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Mol Med. 1996 July; 2(4): 452–459.
PMCID: PMC2230170

Overexpression of select T cell receptor V beta gene families within CD4+ and CD8+ T cell subsets of myasthenia gravis patients: a role for superantigen(s)?

Abstract

BACKGROUND: The principal symptoms of myasthenia gravis (MG), muscle weakness and fatigue due to impaired neuromuscular transmission, are caused by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). The mechanisms underlying the autoimmune response, however, appear to be initiated by activation of specific HLA class II-restricted CD4+ T lymphocytes. Thus, central to elucidating the causation of MG is determining how T cells are recruited to contribute to misguided immunological assaults on the major autoantigenic target, AChR. MATERIALS AND METHODS: By combining a polymerase chain reaction (PCR)-based strategy and Southern blot technique, we have analyzed the frequency of expression of 22 individual T cell receptor (TCR) V beta gene subfamilies in CD4+ and CD8+ peripheral blood T cell subsets derived from eight MG patients and seven healthy controls. The quantification of relative usage of individual TCR J beta gene segments was performed by hybridization of PCR-amplified products (specifically V beta 1-C beta) with a complete panel of 32P-5'-end-labeled J beta-specific oligonucleotide probes, followed by scanning analysis of autoradiographs. RESULTS: Comparisons of data obtained from V beta analyses of T cells from MG patients with those from healthy individuals established that MG patients significantly overexpressed V beta 1, V beta 13.2, V beta 17, and V beta 20 gene family members within both CD4+ and CD8+ T cell subpopulations. Moreover, analysis of the relative utilization of individual TCR J beta gene segments in V beta 1+/CD4+ and V beta 1+/CD8+ T lymphocytes revealed distribution patterns in patients indistinguishable from those recorded in the corresponding cell subsets derived from controls. CONCLUSIONS: T lymphocytes from MG patients displayed a biased overexpression of four TCR V beta gene segments: V beta 1, V beta 13.2, V beta 17, and V beta 20. The relative frequencies of association of individual V beta 1 (D beta) J beta combinations revealed that J beta gene usage in the V beta 1-over-represented T cell subsets had normal distribution patterns. It can thus be deduced that J beta gene segment products appear not to have a selective effect on the process leading to overexpression of V beta 1 exons in MG patients. Hence, our observations suggest a possible role for superantigen(s) in the T cell activation in MG patients.

