Skip to main content
NCBI home page
Journal of Clinical Microbiology logoLink to Journal of Clinical Microbiology
. 1990 Jun;28(6):1403–1410. doi: 10.1128/jcm.28.6.1403-1410.1990

Immunologic abnormalities in chronic fatigue syndrome.

N G Klimas 1, F R Salvato 1, R Morgan 1, M A Fletcher 1
PMCID: PMC267940  PMID: 2166084

Abstract

The chronic fatigue syndrome (CFS), formerly known as chronic Epstein-Barr virus syndrome, is a clinical state of some complexity and uncertain etiology. In order to characterize in a comprehensive manner the status of laboratory markers associated with cellular immune function in patients with this syndrome, 30 patients with clinically defined CFS were studied. All of the subjects were found to have multiple abnormalities in these markers. The most consistent immunological abnormality detected among these patients, when compared with normal controls, was low natural killer (NK) cell cytotoxicity. The number of NK cells, as defined by reactivity with monoclonal antibody NKH.1 (CD56), was elevated, but the killing of K562 tumor cells per CD56 cell was significantly diminished. Lymphoproliferative responses after stimulation with phytohemagglutinin and pokeweed mitogen were decreased in most patients when compared with those in normal controls, as was the production of gamma interferon following mitogen stimulation. Lymphocyte phenotypic marker analysis of peripheral blood lymphocytes showed that there were significant differences between patients with CFS and controls. There was an increase in the percentage of suppressor-cytotoxic T lymphocytes, CD8, and a proportionally larger increase in the number of CD8 cells expressing the class II activation marker. Most patients had an elevated number of CD2 cells which expressed the activation marker CDw26. The numbers of CD4 cells and the helper subset of CD4+CD29+ cells in patients with CFS were not different from those in controls. There was, however, a significant decrease in the suppressor inducer subset of CD4+ CD45RA+ cells. The number of B cells, CD20 and CD21, were elevated, as were the numbers of a subset of B cells which coexpressed CD20 and CD5. The patterns of immune marker abnormalities observed was compatible with a chronic viral reactivation syndrome.

Full text

PDF
1403

Selected References

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

  1. Abruzzo L. V., Rowley D. A. Homeostasis of the antibody response: immunoregulation by NK cells. Science. 1983 Nov 11;222(4624):581–585. doi: 10.1126/science.6685343. [DOI] [PubMed] [Google Scholar]
  2. Alpert S. D., Koide J., Takada S., Engleman E. G. T cell regulatory disturbances in the rheumatic diseases. Rheum Dis Clin North Am. 1987 Dec;13(3):431–445. [PubMed] [Google Scholar]
  3. Baron G. C., Klimas N. G., Fischl M. A., Fletcher M. A. Decreased natural cell-mediated cytotoxicity per effector cell in acquired immunodeficiency syndrome. Diagn Immunol. 1985;3(4):197–204. [PubMed] [Google Scholar]
  4. Borysiewicz L. K., Haworth S. J., Cohen J., Mundin J., Rickinson A., Sissons J. G. Epstein Barr virus-specific immune defects in patients with persistent symptoms following infectious mononucleosis. Q J Med. 1986 Feb;58(226):111–121. [PubMed] [Google Scholar]
  5. Buchwald D., Sullivan J. L., Komaroff A. L. Frequency of 'chronic active Epstein-Barr virus infection' in a general medical practice. JAMA. 1987 May 1;257(17):2303–2307. [PubMed] [Google Scholar]
  6. Caligiuri M., Murray C., Buchwald D., Levine H., Cheney P., Peterson D., Komaroff A. L., Ritz J. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol. 1987 Nov 15;139(10):3306–3313. [PubMed] [Google Scholar]
  7. Callewaert D. M., Johnson D. F., Kearney J. Spontaneous cytotoxicity of cultured human cell lines mediated by normal peripheral blood lymphocytes. III. Kinetic parameters. J Immunol. 1978 Aug;121(2):710–717. [PubMed] [Google Scholar]
  8. Cleland W. W. The statistical analysis of enzyme kinetic data. Adv Enzymol Relat Areas Mol Biol. 1967;29:1–32. doi: 10.1002/9780470122747.ch1. [DOI] [PubMed] [Google Scholar]
  9. Emery P., Gentry K. C., Mackay I. R., Muirden K. D., Rowley M. Deficiency of the suppressor inducer subset of T lymphocytes in rheumatoid arthritis. Arthritis Rheum. 1987 Aug;30(8):849–856. doi: 10.1002/art.1780300802. [DOI] [PubMed] [Google Scholar]
  10. Fletcher M. A., Azen S. P., Adelsberg B., Gjerset G., Hassett J., Kaplan J., Niland J. C., Odom-Maryon T., Parker J. W., Stites D. P. Immunophenotyping in a multicenter study: the Transfusion Safety Study experience. Clin Immunol Immunopathol. 1989 Jul;52(1):38–47. doi: 10.1016/0090-1229(89)90191-8. [DOI] [PubMed] [Google Scholar]
  11. Fletcher M. A., Baron G. C., Ashman M. R., Fischl M. A., Klimas N. G. Use of whole blood methods in assessment of immune parameters in immunodeficiency states. Diagn Clin Immunol. 1987;5(2):69–81. [PubMed] [Google Scholar]
  12. Fox D. A., Hussey R. E., Fitzgerald K. A., Acuto O., Poole C., Palley L., Daley J. F., Schlossman S. F., Reinherz E. L. Ta1, a novel 105 KD human T cell activation antigen defined by a monoclonal antibody. J Immunol. 1984 Sep;133(3):1250–1256. [PubMed] [Google Scholar]
  13. Franco E., Kawa-Ha K., Doi S., Yumura K., Murata M., Ishihara S., Tawa A., Yabuuchi H. Remarkable depression of CD4+2H4+ T cells in severe chronic active Epstein-Barr virus infection. Scand J Immunol. 1987 Dec;26(6):769–773. doi: 10.1111/j.1365-3083.1987.tb02315.x. [DOI] [PubMed] [Google Scholar]
  14. Gottschalk L. A., Welch W. D., Weiss J. Vulnerability and immune response. An overview. Psychother Psychosom. 1983;39(1):23–35. doi: 10.1159/000287718. [DOI] [PubMed] [Google Scholar]
  15. Hafler D. A., Fox D. A., Manning M. E., Schlossman S. F., Reinherz E. L., Weiner H. L. In vivo activated T lymphocytes in the peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. N Engl J Med. 1985 May 30;312(22):1405–1411. doi: 10.1056/NEJM198505303122201. [DOI] [PubMed] [Google Scholar]
  16. Hayakawa K., Hardy R. R., Honda M., Herzenberg L. A., Steinberg A. D., Herzenberg L. A. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2494–2498. doi: 10.1073/pnas.81.8.2494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hellinger W. C., Smith T. F., Van Scoy R. E., Spitzer P. G., Forgacs P., Edson R. S. Chronic fatigue syndrome and the diagnostic utility of antibody to Epstein-Barr virus early antigen. JAMA. 1988 Aug 19;260(7):971–973. [PubMed] [Google Scholar]
