Skip to main content
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1992 May;140(5):1215–1223.

A shared epitope in the acetylcholine receptor-alpha subunit and fast troponin I of skeletal muscle. Is it important for myasthenia gravis?

M Osborn 1, A Marx 1, T Kirchner 1, S J Tzartos 1, U Plessman 1, K Weber 1
PMCID: PMC1886522  PMID: 1374594

Abstract

The monoclonal antibody MAb 155, isolated by Tzartos et al, recognizes the alpha subunit of acetylcholine receptor (AChR) and stains type II skeletal muscle fibers but does not decorate heart muscle. In addition it reacts with most myasthenia gravis-associated thymomas. The authors show by immunoblotting techniques that the myofibrillar antigen is a 23 kd protein and by partial protein sequence data identify it as fast troponin I. Fast troponin I from various species contains the sequence EEKSGMEGRK close to the C-terminal end at positions 165 to 174. The first lysine (K) is crucial for MAb 155 reactivity since its substitution by methionine and leucine in slow troponin I and cardiac troponin I, respectively, abolishes MAb 155 reactivity. The epitope identified on troponin I is homologous in sequence with the MAb 155 epitope on the AChR alpha subunit established by direct peptide binding as KSAIEGIK (positions 373-380). The authors consider whether fortuitously shared epitopes can be responsible for the high level of autoantibodies to AChR and to muscle proteins seen in many MG patients.

