The peculiar autoimmunity of primary biliary cirrhosis

Abstract

Autoantibodies to mitochondria (AMA, anti-M2) are a serologic hallmark of primary biliary cirrhosis (PBC). These react with three structurally and functionally related multienzymic complexes, the 2-oxoacid dehydrogenase complexes, but chiefly with the E2 subunit of pyruvate dehydrogenase complex (PDC-E2). Their very dose (95%) and specific association with PBC underpins the autoimmune concept of pathogenesis of that disease, notwithstanding several non-congruent features. Detailed studies, including structural analysis of epitopes, do not disclose how these autoantibodies originate. Their ubiquity in PBC has overshadowed the existence of a second set of relatively PBC-specific autoantibodies to nuclear antigens for which reactants have been cloned and characterized. These include centromeric proteins; proteins of the nuclear pore complex; nuclear dot proteins, which include Sp-100 and the promyelocytic leukemia antigen; and a recently identified autoantigen, SOX13. Certain of these reactants are DNA-binding proteins with transcriptional regulatory activity. Thus serum from individuals with the same clinical syndrome can have autoimmune reactivity to disparate mitochondrial and nuclear constituents in different cellular compartments. Antibody probing of phage displayed random peptide libraries, together with epitope scanning using overlapping sequential octameric peptides from the PDC-E2 sequence, showed that the discontinuous motifs MH, FV(E) and SYP contributed to a predicted conformational antibody epitope in the inner lipoyl domain of PDC-E2.

Key Residues of a Major Cytochrome P4502D6 Epitope Are Located on the Surface of the Molecule

“…B cell epitopes, unlike T cell epitopes, are usually conformational, i.e., highly dependent on the three-dimensional structure of the protein (21)(22)(23)(24)(25)(26). The presence of conformational epitopes on CYP2D6 was first suggested by Duclos-Vallee et al (10) who were unable to reverse inhibition of the CYP2D6 enzymatic activity by preincubation of LKM1-positive sera with synthetic peptides spanning known linear epitopes.…”

Apparent mitochondrial asymmetry in Xenopus eggs

“…The presence of autoantibodies to mitochondria, especially to the E2 component of pyruvate dehydrogenase complex, is a serologic hallmark of primary biliary cirrhosis (PBC) in human patients (reviewed in Gershwin et al, 2000;Mackay et al, 2000). We used hPDC-E2-specific PBC patient serum (Nishio et al, 1997) to probe frog oocyte proteins by Western blot analysis.…”

Autoimmune Liver Diseases and Antiphospholipid Antibodies Positivity: a Meta-analysis of Literature Studies

“…24 No 1: [25][26][27][28][29][30][31][32][33][34] mechanism [8,9]. Although classically considered as distinct entities, these autoimmune liver diseases (AiLD) may share biochemical and immunological features [9,10], such as the positivity of specific autoantibodies [11,12], that plays a central role in the diagnosis and classification of AiLD [13]. However, their pathogenic and clinical significance in these liver disorders still remains controversial [14].…”