Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1993 May;92(2):308–316. doi: 10.1111/j.1365-2249.1993.tb03397.x

Sera from patients with tuberculosis recognize the M2a-epitope (E2-subunit of pyruvate dehydrogenase) specific for primary biliary cirrhosis.

R Klein 1, M Wiebel 1, S Engelhart 1, P A Berg 1
PMCID: PMC1554802  PMID: 7683589

Abstract

Anti-M2 antibodies in primary biliary cirrhosis (PBC) have been shown to react with the alpha-ketoacid dehydrogenase complex of the inner mitochondrial membrane consisting of six epitopes (E2 subunit of the pyruvate dehydrogenase complex (PDC), 70 kD; protein X of the PDC, 56 kD; alpha-ketoglutarate dehydrogenase complex, 52 kD; branched-chain alpha-ketoacid dehydrogenase, 52 kD; E1 alpha subunit of PDC, 45 kD; and E1 beta-subunit of PDC, 36 kD). These epitopes are also present in the M2 fraction which is a chloroform extract from beef heart mitochondria. The E2 subunit of the PDC at 70 kD (M2a), especially, is a major target epitope which is recognized by about 85% of all PBC sera. However, analysing sera from 28 patients with active pulmonary tuberculosis it became evident that 12 (43%) also recognized the PDC-E2 subunit (M2a), as shown by Western blotting using the M2 fraction, the purified PDC, and the recombinant PDC-E2. In contrast, only two of 82 patients with other bacterial and viral infections including 25 patients with Escherichia coli infections reacted with the PBC-specific epitope at 70 kD. Naturally occurring mitochondrial antibodies (NOMA) were present in 54% of the patients with tuberculosis and in 50% of patients with other infectious disorders. They recognized either a determinant at 65 kD (epsilon) or at 60/55 kD (zeta/eta). None of the sera from 100 blood donors had anti-M2 but 14 had NOMA. Testing anti-M2 and NOMA-positive marker sera by Western blotting against membrane fractions derived from mycobacteria and E. coli it could be shown that--like mammalian mitochondria--they contain both the PBC-specific M2 antigen as well as the non-PBC-specific naturally occurring mitochondrial antigen system (NOMAg). The observation that PBC-specific antibodies were preferentially induced in patients suffering from a mycobacterial infection may provide some new clues to the still unknown etiology of PBC.