  18. Henle W., Henle G. E., Horwitz C. A. Epstein-Barr virus specific diagnostic tests in infectious mononucleosis. Hum Pathol. 1974 Sep;5(5):551–565. doi: 10.1016/s0046-8177(74)80006-7. [DOI] [PubMed] [Google Scholar]
  19. Hercend T., Griffin J. D., Bensussan A., Schmidt R. E., Edson M. A., Brennan A., Murray C., Daley J. F., Schlossman S. F., Ritz J. Generation of monoclonal antibodies to a human natural killer clone. Characterization of two natural killer-associated antigens, NKH1A and NKH2, expressed on subsets of large granular lymphocytes. J Clin Invest. 1985 Mar;75(3):932–943. doi: 10.1172/JCI111794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Holmes G. P., Kaplan J. E., Gantz N. M., Komaroff A. L., Schonberger L. B., Straus S. E., Jones J. F., Dubois R. E., Cunningham-Rundles C., Pahwa S. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988 Mar;108(3):387–389. doi: 10.7326/0003-4819-108-3-387. [DOI] [PubMed] [Google Scholar]
  21. Holmes G. P., Kaplan J. E., Stewart J. A., Hunt B., Pinsky P. F., Schonberger L. B. A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause? JAMA. 1987 May 1;257(17):2297–2302. [PubMed] [Google Scholar]
  22. Janeway C. A., Jr, Carding S., Jones B., Murray J., Portoles P., Rasmussen R., Rojo J., Saizawa K., West J., Bottomly K. CD4+ T cells: specificity and function. Immunol Rev. 1988 Jan;101:39–80. doi: 10.1111/j.1600-065x.1988.tb00732.x. [DOI] [PubMed] [Google Scholar]
  23. Jones J. F., Ray C. G., Minnich L. L., Hicks M. J., Kibler R., Lucas D. O. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. 1985 Jan;102(1):1–7. doi: 10.7326/0003-4819-102-1-. [DOI] [PubMed] [Google Scholar]
  24. Jones J. F., Straus S. E. Chronic Epstein-Barr virus infection. Annu Rev Med. 1987;38:195–209. doi: 10.1146/annurev.me.38.020187.001211. [DOI] [PubMed] [Google Scholar]
  25. Kibler R., Lucas D. O., Hicks M. J., Poulos B. T., Jones J. F. Immune function in chronic active Epstein-Barr virus infection. J Clin Immunol. 1985 Jan;5(1):46–54. doi: 10.1007/BF00915168. [DOI] [PubMed] [Google Scholar]
  26. Kruesi M. J., Dale J., Straus S. E. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry. 1989 Feb;50(2):53–56. [PubMed] [Google Scholar]
  27. Ledbetter J. A., Rose L. M., Spooner C. E., Beatty P. G., Martin P. J., Clark E. A. Antibodies to common leukocyte antigen p220 influence human T cell proliferation by modifying IL 2 receptor expression. J Immunol. 1985 Sep;135(3):1819–1825. [PubMed] [Google Scholar]
  28. Mangi R. J., Niederman J. C., Kelleher J. E., Jr, Dwyer J. M., Evans A. S., Kantor F. S. Depression of cell-mediated immunity during acute infectious mononucleosis. N Engl J Med. 1974 Nov 28;291(22):1149–1153. doi: 10.1056/NEJM197411282912202. [DOI] [PubMed] [Google Scholar]
  29. Masucci M. G., Bejarano M. T., Masucci G., Klein E. Large granular lymphocytes inhibit the in vitro growth of autologous Epstein-Barr virus-infected B cells. Cell Immunol. 1983 Mar;76(2):311–321. doi: 10.1016/0008-8749(83)90374-x. [DOI] [PubMed] [Google Scholar]
  30. Morimoto C., Letvin N. L., Boyd A. W., Hagan M., Brown H. M., Kornacki M. M., Schlossman S. F. The isolation and characterization of the human helper inducer T cell subset. J Immunol. 1985 Jun;134(6):3762–3769. [PubMed] [Google Scholar]
  31. Morimoto C., Steinberg A. D., Letvin N. L., Hagan M., Takeuchi T., Daley J., Levine H., Schlossman S. F. A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody. J Clin Invest. 1987 Mar;79(3):762–768. doi: 10.1172/JCI112882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Niederman J. C., Liu C. R., Kaplan M. H., Brown N. A. Clinical and serological features of human herpesvirus-6 infection in three adults. Lancet. 1988 Oct 8;2(8615):817–819. doi: 10.1016/s0140-6736(88)92783-3. [DOI] [PubMed] [Google Scholar]
  33. Okano M., Thiele G. M., Davis J. R., Nauseef W. M., Mitros F., Purtilo D. T. Adenovirus type-2 in a patient with lethal hemorrhagic colonic ulcers and chronic active Epstein-Barr virus infection. Ann Intern Med. 1988 May;108(5):693–699. doi: 10.7326/0003-4819-108-5-693. [DOI] [PubMed] [Google Scholar]
  34. Reinherz E. L., Kung P. C., Goldstein G., Schlossman S. F. A monoclonal antibody reactive with the human cytotoxic/suppressor T cell subset previously defined by a heteroantiserum termed TH2. J Immunol. 1980 Mar;124(3):1301–1307. [PubMed] [Google Scholar]
