Comparative studies of antimitochondrial autoantibodies in sera and bile in primary biliary cirrhosis

Abstract

9%), to the branched-chain 2-oxo-acid dehydrogenase complex E2 (BCOADC-E2) in 6 of 19 patientsOrgan-specific autoimmune diseases are characterized by (31.6%), and to the 2-oxoglutarate dehydrogenase com-the production of autoantibodies and the destruction of speplex E2 (OGDC-E2) in 1 of 19 patients (5.3%). In a compar-cific tissues. Primary biliary cirrhosis (PBC) has been considative study of sera from the same patients, anti-PDC-ered a model autoimmune disease and a paradigm for dis-E2 antibodies were found in 19 of 19 patients (100%), eases such as Hashimoto's thyroiditis 1 and type I diabetes anti-BCOADC in 9 of 19 patients (47.3%), and anti-mellitus. 2 PBC is characterized by destruction of intrahepatic OGDC-E2 in 4 of 19 patients (21.1%) patients. AMA in bile ducts and production of high-titer autoantibodies against bile were always found together with antibodies of cor-mitochondrial autoantigens. 3 Much work has been directed responding specificities in the serum from the same pa-at the detection and characterization of antimitochondrial tient. Immunoglobulin (Ig)A AMA were found in the bile autoantibodies (AMA). Earlier studies from both our laboraof 9 of 19 patients (47.7%) with PBC; they were specifi-tory and others have shown that AMA react with a series of cally directed against PDC-E2 in 8 of 19 patients (42.1%) highly conserved intramitochondrial proteins, in particular and to BCOADC in 2 of 19 patients (10.5%). Epitope map-the 2-oxo acid dehydrogenase complexes, including the dihyping of IgA anti-PDC-E2 antibodies indicated that, like drolipoylacetyltransferase component of the pyruvate dehyserum autoantibodies, the immunodominant epitope is drogenase complex E2 (PDC-E2), the branched-chain 2-oxo directed against the inner lipoyl domain of PDC-E2. The acid dehydrogenase complex E2 (BCOADC-E2), and the 2-prevalence and antigen reactivity of IgA AMA in sera oxoglutarate dehydrogenase complex E2 (OGDC-E2). [4][5][6][7][8][9][10][11] The correlated completely with IgA AMA in bile. Autoanti-major autoantibody reactivity is directed against the 74-kd bodies against nuclear envelope pore proteins (gp210) protein, PDC-E2. were found in 1 of 8 (12.5%) sera of patients with PBC, Although the pathogenesis of PBC remains unknown, utilibut not in bile. Furthermore, and of particular interest, zation of immunohistochemical techniques, monoclonal, combinatorial derived, and experimentally induced rabbit antibodies specific for PDC-E2 has revealed the selective expression of a cross-reactive molecule at the apex of biliary Abbreviations: PBC, primary biliary cirrhosis; AMA, antimitochondrial autoantibodies; PDC, pyruvate dehydrogenase complex; BCOADC, branched-chain 2-oxo-acid dehydrogeepithelial cells of patients with PBC, but not patients with nase complex; OGDC, 2-oxoglutarate dehydrogenase complex; Ig, immunoglobulin; PBS, primary sclerosing cholangitis or autoimmune hepatitis. 12-14 phosphate-buffered saline; SDS, sodium dodecyl sulfate; BHM, bovine heart mitochondrial Furthermore, deposition of immunoglobul...

Heterogeneous Response of Antimitochondrial Autoantibodies and Bile Duct Apical Staining Monoclonal Antibodies to Pyruvate Dehydrogenase Complex E2: the Molecule Versus the Mimic

“…Previous studies on identification of the T cell and AMA epitopes have focused on the major domains of the PDC-E2 as well as the requirement of LA for epitope recognition. [24][25][26][27][28][29][30][31][32] The consensus of these studies is that the immunodominant epitope is located within the ILD. We report herein on the characterization of 17 mAbs against the major autoantigen of PBC, PDC-E2, with particular emphasis on fine mapping of the epitopes that are recognized.…”

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. As shown in Figure 6A (lane 1), anti-hPDC-E2 recognizes a Xenopus antigen of ϳ67 kDa.…”

Evidence for a locally driven mucosal response and the presence of mitochondrial antigens in saliva in primary biliary cirrhosis

“…The reactivity of the IgA antibodies to PDC-E2 was reduced or abolished by preabsorption of the saliva with E. coli lysate containing fragment B but not fragments A, C, and D. This is identical to the previously reported data on the PDC-E2 fragment specificity of serum and bile AMA. 19,20 Detection of Antimitochondrial Antibody Isotypes in Sera and Saliva. PDC-E2-specific IgG was found in the saliva of 6 of 17(35%) patients tested, PDC-E2-specific IgA in saliva of 16 of 20 patients (80%) and PDC-E2-specific IgM in 3 of 17 (18%).…”