Abstract
Antimitochondrial antibodies (AMA) may be detected in 95% of patients with primary biliary cirrhosis (PBC). The target autoantigens for the AMA were recently identified as four closely related metabolic enzymes located in the mitochondria. We have purified the pyruvate dehydrogenase (PDH) enzyme from bovine heart, showing that all PBC sera reacted with a 74-kd band. PDH was utilized to establish an ELISA assay for detecting the relevant antibodies. One hundred twelve of 120 sera from patients with PBC (95%) reacted with the PDH but none of the 201 control sera, including normal subjects and a panel of sera from other patients with liver diseases, showed similar reactivity. In 77% of the PBC sera the anti-PDH antibody isotype was identified as a combination of IgG and IgM, while in 18% only IgM was detected. In 5% of the sera the isotype was confined to IgG. PBC sera specifically inhibited the PDH enzyme activity. The enzyme inhibition correlated with the anti-PDH antibody titers. Thus, PDH seems to be one of the major target epitopes for AMA observed in sera of patients with PBC.
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References
James SP, Hoofnagle JH, Strober W, James EA: Primary biliary cirrhosis: A model autoimmune disease. Ann Intern Med 99:512–550, 1983
Kaplan M: Primary biliary cirrhosis. N Engl J Med 316:521–528, 1987
Gershwin ME, Coppel RI, Mackay IR: Primary biliary cirrhosis and mitochondrial autoantigens—insights from molecular biology. Hepatology 8:147–151, 1988
Zurgil N, Konikof F, Bakimer R, Slor H, Shoenfeld Y: Detection of antimitochondrial antibodies: Characterization by enzyme immunoassay and immunoblotting. Autoimmunity 4:289–297, 1989
Berg PA, Klein R: Molecular determination of primary biliary cirrhosis specific M2 antigen. Hepatology 8:200–201, 1988
Gershwin ME, Mackay IR, Sturgess A,et al. Identification and specificity of cDNA encoding the 70Kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 139:3525–3531, 1988
Yeaman SJ, Danner DJ, Muriner DJ, Gussey SPM, James OFW, Bassendine MF: PBC: Identification of two major M2 mitochondrial autoantigens. Lancet 1:1067–1069, 1988
Fussey SPM, Guest JR, James OFW, Bassendine MF, Yaemane SJ: Identification and analysis of the major M2 autoantigens in primary biliary cirrhosis. Proc Natl Acad Sci USA 85:8654–8658, 1988
Surch CD, Roche TE, Danher DJ,et al. Antimitochondrial autoantibodies in primary biliary cirrhosis recognize cross reactive epitopes on protein x and dihydrolipoamide acyltransferase of pyruvate dehydrogenases complex. Hepatology 10:127–133, 1989
Fregeau DR, Roche TE, Davis PA,et al. Inhibition of pyruvate dehydrogenase activity by autoantibodies specific for Elα, a non-lipoic acid containing mitochondrial enzyme. J Immunol 144:1671–1676, 1990
Van de Water J, Fregeau DR, Davis P,et al. Autoantibodies of primary biliary cirrhosis (PBC) recognize dihydrolipoamide acyltransferase and inhibit enzyme function. J Immunol 141:2321–2324, 1988
Fregeau DR, Davis PA, Danner DJ,et al. Antimitochondrial antibodies of primary biliary cirrhosis recognize dihydrolipoamide acyltransferases and inhibit enzyme function of the branched chain and ketoacid dehydrogenases complex. J Immunol 142:3815–3820, 1989
Leevy CM, Popper H, Sherlock S: Diseases of the Liver and Biliary Tract. Standardization of Nomenclature, Diagnostic Criteria and Diagnostic Methodology. Chicago, Yearbook Medical, 1976
Stanley CJ, Perham RN: Purification of 2-oxo-acid dehydrogenase multienzyme complexes from ox heart by a new method. Biochem J 191:147–150, 1980
Laemmli UK: Cleavage of structural proteins during assembly of the head of bacteriophage. Nature 227:680–685, 1970
Broun JP, Perham RN: Selective inactivation of the transacylase components of the 2-oxo-acide dehydrogenase multienzyme complexes of Escherichia coli. Biochem J 155:419–427, 1976
Muno D, Komonami E, Ishul H,et al. Isolation of trypic fragment of antigen from mitochondrial inner membrane proteins reacting with antimitochondrial antibody in sera of patients with primary biliary cirrhosis. Hepatology 11:16–23, 1990
Tan EM: Antinuclear antibodies: Diagnostic markers for autoimmune disease and probes for cell biology. Adv Immunol 44:93–151, 1989
Goldschmeding R, Van der Schoot CE, Ten Bokkel Hvinink,et al. Wegener's granulomatosis autoantibodies identify a novel diisopropylflurophosphate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest 84:1577–1587, 1989
Flannery GR, Burroughs AK, Butler P,et al. Antimitochondrial antibodies in primary biliary cirrhosis recognize both specific peptides and shared epitopes of the M2 family of antigens. Hepatology 10:370–374, 1989
Tan EM, Sullivan K, Li X, Tan EM, Downey KW, So AG: Autoantibody to the proliferating cell nuclear antigen neutralizes the activity of the auxiliary protein for DNA polymerase delta. Nucleic Acids Res 15:9299–9308, 1987
Mathews MB, Bernstein RM: Myositis autoantibody inhibits histidyl tRNA synthetase: A model for autoimmunity. Nature 304:177–179, 1983
Ludemann J, Utecht B, Gross WL: Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme. J Exp Med 171:357–362, 1990
Van De Water J, Cooper AMS, Surch CD,et al. Detection of autoantibodies to recombinant mitochondrial proteins in patients with primary biliary cirrhosis. N Engl J Med 320:1377–1380, 1989
Wiesner RH, Ludwig J, Lindor K,et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 322:1419–1424, 1990
Kaplan MM, Knox TA: Effective treatment of pre-cirrhotic primary biliary cirrhosis (PBC) with methotrexate, remission in some. Hepatology 10:585, 1989 (abstr)
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Zurgil, N., Bakimer, R., Kaplan, M. et al. Anti-pyruvate dehydrogenase autoantibodies in primary biliary cirrhosis. J Clin Immunol 11, 239–245 (1991). https://doi.org/10.1007/BF00918181
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DOI: https://doi.org/10.1007/BF00918181