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Selected References

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  • Lindstrom J, Shelton D, Fujii Y. Myasthenia gravis. Adv Immunol. 1988;42:233–284. [PubMed]
  • Vincent A, Newsom Davis J. Anti-acetylcholine receptor antibodies. J Neurol Neurosurg Psychiatry. 1980 Jul;43(7):590–600. [PMC free article] [PubMed]
  • Melms A, Schalke BC, Kirchner T, Müller-Hermelink HK, Albert E, Wekerle H. Thymus in myasthenia gravis. Isolation of T-lymphocyte lines specific for the nicotinic acetylcholine receptor from thymuses of myasthenic patients. J Clin Invest. 1988 Mar;81(3):902–908. [PMC free article] [PubMed]
  • Ahlberg RE, Pirskanen R, Lefvert AK. Defective T lymphocyte function in nonthymectomized patients with myasthenia gravis. Clin Immunol Immunopathol. 1991 Jul;60(1):93–105. [PubMed]
  • Hohlfeld R, Toyka KV, Heininger K, Grosse-Wilde H, Kalies I. Autoimmune human T lymphocytes specific for acetylcholine receptor. Nature. 1984 Jul 19;310(5974):244–246. [PubMed]
  • Hohlfeld R, Toyka KV, Tzartos SJ, Carson W, Conti-Tronconi BM. Human T-helper lymphocytes in myasthenia gravis recognize the nicotinic receptor alpha subunit. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5379–5383. [PubMed]
  • Ahlberg R, Yi Q, Pirskanen R, Matell G, Swerup C, Rieber P, Riethmüller G, Holm G, Lefvert AK. Clinical improvement of myasthenia gravis by treatment with a chimeric anti-CD4 monoclonal antibody. Ann N Y Acad Sci. 1993 Jun 21;681:552–555. [PubMed]
  • Davis MM, Bjorkman PJ. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. [PubMed]
  • Drake CG, Kotzin BL. Superantigens: biology, immunology, and potential role in disease. J Clin Immunol. 1992 May;12(3):149–162. [PubMed]
  • Woodland DL, Blackman MA. How do T-cell receptors, MHC molecules and superantigens get together? Immunol Today. 1993 May;14(5):208–212. [PubMed]
  • Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. [PubMed]
  • Kappler J, Kotzin B, Herron L, Gelfand EW, Bigler RD, Boylston A, Carrel S, Posnett DN, Choi Y, Marrack P. V beta-specific stimulation of human T cells by staphylococcal toxins. Science. 1989 May 19;244(4906):811–813. [PubMed]
  • Dellabona P, Peccoud J, Kappler J, Marrack P, Benoist C, Mathis D. Superantigens interact with MHC class II molecules outside of the antigen groove. Cell. 1990 Sep 21;62(6):1115–1121. [PubMed]
  • Friedman SM, Posnett DN, Tumang JR, Cole BC, Crow MK. A potential role for microbial superantigens in the pathogenesis of systemic autoimmune disease. Arthritis Rheum. 1991 Apr;34(4):468–480. [PubMed]
  • Howell MD, Diveley JP, Lundeen KA, Esty A, Winters ST, Carlo DJ, Brostoff SW. Limited T-cell receptor beta-chain heterogeneity among interleukin 2 receptor-positive synovial T cells suggests a role for superantigen in rheumatoid arthritis. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10921–10925. [PubMed]
  • Davies TF, Martin A, Concepcion ES, Graves P, Cohen L, Ben-Nun A. Evidence of limited variability of antigen receptors on intrathyroidal T cells in autoimmune thyroid disease. N Engl J Med. 1991 Jul 25;325(4):238–244. [PubMed]
  • Davies TF, Martin A, Concepcion ES, Graves P, Lahat N, Cohen WL, Ben-Nun A. Evidence for selective accumulation of intrathyroidal T lymphocytes in human autoimmune thyroid disease based on T cell receptor V gene usage. J Clin Invest. 1992 Jan;89(1):157–162. [PMC free article] [PubMed]
  • Oksenberg JR, Stuart S, Begovich AB, Bell RB, Erlich HA, Steinman L, Bernard CC. Limited heterogeneity of rearranged T-cell receptor V alpha transcripts in brains of multiple sclerosis patients. Nature. 1990 May 24;345(6273):344–346. [PubMed]
  • Zouali M, Kalsi J, Isenberg D. Autoimmune diseases--at the molecular level. Immunol Today. 1993 Oct;14(10):473–476. [PubMed]
  • Grunewald J, Ahlberg R, Lefvert AK, DerSimonian H, Wigzell H, Janson CH. Abnormal T-cell expansion and V-gene usage in myasthenia gravis patients. Scand J Immunol. 1991 Aug;34(2):161–168. [PubMed]
  • OOSTERHUIS HJ. STUDIES IN MYASTHENIA GRAVIS. 1. A CLINICAL STUDY OF 180 PATIENTS. J Neurol Sci. 1964 Nov-Dec;1(6):512–546. [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Grunewald J, Jeddi-Tehrani M, Pisa E, Janson CH, Andersson R, Wigzell H. Analysis of J beta gene segment usage by CD4+ and CD8+ human peripheral blood T lymphocytes. Int Immunol. 1992 Jun;4(6):643–650. [PubMed]
  • Choi YW, Kotzin B, Herron L, Callahan J, Marrack P, Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941–8945. [PubMed]
  • Doherty PJ, Roifman CM, Pan SH, Cymerman U, Ho SW, Thompson E, Kamel-Reid S, Cohen A. Expression of the human T cell receptor V beta repertoire. Mol Immunol. 1991 Jun;28(6):607–612. [PubMed]
  • Jeddi-Tehrani M, Grunewald J, Hodara V, Andersson R, Wigzell H. Nonrandom T-cell receptor J beta usage pattern in human CD4+ and CD8+ peripheral T cells. Hum Immunol. 1994 Jun;40(2):93–100. [PubMed]
  • Lu CZ, Link H, Mo XA, Xiao BG, Zhang YL, Qin Z. Anti-presynaptic membrane receptor antibodies in myasthenia gravis. J Neurol Sci. 1991 Mar;102(1):39–45. [PubMed]
  • Mygland A, Tysnes OB, Aarli JA, Flood PR, Gilhus NE. Myasthenia gravis patients with a thymoma have antibodies against a high molecular weight protein in sarcoplasmic reticulum. J Neuroimmunol. 1992 Mar;37(1-2):1–7. [PubMed]
  • Zhang Y, Schluep M, Frutiger S, Hughes GJ, Jeannet M, Steck A, Barkas T. Immunological heterogeneity of autoreactive T lymphocytes against the nicotinic acetylcholine receptor in myasthenic patients. Eur J Immunol. 1990 Dec;20(12):2577–2583. [PubMed]
  • Protti MP, Manfredi AA, Wu XD, Moiola L, Howard JF, Jr, Conti-Tronconi BM. Myasthenia gravis. T epitopes on the delta subunit of human muscle acetylcholine receptor. J Immunol. 1991 Apr 1;146(7):2253–2261. [PubMed]
  • Protti MP, Manfredi AA, Wu XD, Moiola L, Dalton MW, Howard JF, Jr, Conti-Tronconi BM. Myasthenia gravis. CD4+ T epitopes on the embryonic gamma subunit of human muscle acetylcholine receptor. J Clin Invest. 1992 Oct;90(4):1558–1567. [PMC free article] [PubMed]
  • Kotzin BL, Leung DY, Kappler J, Marrack P. Superantigens and their potential role in human disease. Adv Immunol. 1993;54:99–166. [PubMed]

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