Full text

PDF
308

Images in this article

310Fig. 2
on p.310
311Fig. 2
on p.311
312Fig. 3
on p.312

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bassendine M. F., Fussey S. P., Mutimer D. J., James O. F., Yeaman S. J. Identification and characterization of four M2 mitochondrial autoantigens in primary biliary cirrhosis. Semin Liver Dis. 1989 May;9(2):124–131. doi: 10.1055/s-2008-1040503. [DOI] [PubMed] [Google Scholar]
  2. Baum H. Nature of the mitochondrial antigens of primary biliary cirrhosis and their possible relationships to the etiology of the disease. Semin Liver Dis. 1989 May;9(2):117–123. doi: 10.1055/s-2008-1040502. [DOI] [PubMed] [Google Scholar]
  3. Berg P. A., Doniach D., Roitt I. M. Mitochondrial antibodies in primary biliary cirrhosis. I. Localization of the antigen to mitochondrial membranes. J Exp Med. 1967 Aug 1;126(2):277–290. doi: 10.1084/jem.126.2.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berg P. A., Klein R. Antimitochondrial antibodies in primary biliary cirrhosis and other disorders: definition and clinical relevance. Dig Dis. 1992;10(2):85–101. doi: 10.1159/000171347. [DOI] [PubMed] [Google Scholar]
  5. Berg P. A., Klein R., Lindenborn-Fotinos J. Antimitochondrial antibodies in primary biliary cirrhosis. J Hepatol. 1986;2(1):123–131. doi: 10.1016/s0168-8278(86)80015-0. [DOI] [PubMed] [Google Scholar]
  6. Berg P. A., Klein R., Lindenborn-Fotinos J., Klöppel W. ATPase-associated antigen (M2): marker antigen for serological diagnosis of primary biliary cirrhosis. Lancet. 1982 Dec 25;2(8313):1423–1426. doi: 10.1016/s0140-6736(82)91327-7. [DOI] [PubMed] [Google Scholar]
  7. Dannenberg A. M., Jr Delayed-type hypersensitivity and cell-mediated immunity in the pathogenesis of tuberculosis. Immunol Today. 1991 Jul;12(7):228–233. doi: 10.1016/0167-5699(91)90035-R. [DOI] [PubMed] [Google Scholar]
  8. Fussey S. P., Bassendine M. F., Fittes D., Turner I. B., James O. F., Yeaman S. J. The E1 alpha and beta subunits of the pyruvate dehydrogenase complex are M2'd' and M2'e' autoantigens in primary biliary cirrhosis. Clin Sci (Lond) 1989 Oct;77(4):365–368. doi: 10.1042/cs0770365. [DOI] [PubMed] [Google Scholar]
  9. Fussey S. P., Lindsay J. G., Fuller C., Perham R. N., Dale S., James O. F., Bassendine M. F., Yeaman S. J. Autoantibodies in primary biliary cirrhosis: analysis of reactivity against eukaryotic and prokaryotic 2-oxo acid dehydrogenase complexes. Hepatology. 1991 Mar;13(3):467–474. [PubMed] [Google Scholar]
  10. Gershwin M. E., Mackay I. R., Sturgess A., Coppel R. L. Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol. 1987 May 15;138(10):3525–3531. [PubMed] [Google Scholar]
  11. Haagsma E. B., Manns M., Klein R., Grond J., Huizenga J. R., Slooff M. J., Meyer zum Büschenfelde K. H., Berg P. A., Gips C. H. Subtypes of antimitochondrial antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation. Hepatology. 1987 Jan-Feb;7(1):129–133. doi: 10.1002/hep.1840070125. [DOI] [PubMed] [Google Scholar]
  12. Kaufmann S. H. Heat shock proteins and the immune response. Immunol Today. 1990 Apr;11(4):129–136. doi: 10.1016/0167-5699(90)90050-j. [DOI] [PubMed] [Google Scholar]
  13. Klein R., Berg P. A. Demonstration of "naturally occurring mitochondrial antibodies" in family members of patients with primary biliary cirrhosis. Hepatology. 1990 Aug;12(2):335–341. doi: 10.1002/hep.1840120222. [DOI] [PubMed] [Google Scholar]
  14. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  15. Lindenborn-Fotinos J., Baum H., Berg P. A. Mitochondrial antibodies in primary biliary cirrhosis: species and nonspecies specific determinants of M2 antigen. Hepatology. 1985 Sep-Oct;5(5):763–769. doi: 10.1002/hep.1840050510. [DOI] [PubMed] [Google Scholar]
  16. Lindenborn-Fotinos J., Sayers T. J., Berg P. A. Mitochondrial antibodies in primary biliary cirrhosis. VI. Association of the complement fixing antigen with a component of the mitochondrial F1-ATPase complex. Clin Exp Immunol. 1982 Nov;50(2):267–274. [PMC free article] [PubMed] [Google Scholar]
  17. Mitochondrial M2 autoantigens and primary biliary cirrhosis. Lancet. 1989 Feb 25;1(8635):447–448. [PubMed] [Google Scholar]
  18. Rook G. A., Stanford J. L. Slow bacterial infections or autoimmunity? Immunol Today. 1992 May;13(5):160–164. doi: 10.1016/0167-5699(92)90119-R. [DOI] [PubMed] [Google Scholar]
  19. Saboor S. A., Johnson N. M., McFadden J. Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction. Lancet. 1992 Apr 25;339(8800):1012–1015. doi: 10.1016/0140-6736(92)90535-b. [DOI] [PubMed] [Google Scholar]
  20. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Van de Water J., Gershwin M. E., Leung P., Ansari A., Coppel R. L. The autoepitope of the 74-kD mitochondrial autoantigen of primary biliary cirrhosis corresponds to the functional site of dihydrolipoamide acetyltransferase. J Exp Med. 1988 Jun 1;167(6):1791–1799. doi: 10.1084/jem.167.6.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Van de Water J., Surh C. D., Leung P. S., Krams S. M., Fregeau D., Davis P., Coppel R., Mackay I. R., Gershwin M. E. Molecular definitions, autoepitopes, and enzymatic activities of the mitochondrial autoantigens of primary biliary cirrhosis. Semin Liver Dis. 1989 May;9(2):132–137. doi: 10.1055/s-2008-1040504. [DOI] [PubMed] [Google Scholar]
  23. Yeaman S. J., Fussey S. P., Danner D. J., James O. F., Mutimer D. J., Bassendine M. F. Primary biliary cirrhosis: identification of two major M2 mitochondrial autoantigens. Lancet. 1988 May 14;1(8594):1067–1070. doi: 10.1016/s0140-6736(88)91894-6. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES