Journal of Clinical Immunology

, Volume 4, Issue 5, pp 369–382 | Cite as

Epstein-Barr virus (EBV)-specific cell-mediated and humoral immune responses in ataxia-telangectasia patients

  • Giuseppe Masucci
  • Izzet Berkel
  • Maria Grazia Masucci
  • Ingemar Ernberg
  • Robert Szigeti
  • Fugen Ersoy
  • Özden Sanal
  • Olcay Yegin
  • Gertrude Henle
  • Werner Henle
  • Gary Pearson
  • Pierre Åman
  • George Klein
Original Articles


As a part of studies on cell-mediated immune (CMI) responses of immunocompromised, Epstein-Barr virus (EBV)-infected patients who can or cannot restrict the proliferation of EBV-transformed B cells, we have studied 16 Turkish patients with ataxia-telangectasia (AT). Fifteen were EBV seropositive; one was seronegative. Among the seropositives, eight had no or only low anti-EBV-determined nuclear antigen (EBNA) antibody titers, while seven had normal anti-EBNA levels. EBV-seropositive and -seronegative healthy Turkish children were used as controls. We have particularly asked the question whether low EBNA antibody titers can be correlated with the level of EBV-specific and -nonspecific cell-mediated immunity. Non-EBV-specific tests included cell count, phenotypical characterization with monoclonal antibodies, assessment of natural killer (NK)-cell activity, and ability to suppress mitogen-induced immunoglobulin production. Two EBV-specific CMI tests were used: outgrowth inhibition (OI) and leukocyte migration inhibition (LMI). The majority of the patients of the low-EBNA antibody group was IgA deficient and had high levels of α-fetoprotein (a-FP). Cells reacting with OKT8 monoclonal antibody predominated in both AT patient groups. In contrast, the suppressor activity was present in only a few patients and NK and interferon-activated killing (IAK) activities were normal. EBV-specific cell-mediated responses were defective in seven of eight patients in the low-anti-EBNA group and five of seven patients in the group with normal anti-EBNA titers. It is concluded that AT patients are often defective in their EBV-specific cell-mediated immune responses and with regard to their EBNA antibody levels. These defects are associated with a predominance of T cells reacting with OKT8 monoclonal antibody.

Key words

Ataxia-Telangectasia Epstein-Barr virus immunodeficiency 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Boder E: Ataxia-telangectasia: Some historic, clinical and pathologic observation.In Immunodeficiency in Man and Animals, D. Bergsma, RA Good, J Finstad (eds). Sunderland, MA, Sinauer Associates, 1975, pp 255–265Google Scholar
  2. 2.
    Waldmann TA, McIntire KP: Serum alphafetoprotein levels in patients with ataxia-telangectasia. Lancet 2:1112–1115, 1972Google Scholar
  3. 3.
    Cohen MM, Sagi M, Ben-Zur Z, Scharp T, Voss R, Kohn G: Ataxia-telangectasia: Chromosomal stability in continuous lymphoblastoid cell lines. Cytogenet Cell Genet 23:44–52, 1979Google Scholar
  4. 4.
    Becht F, McGaw BK, Koler RD: Ataxia-telangectasia. Clinical growth of translocation lymphocytes. N Engl J Med 289:286–291, 1973Google Scholar
  5. 5.
    McGaw BK, Becht P, Harnden DG, Teplitz RL: Somatic rearrangement of chromosome 14 in human lymphocytes. Proc Natl Acad Sci USA 72:2072–2075, 1975Google Scholar
  6. 6.
    Cox R, Hosking GP, Wilson J: Ataxia telangectasia. Evaluation of radiosensitivity in cultured skin fibroblast as diagnostic test. Arch Dis Child 53:386–390, 1978Google Scholar
  7. 7.
    Kersey JH, Spector BD, Good RA: Primary immunodeficiency diseases and cancer: The immunodeficiency cancer registry. Int J Cancer 12:333–347, 1973Google Scholar
  8. 8.
    Swift M, Sholman L, Perry M, Chase C: Malignant neoplasms in the families of patients with ataxia-telangectasia. Cancer Res 36:209–215, 1976Google Scholar
  9. 9.
    Ersoy F, Berkel I: Clinical and immunological studies in twenty families with ataxia-telangectasia. Turk J Pediat 16:145–160, 1974Google Scholar
  10. 10.
    Berkel AI, Henle W, Henle G, Klein G, Ersoy F, Sanal O: Epstein-Barr virus related antibody patterns in ataxia-telangectasia. Clin Exp Immunol 35:196–201, 1979Google Scholar
  11. 11.
    Joncas JH, Willis A, Reece E, Fox Z: Epstein-Barr virus antibodies in patients with ataxia-telangectasia and other immunodeficiency disease. Can Med Assoc J 125:845–849, 1981Google Scholar
  12. 12.
    Johansson B, Holm G, Mellstedt H, Henle W, Henle G, Söderberg G, Klein G, Killander D: Epstein-Barr virus (EBV)-associated antibody patterns in relation to the deficiency of cell-mediated immunity in patients with Hodgkin's disease (HD).In Oncogenesis and Herpesviruses II, Part 2, G de The, MA Epstein, H zur Hausen (eds). Lyon, IARC, 1975, pp 237–247Google Scholar
  13. 13.
    Henle W, Henle G, Lennette F: The Epstein Barr virus. Sci Am 241:40–51, 1980Google Scholar
  14. 14.
    Chang RS, Lewis JP, Reynold RD, Sullivan MJ, Neuman J: Oropharyngeal excretion of Epstein-Barr virus by patients with lymphoproliferative disorders and renal homografts. Ann Intern Med 88:34–40, 1978Google Scholar
  15. 15.
    Strauch B, Andrews LL, Siegel N, Miller G: Oropharyngeal excretion of Epstein-Barr virus by renal transplant recipients and other patients treated with immunosuppressive drugs. Lancet 1:234–237, 1974Google Scholar
  16. 16.
    Henle G, Henle W, Horwitz CA: Antibodies to Epstein-Barr virus associated nuclear antigen in infectious mononucleosis. J Infect Dis 130:231–239, 1974Google Scholar
  17. 17.
    Henle W, Henle G: Epstein-Barr virus specific serology in immunologically compromised individuals. Cancer Res 41:4222–4224, 1981Google Scholar
  18. 18.
    Sakamoto K, Freed HJ, Purtilo DT: Antibody respones to the Epstein-Barr virus in patients with the x-linked lympho-proliferative syndrome. J Immunol 125:921–925, 1980Google Scholar
  19. 19.
    Saemundsen A, Purtilo DT, Sakamoto K, Sullivan JL, Synnerholm AC, Hanto D, Simmons R, Anvret M, Collins R, Klein G: Documentation of Epstein-Barr virus infection in immunodeficient patients with life threatening lymphoproliferative diseases by Epstein-Barr virus complementary RNA and viral DNA/DNA hybridization. Cancer Res 41:4237–4242, 1981Google Scholar
  20. 20.
    Saemundsen AK, Berkel AI, Henle W, Henle G, Anvret M, Sanal Ö, Ersoy F, Caglar M, Klein G: Epstein-Barr virus carryiing lymphoma in a patient with ataxia-telangectasia. Br Med J 282:425–427, 1981Google Scholar
  21. 21.
    Rickinson AB, Moss DJ, Wallace LE, Rowe M, Misko IS, Epstein M, Pope JH: Long term T-cell mediate immunity to Epstein Barr virus. Cancer Res 41:4216–4221, 1981Google Scholar
  22. 22.
    Moss DJ, Rickinson AB, Pope JH: Long term T-cell mediated immunity to Epstein-Barr virus in leukocyte cultures. Int J Cancer 58:269–276, 1981Google Scholar
  23. 23.
    Moss DJ, Rickinson AB, Pope JH: Long term cell mediate immunity to Epstein-Barr virus in man. I. Complete regression of virus induced transformation in cultures of seropositive donor leukocytes. Int J Cancer 22:662–668, 1978Google Scholar
  24. 24.
    Szigeti R, Timar L, Revesz T: Leukocyte migration inhibition with Epstein-Barr virus negative and positive cell extracts. Allergy 35:95–103, 1980Google Scholar
  25. 25.
    Szigeti R, Masucci MG, Henle W, Henle G, Purtilo D, Klein G: Effect of different Epstein-Barr virus determined antigen (EBNA), EA, and VCA on the leukocyte migration of healthy donors and patients with infectious mononucleosis and certain immunodeficiencies. Clin Immunol Immunopathol 22:128–138, 1982Google Scholar
  26. 26.
    Henle G, Henle W: Epstein-Barr virus specific IgA serum antibodies as an outstanding feature of nasopharyngeal carcinoma. Int J Cancer 17:1–7, 1976Google Scholar
  27. 27.
    Henle W, Henle G, Horvitz CA: Epstein-Barr virus specific diagnostic tests in infectious mononucleosis. Hum Pathol 5:551–565, 1974Google Scholar
  28. 28.
    Reedman EM, Klein G: Cellular localization of Epstein-Barr virus (EBV) associated complement-fixing antigen in producer and non producer lymphoblastoid cell lines. Int J Cancer 11:499–520, 1973Google Scholar
  29. 29.
    Pearson G, Johansson B, Klein G: Antibody dependent cellular cytotoxicity against Epstein-Barr virus associated antigens in African patients with nasopharyngeal carcinoma. Int J Cancer 22:120–125, 1978Google Scholar
  30. 30.
    Pearson GR, Henle G, Henle W: Production of antigens associated with Epstein-Barr virus in experimentally infected lymphoblastoid cell lines. J Natl Cancer Inst 46:1243–1250, 1971Google Scholar
  31. 31.
    Prevost JM, Pearson G, Wallen WC, Rabbin H, Qualtiere LF: Antibody responses to membrane antigen in monkeys infected with herpesvirus saimiri. Int J Cancer 18:679–686, 1976Google Scholar
  32. 32.
    Reinherz RL, Kung PC, Goldstein G, Schlossman SF: Separation of functional subsets of human T cells by a monoclonal antibody. Proc Natl Acad Sci USA 76:4061–4063, 1979Google Scholar
  33. 33.
    Reinherz EL, Kung PC, Goldstein G, Schlossman SF: A monoclonal antibody with selective reactive functionally mature human thymocytes and all peripheral human T cells. J Immunol 123:1312–1317, 1979Google Scholar
  34. 34.
    Kung PC, Goldstein G, Reinherz EL, Schlossman SF: Monoclonal antibodies defining distinctive human T-cell surface antigens. Science 206:347–349, 1979Google Scholar
  35. 35.
    Reinherz EL, Kung PC, Goldstein G, Schlossman SF: Characterization of human inducer T cell subset defined by monoclonal antibody. J Immunol 123:2894–2896, 1979Google Scholar
  36. 36.
    Reinherz EL, Kung PC, Pesanto JM, Ritz J, Goldstein G, Schlossman SF: Ia determinants on human T cell subsets defined by monoclonal antibody: Activation stimuli required for expression. J Exp Med 150:1472–1482, 1979Google Scholar
  37. 37.
    Breard J, Reinherz EL, Kung PC, Goldstein G, Schlossman SF: A monoclonal antibody reactive with human peripheral blood monocytes. J Immunol 124:1943–1948, 1980Google Scholar
  38. 38.
    Masucci G, Masucci MG, Klein E: Human blood lymphocyte subsets separated on the basis of nylon adherence, SRBC and EA rosetting: natural cytotoxicity and characterization with monoclonal reagents. Cell Immunol 69:166–174, 1982Google Scholar
  39. 39.
    Siegal F, Siegal M: Enhancement of irradiated T cells of Human plasma cell production: Dissection of helper and suppressor function in vitro. J Immunol 118:642–647, 1977Google Scholar
  40. 40.
    Wasserman J, Von Stedingk LV, Biberfeld G, Petrini B, Blomgren H, Baral E: The effect of irradiation on T-cell suppression of ELISA-determined Ig production by human blood B-cells in vitro. Clin Exp Immunol 38:366–369, 1979Google Scholar
  41. 41.
    Peters M, Fauci A: Antigen-specific human B-cell responses: Modulation by immunoregulatory T-cell subsets. Cell Immunol 82:223–231, 1983Google Scholar
  42. 42.
    Benveniste E, Schroff R, Stevens R, Gottlieb M: Immunoregulatory T cell in man with a new acquired immunodeficiency syndrome. J Clin Immunol 3:359–367, 1983Google Scholar
  43. 43.
    Tsukuda K, Tsukuda Y, Klein G: Suppressor T cells activated by lymphoblastoid cell-lines inhibit pokeweed mitogen-induced immunoglobulin synthesis. Cell Immunol 60:191–202, 1981Google Scholar
  44. 44.
    Engvall E, Perlmann P: Enzyme linked immunosorbent assay, ELISA. Quantitation of specific antibodies by enzyme labeled antiimmunoglobulins in antigen-coated tubes. J Immunol 109:129–135, 1972Google Scholar
  45. 45.
    Voller A, Bidwell DE, Bartlett A: Enzyme immunoassays in diagnostic medicine. Theory and practice. Bull WHO 53:55–59, 1976Google Scholar
  46. 46.
    Bakács T, Gergely P, Klein E: Characterization of cytotoxic human lymphocyte subpopulations: Role of Fc-receptor carrying cells. Cell Immunol 32:317–328, 1977Google Scholar
  47. 47.
    Masucci MG, Klein E, Argov S: Disappearance of NK effect after explantation of lymphocytes and generation of similar non specific cytotoxicity correlated to the level of blastogeneis in active cultures. J Immunol 124:2458–2463, 1980Google Scholar
  48. 48.
    Masucci MG, Masucci G, Klein E, Berthold W: Interferon induced cytotoxicity of human lymphocytes.In International Symposium on New Trends in Human Immunology and Cancer Immunotherapy, S Serrou, C Rosenfeld (eds). Paris, Doin Editeurs, 1980, pp 887–900Google Scholar
  49. 49.
    Luka J, Lindhal T, Klein G: Purification of the Epstein-Barr virus determined nuclear antigen (EBNA) from EBV transformed human lymphoid cell lines. J Virol 27:604–611, 1978Google Scholar
  50. 50.
    Szigeti R, Luka J, Klein G: Leukocyte migration inhibition studies. Cell Immunol 58:269–276, 1981Google Scholar
  51. 51.
    McCoy JL, Dean JH, Herberman R: Human cell-mediated immunity to tubercoline as assayed by the agarose microplet leukocyte migration inhibition technique: Comparison with the capillary tube assay. J Immunol Methods 15:353–371, 1977Google Scholar
  52. 52.
    Clausen JE: Tubercoline-induced migration inhibition of human peripheral leukocytes in agarose medium. Acta Allerg 26:56–63, 1971Google Scholar
  53. 53.