Full text

PDF
1215

Images in this article

Selected References

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

  1. Aarli J. A., Stefansson K., Marton L. S., Wollmann R. L. Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin. Clin Exp Immunol. 1990 Nov;82(2):284–288. doi: 10.1111/j.1365-2249.1990.tb05440.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baldwin A. S., Jr, Kittler E. L., Emerson C. P., Jr Structure, evolution, and regulation of a fast skeletal muscle troponin I gene. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8080–8084. doi: 10.1073/pnas.82.23.8080. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dhoot G. K., Perry S. V. Distribution of polymorphic forms of troponin components and tropomyosin in skeletal muscle. Nature. 1979 Apr 19;278(5706):714–718. doi: 10.1038/278714a0. [DOI] [PubMed] [Google Scholar]
  4. Fürst D. O., Osborn M., Nave R., Weber K. The organization of titin filaments in the half-sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: a map of ten nonrepetitive epitopes starting at the Z line extends close to the M line. J Cell Biol. 1988 May;106(5):1563–1572. doi: 10.1083/jcb.106.5.1563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Geuder K. I., Schoepfer R., Kirchner T., Marx A., Müller-Hermelink H. K. The gene of the alpha-subunit of the acetylcholine receptor: molecular organisation and transcription in myasthenia-associated thymomas. Thymus. 1989;14(1-3):179–186. [PubMed] [Google Scholar]
  6. Greaser M. L., Gergely J. Reconstitution of troponin activity from three protein components. J Biol Chem. 1971 Jul 10;246(13):4226–4233. [PubMed] [Google Scholar]
  7. Hara Y., Ueno S., Uemichi T., Takahashi N., Yorifuji S., Fujii Y., Tarui S. Neoplastic epithelial cells express alpha-subunit of muscle nicotinic acetylcholine receptor in thymomas from patients with myasthenia gravis. FEBS Lett. 1991 Feb 11;279(1):137–140. doi: 10.1016/0014-5793(91)80268-8. [DOI] [PubMed] [Google Scholar]
  8. Hohlfeld R. Myasthenia gravis and thymoma: paraneoplastic failure of neuromuscular transmission. Lab Invest. 1990 Mar;62(3):241–243. [PubMed] [Google Scholar]
  9. Kirchner T., Tzartos S., Hoppe F., Schalke B., Wekerle H., Müller-Hermelink H. K. Pathogenesis of myasthenia gravis. Acetylcholine receptor-related antigenic determinants in tumor-free thymuses and thymic epithelial tumors. Am J Pathol. 1988 Feb;130(2):268–280. [PMC free article] [PubMed] [Google Scholar]
  10. Knight P. J., Trinick J. A. Preparation of myofibrils. Methods Enzymol. 1982;85(Pt B):9–12. doi: 10.1016/0076-6879(82)85004-0. [DOI] [PubMed] [Google Scholar]
  11. Koppe R. I., Hallauer P. L., Karpati G., Hastings K. E. cDNA clone and expression analysis of rodent fast and slow skeletal muscle troponin I mRNAs. J Biol Chem. 1989 Aug 25;264(24):14327–14333. [PubMed] [Google Scholar]
  12. Leszyk J., Dumaswala R., Potter J. D., Collins J. H. Amino acid sequence of bovine cardiac troponin I. Biochemistry. 1988 Apr 19;27(8):2821–2827. doi: 10.1021/bi00408a024. [DOI] [PubMed] [Google Scholar]
  13. Marx A., Kirchner T., Hoppe F., O'Connor R., Schalke B., Tzartos S., Müller-Hermelink H. K. Proteins with epitopes of the acetylcholine receptor in epithelial cell cultures of thymomas in myasthenia gravis. Am J Pathol. 1989 Apr;134(4):865–877. [PMC free article] [PubMed] [Google Scholar]
  14. Marx A., O'Connor R., Geuder K. I., Hoppe F., Schalke B., Tzartos S., Kalies I., Kirchner T., Müller-Hermelink H. K. Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis-associated thymomas. Lab Invest. 1990 Mar;62(3):279–286. [PubMed] [Google Scholar]
  15. Noda M., Furutani Y., Takahashi H., Toyosato M., Tanabe T., Shimizu S., Kikyotani S., Kayano T., Hirose T., Inayama S. Cloning and sequence analysis of calf cDNA and human genomic DNA encoding alpha-subunit precursor of muscle acetylcholine receptor. 1983 Oct 27-Nov 2Nature. 305(5937):818–823. doi: 10.1038/305818a0. [DOI] [PubMed] [Google Scholar]
  16. Ohta M., Ohta K., Itoh N., Kurobe M., Hayashi K., Nishitani H. Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis. Clin Chim Acta. 1990 Mar 15;187(3):255–264. doi: 10.1016/0009-8981(90)90110-e. [DOI] [PubMed] [Google Scholar]
  17. Penn A. S., Schotland D. L., Lamme S. Antimuscle and antiacetylcholine receptor antibodies in myasthenia gravis. Muscle Nerve. 1986 Jun;9(5):407–415. doi: 10.1002/mus.880090505. [DOI] [PubMed] [Google Scholar]
  18. Schluep M., Willcox N., Vincent A., Dhoot G. K., Newsom-Davis J. Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study. Ann Neurol. 1987 Aug;22(2):212–222. doi: 10.1002/ana.410220205. [DOI] [PubMed] [Google Scholar]
  19. Siara J., Rüdel R., Marx A. Absence of acetylcholine-induced current in epithelial cells from thymus glands and thymomas of myasthenia gravis patients. Neurology. 1991 Jan;41(1):128–131. doi: 10.1212/wnl.41.1.128. [DOI] [PubMed] [Google Scholar]
  20. Toyota N., Shimada Y. Differentiation of troponin in cardiac and skeletal muscles in chicken embryos as studied by immunofluorescence microscopy. J Cell Biol. 1981 Nov;91(2 Pt 1):497–504. doi: 10.1083/jcb.91.2.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Tzartos S. J., Kokla A., Walgrave S. L., Conti-Tronconi B. M. Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67-76 of the alpha subunit. Proc Natl Acad Sci U S A. 1988 May;85(9):2899–2903. doi: 10.1073/pnas.85.9.2899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Tzartos S., Hochschwender S., Vasquez P., Lindstrom J. Passive transfer of experimental autoimmune myasthenia gravis by monoclonal antibodies to the main immunogenic region of the acetylcholine receptor. J Neuroimmunol. 1987 Jun;15(2):185–194. doi: 10.1016/0165-5728(87)90092-0. [DOI] [PubMed] [Google Scholar]
  23. Tzartos S., Langeberg L., Hochschwender S., Lindstrom J. Demonstration of a main immunogenic region on acetylcholine receptors from human muscle using monoclonal antibodies to human receptor. FEBS Lett. 1983 Jul 11;158(1):116–118. doi: 10.1016/0014-5793(83)80688-7. [DOI] [PubMed] [Google Scholar]
  24. Tzartos S., Langeberg L., Hochschwender S., Swanson L. W., Lindstrom J. Characteristics of monoclonal antibodies to denatured Torpedo and to native calf acetylcholine receptors: species, subunit and region specificity. J Neuroimmunol. 1986 Jan;10(3):235–253. doi: 10.1016/0165-5728(86)90105-0. [DOI] [PubMed] [Google Scholar]
  25. Vetters J. M. Muscle antibodies in myasthenia gravis. Immunology. 1967 Sep;13(3):275–280. [PMC free article] [PubMed] [Google Scholar]
  26. Wilkinson J. M., Grand R. J. Comparison of amino acid sequence of troponin I from different striated muscles. Nature. 1978 Jan 5;271(5640):31–35. doi: 10.1038/271031a0. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES