steatohepatitis and 36 chronic viral hepatitis).Group 2 was used as the controls.
Previous studies on Spanish patients with Primary Biliary Cirrhosis (PBC) have shown extensive, disease-specific cross-reactivity between the 65-kDa heat shock protein (hsp65) of Mycobacterium gordonae and pyruvate dehydrogenase complex-E2 (PDC-E2), the major target of anti-mitochondrial antibody (AMA).
E. coli/PDC-E2 cross-reactive immunity characterizes primary biliary cirrhosis; the large number of E. coli immunogenic mimics may account for the dominance of the major PDC-E2 autoepitope.
We investigated the uptake transporters OATP2 (SLC21A6), OATP8 (SLC21A8), and NTCP (SLC10A1), the export pumps MRP2 (ABCC2), MRP3 (ABCC3), MRP6 (ABCC6), and P-glycoproteins (ABCB1, ABCB4, ABCB11), and radixin, in non-icteric primary biliary cirrhosis (PBC stages I-III) and control human liver needle-biopsies using immunofluorescence microscopy and semi-quantitative RT-PCR.
In particular, we studied the effects of the proteasome inhibitor lactacystin and the endosomal acidification inhibitor bafilomycin on the induction of PDC-E2-specific CTL response in PBC.
To develope a new enzyme immune assay (ELISA) for detection of M2 antibody specific for primary biliary cirrhosis (PBC) by using a triple hybrid clone as antigen, which coexpresses the three immunodominant lipoyl domains of PDC-E2, BCOADC-E2 and OGDC-E2 from human sources.
Molecular mimicry between the regulatory subunit ClpX and the principal T-cell epitope of pyruvate dehydrogenase complex (PDC-E2) in PBC, has been proposed to account for this.