    Bendixen G, Bendtzen K, Clausen JE, Kajer M, Söborg M: Human leukocyte migration inhibition. Scand J Immunol Suppl 5:175–185, 1976Google Scholar
  54. 54.
    Szigeti R, Stevens D, Ernberg I, Klein G, Masucci MG, Svedmyr E, Klein E: Use of cryopreserved lymphocytes for the indirect leukocyte migration inhibition assay. J Immunol Methods 46:269–276, 1981Google Scholar
  55. 55.
    Masucci MG, Szigeti R, Ernberg I, Björkholm M, Mellstedt H, Henle G, Henle W, Pearson G, Masucci G, Svedmyr E, Johansson B, Klein G: Cell-mediated immune reaction in three patients with lymphoproliferative disease in remission and abnormally high Epstein-Barr virus antibody titers. Cancer Res 41:4292–4301, 1981Google Scholar
  56. 56.
    Moss DJ, Wallace LE, Rickinson AB, Epstein MA: Cytotoxic T cell recognition of Epstein-Barr virus infected B cells. I. Specificity and HLA-restriction of effector cells reactivated in vitro. Eur J Immunol 11:686–693, 1981Google Scholar
  57. 57.
    Moss DJ, Rickinson AB, Pope JH: Long term T cell mediated immunity to Epstein-Barr virus in man. III. Activation of cytotoxic T cells in Virus infected leukocyte cultures. Int J Cancer 23:618–625, 1979Google Scholar
  58. 58.
    Thorley-Lawson DA, Chess L, Strominger JL: Suppression of in vitro Epstein-Barr virus infection, a new role for adult human T lymphocytes. J Exp Med 146:495–508, 1977Google Scholar
  59. 59.
    Gatti RD, Bick M, Tam CF, Medici M, Oxelius VA, Holland M, Goldstein ASL, Boder E: Ataxia-telangectasia: A multi-parameter analysis of eight families. Clin Immunol Immunopathol 23:501–516, 1982Google Scholar
  60. 60.
    Svedmyr E, Ernberg I, Seeley J, Weiland O, Masucci G, Tsukuda K, Szigeti R, Masucci MG, Blomgren H, Berthold W, Henle W, Klein G: Virologic immunologic and clinical observation on a patient during the incubation, acute and convalescent phases of infectious mononucleosis. Clin Immunol Immunopathol 30:437–450, 1984Google Scholar
  61. 61.
    Masucci MG, Szigeti R, Ernberg I, Masucci G, Klein G, Chessels J, Sieff C, Lie S, Glomstein A, Businco L, Henle G, Henle W, Pearson G, Sakamoto K, Purtilo DT: Cellular immune defects to Epstein-Barr virus determined antigens in young males. Cancer Res 41:4284–4291, 1981Google Scholar
  62. 62.
    Frizzera G, Hanto DW, Gajl-Peczalska K, Rosaj J, McKenna R, Sibley R, Holahan K, Lindquist L: Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 41:4262–4279, 1981Google Scholar
  63. 63.
    Weintraub J, Warnke RA: Lymphoma in cardiac allotransplant recipients: Clinical and histological features and immunological phenotype. Transplantation 33:347–351, 1982Google Scholar
  64. 64.
    Joncas J, Lapointe N, Gervais F, Leyritz M, Willis A: Unusual prevalence of antibodies to Epstein-Barr virus early antigen in ataxia-telangectasia. Lancet 1:1160, 1977Google Scholar

Copyright information

© Plenum Publishing Corporation 1984

Authors and Affiliations

  • Giuseppe Masucci
    • 1
  • Izzet Berkel
    • 2
  • Maria Grazia Masucci
    • 1
  • Ingemar Ernberg
    • 1
  • Robert Szigeti
    • 1
  • Fugen Ersoy
    • 2
  • Özden Sanal
    • 2
  • Olcay Yegin
    • 2
  • Gertrude Henle
    • 3
    • 4
  • Werner Henle
    • 3
    • 4
  • Gary Pearson
    • 5
  • Pierre Åman
    • 1
  • George Klein
    • 1
  1. 1.Department of Tumor BiologyKarolinska InstitutetStockholmSweden
  2. 2.Institute of Child HealthHacettepe University, HacettepeAnkaraTurkey
  3. 3.The Joseph Stokes, Jr., Research InstituteThe Children Hospital of PhiladelphraPhiladelphia
  4. 4.School of MedicineUniversity of PennsylvaniaPhiladelphia
  5. 5.Mayo ClinicSection of Microbiology Rochester

Personalised recommendations