  35. Reinherz E. L., Kung P. C., Goldstein G., Schlossman S. F. Separation of functional subsets of human T cells by a monoclonal antibody. Proc Natl Acad Sci U S A. 1979 Aug;76(8):4061–4065. doi: 10.1073/pnas.76.8.4061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Reinherz E. L., Kung P. C., Pesando J. M., Ritz J., Goldstein G., Schlossman S. F. Ia determinants on human T-cell subsets defined by monoclonal antibody. Activation stimuli required for expression. J Exp Med. 1979 Dec 1;150(6):1472–1482. doi: 10.1084/jem.150.6.1472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rose L. M., Ginsberg A. H., Rothstein T. L., Ledbetter J. A., Clark E. A. Fluctuations of CD4+ T-cell subsets in remitting-relapsing multiple sclerosis. Ann Neurol. 1988 Aug;24(2):192–199. doi: 10.1002/ana.410240204. [DOI] [PubMed] [Google Scholar]
  38. Rose L. M., Ginsberg A. H., Rothstein T. L., Ledbetter J. A., Clark E. A. Selective loss of a subset of T helper cells in active multiple sclerosis. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7389–7393. doi: 10.1073/pnas.82.21.7389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sato K., Miyasaka N., Yamaoka K., Okuda M., Yata J., Nishioka K. Quantitative defect of CD4+2H4+ cells in systemic lupus erythematosus and Sjögren's syndrome. Arthritis Rheum. 1987 Dec;30(12):1407–1411. doi: 10.1002/art.1780301212. [DOI] [PubMed] [Google Scholar]
  40. Schattner A., Wallach D., Merlin G., Hahn T., Levin S., Revel M. Assay of an interferon-induced enzyme in white blood cells as a diagnostic aid in viral diseases. Lancet. 1981 Sep 5;2(8245):497–500. doi: 10.1016/s0140-6736(81)90883-7. [DOI] [PubMed] [Google Scholar]
  41. Schleifer S. J., Keller S. E., Meyerson A. T., Raskin M. J., Davis K. L., Stein M. Lymphocyte function in major depressive disorder. Arch Gen Psychiatry. 1984 May;41(5):484–486. doi: 10.1001/archpsyc.1984.01790160070008. [DOI] [PubMed] [Google Scholar]
  42. Spinozzi F., Guerciolini R., Gerli R., Gernini I., Rondoni F., Frascarelli A., Rambotti P., Grignani F., Davis S. Immunological studies in patients with alcoholic liver disease: evidence for the in vivo activation of helper T cells and of the monocyte-macrophage system. Int Arch Allergy Appl Immunol. 1986;80(4):361–368. doi: 10.1159/000234082. [DOI] [PubMed] [Google Scholar]
  43. Stashenko P., Nadler L. M., Hardy R., Schlossman S. F. Characterization of a human B lymphocyte-specific antigen. J Immunol. 1980 Oct;125(4):1678–1685. [PubMed] [Google Scholar]
  44. Straus S. E. The chronic mononucleosis syndrome. J Infect Dis. 1988 Mar;157(3):405–412. doi: 10.1093/infdis/157.3.405. [DOI] [PubMed] [Google Scholar]
  45. Straus S. E., Tosato G., Armstrong G., Lawley T., Preble O. T., Henle W., Davey R., Pearson G., Epstein J., Brus I. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med. 1985 Jan;102(1):7–16. doi: 10.7326/0003-4819-102-1-7. [DOI] [PubMed] [Google Scholar]
  46. Targan S., Stebbing N. In vitro interactions of purified cloned human interferons on NK cells: enhanced activation. J Immunol. 1982 Sep;129(3):934–935. [PubMed] [Google Scholar]
  47. Tobi M., Morag A., Ravid Z., Chowers I., Feldman-Weiss V., Michaeli Y., Ben-Chetrit E., Shalit M., Knobler H. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet. 1982 Jan 9;1(8263):61–64. doi: 10.1016/s0140-6736(82)90210-0. [DOI] [PubMed] [Google Scholar]
  48. Tosato G., Straus S., Henle W., Pike S. E., Blaese R. M. Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic infectious mononucleosis). J Immunol. 1985 May;134(5):3082–3088. [PubMed] [Google Scholar]
  49. Zlotnik A., Shimonkevitz R. P., Gefter M. L., Kappler J., Marrack P. Characterization of the gamma-interferon-mediated induction of antigen-presenting ability in P388D1 cells. J Immunol. 1983 Dec;131(6):2814–2820. [PubMed] [Google Scholar]
  50. Zwick R. Nonparametric one-way multivariate analysis of variance: a computational approach based on the Pillai-Bartlett trace. Psychol Bull. 1985 Jan;97(1):148–152. [PubMed] [Google Scholar]

Articles from Journal of Clinical Microbiology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES