Journal of Clinical Immunology

, Volume 13, Issue 1, pp 30–40 | Cite as

Lymphocyte phenotype and function in the chronic fatigue syndrome

  • Stephen E. Straus
  • Scott Fritz
  • Janet K. Dale
  • Barbara Gould
  • Warren Strober
Original Articles


Lymphocytes of 18 patients meeting the Centers for Disease Control (CDC) case definition for the chronic fatigue syndrome (CFS), 10 similar, chronically fatigued patients not fully conforming to the CDC case definition, and 17 matched, healthy individuals were studied to determine the presence of abnormalities of peripheral cell phenotype and function. Extensive phenotypic analyses of B- and T-cell subsets, natural killer (NK) cells, and macrophages were performed using single-, dual-, and three-color flow cytometry. Compared to controls, in CFS patients the percentage of CD4 T cells and CD4, CD45RA, or naive T cells, was reduced. The CD4, CD45RO, or memory T-cell, subset was numerically normal but expressed increased levels of adhesion markers (CD29, CD54, and CD58). CFS patient lymphocytes showed reduced proliferative responses to phytohemagglutinin, concanavalin A, and staphylococcal enterotoxin B. Lymphocytes from fatigue patients not meeting the CDC definition showed similar abnormalities. These data indicate that peripheral T cells manifest an increased state of differentiation in CFS and related conditions. This may arise as a consequence of an underlying neuropsychiatric and/or neuroendocrine disorder or because of exposure to antigens or superantigens of an infectious agent.

Key words

Chronic fatigue syndrome CD45RA/RO proliferative responses T-cell subsets 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Schluederberg A, Straus SE, Grufferman S (eds): Considerations in the design of studies of chronic fatigue syndrome. Rev Infect Dis 13:Suppl 1, 1991Google Scholar
  2. 2.
    Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, DuBois RE, Cunningham-Rundles C, Pahwa S, Tosato G, Zegans LS, Purtilo DT, Brown N, Schooley RT, Brus I: Chronic fatigue syndrome: A working case definition. Ann Intern Med 108:387–389, 1988Google Scholar
  3. 3.
    Komaroff AL, Straus SE, Gantz NM, Jones JF: The chronic fatigue syndrome (Letter to the Editor). Ann Intern Med 110:407–408, 1989Google Scholar
  4. 4.
    Tobi M, Morag A, Ravid Z, Showers 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 9:61–64, 1982Google Scholar
  5. 5.
    DuBois RE, Seeley JK, Brus I, Sakamoto K, Ballow M, Harada S, Bechtold TA, Pearson G, Purtilo DT: Chronic mononucleosis syndrome. South Med J 77:1376–1382, 1984Google Scholar
  6. 6.
    Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein J, Brus I, Blaese RM: Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 102:7–16, 1985Google Scholar
  7. 7.
    Salit IE: Sporadic postinfectious neuromyasthenia. Can Med Assoc J 133:659–663, 1985Google Scholar
  8. 8.
    Manu P, Lane TJ, Matthews DA: The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 109:554–556, 1988Google Scholar
  9. 9.
    Gold D, Bowden R, Sixbey J, Riggs R, Katon WJ, Ashley R, Obrigewitch R, Corey L: Chronic fatigue. A prospective clinical and virologic study. JAMA 264:48–53, 1990Google Scholar
  10. 10.
    Straus SE: History of chronic fatigue syndrome. Rev Infect Dis 13 (Suppl 1):S2-S7, 1991Google Scholar
  11. 11.
    Swartz MN: The chronic fatigue syndrome—one entity or many? N Engl J Med 319:1726–1728, 1988Google Scholar
  12. 12.
    White P: Fatigue syndrome: Neurasthenia revived. Psychiatric illnesses are worth considering. Br Med J 298:1199–1200, 1989Google Scholar
  13. 13.
    Behan PO, Behan WMH: Postviral fatigue syndrome. Crit Rev Neurobiol 4:157–178, 1988Google Scholar
  14. 14.
    Barnes DM: Mystery disease at Lake Tahoe challenges virologists and clinicians. Science 234:541–542, 1986Google Scholar
  15. 15.
    Straus SE: EB or not EB—that is the question. JAMA 257:2335–2336, 1987Google Scholar
  16. 16.
    Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO: Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: Elevated anti-early antigen antibodies. Ann Intern Med 102:1–7, 1985Google Scholar
  17. 17.
    Jones JF: Epstein-Barr virus and the chronic fatigue syndrome: A short review. Microbiol Sci 5:366–373, 1988Google Scholar
  18. 18.
    DeFreitas E, Hilliard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H: Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA 88:2922–2926, 1991Google Scholar
  19. 19.
    Tosato G, Straus S, Henle W, Pike SE, Blaese RM: Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic infectious mononucleosis). J Immunol 134:3082–3088, 1985Google Scholar
  20. 20.
    Kibler R, Lucas DO, Hicks MJ, Poulos BT, Jones JF: Immune function in chronic active Epstein-Barr virus infection. J Clin Immunol 5:46–54, 1985Google Scholar
  21. 21.
    Caligiuri M, Murray C, Buchwald D, Levine H, Cheny P, Peterson D, Komaroff AL, Ritz J: Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol 139:3306–3313, 1987Google Scholar
  22. 22.
    Lloyd AR, Wakefield D, Boughton CR, Dwyer JM: Immunological abnormalities in the chronic fatigue syndrome. Med J Aust 151:122–124, 1989Google Scholar
  23. 23.
    Klimas NG, Salvato FR, Morgan R, Fletcher MA: Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 28:1403–1410, 1990Google Scholar
  24. 24.
    Jones JF: Serologic and immunologic responses in chronic fatigue syndrome with emphasis on the Epstein-Barr virus. Rev Infect Dis 13 (Suppl 1):S26-S32, 1991Google Scholar
  25. 25.
    Straus SE, Dale JK, Tobi M, Lawley T, Preble O, Blaese RM, Hallahan C, Henle W: Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial. N Engl J Med 319:1692–1698, 1988Google Scholar
  26. 26.
    Buchwald D, Komaroff AL: Review of laboratory findings for patients with chronic fatigue syndrome. Rev Infect Dis 13 (Suppl 1):S12-S18, 1991Google Scholar
  27. 27.
    Komaroff AL, Geiger AM, Wormsely S: IgG subclass deficiencies in chronic fatigue syndrome. Lancet 1:1288–1289, 1988Google Scholar
  28. 28.
    Gin W, Christiansen FT, Peter JB: Immune function and the chronic fatigue syndrome. Med J Aust 151:117–118, 1989Google Scholar
  29. 29.
    Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J: A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med 89:561–568, 1990Google Scholar
  30. 30.
    Peterson PK, Shepard J, Macres M, Schenck C, Crosson J, Rechtman D, Lurie N: A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Am J Med 89:554–560, 1990Google Scholar
  31. 31.
    Cheney PR, Dorman SE, Bell DS: Interleukin-2 and the chronic fatigue syndrome. Ann Intern Med 110:321, 1989Google Scholar
  32. 32.
    Straus SE, Dale JK, Peter JB, Dinarello CA: Circulating lymphokine levels in the chronic fatigue syndrome. J Infect Dis 160:1085–1086, 1989Google Scholar
  33. 33.
    Chao CC, Gallagher M, Phair J, Peterson PK: Serum neopterin and interleukin-6 levels in chronic fatigue syndrome. J Infect Dis 162:1412–1413, 1990Google Scholar
  34. 34.
    Chao CC, Janoff EN, Hu S, Thomas K, Gallagher M, Tsang M, Peterson PK: Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine 3:292–298, 1991Google Scholar
  35. 35.
    Landay AL, Jessop C, Lennette ET, Levy JA: Chronic fatigue syndrome: Clinical condition associated with immune activation. Lancet 338:707–712, 1991Google Scholar
  36. 36.
    Rose NR, Friedman H, Fahey JL: Manual of Clinical Laboratory Immunology, 3rd ed. Washington, DC, American Society for Microbiology, 1986, pp 274–281Google Scholar
  37. 37.
    Gupta S, Vayuvegula B: A comprehensive immunological analysis in chronic fatigue syndrome. Scand J Immunol 33:319–327, 1991Google Scholar
  38. 38.
    Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP, Chrousos GP, Gold PW: Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome. J Clin Endocrinol Metab 73:1224–1234, 1991Google Scholar
  39. 39.
    Sanders ME, Malegapuru W, Makgobo MW, Shaw S: Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets. Immunol Today 9:195–199, 1988Google Scholar
  40. 40.
    Streuli M, Hall LR, Saga Y, Schlossman SF, Saito H: Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens. J Exp Med 166:1548–1566, 1987Google Scholar
  41. 41.
    Seldin MF, Morse HC, LeBoeuf RC, Steinberg AD: Establishment of a molecular genetic map of distal mouse chromosome 1: Further definition of a conserved linkage group syntenic with human chromosome 1q. Genomics 2:41–56, 1988Google Scholar
  42. 42.
    Thomas ML: The leukocyte common antigen family. Annu Rev Immunol 7:339–369, 1989Google Scholar
  43. 43.
    Tonks NK, Charbonneau H, Diltz CD, Fischer EH, Walsh KA: Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase. Biochemistry 27:8698–8701, 1988Google Scholar
  44. 44.
    Tedder TF, Cooper MD, Clement LT: Human lymphocytic differentiation antigens HB-10 and HB-11. II. Differential production of B cell growth and differentiation factors by distinct helper T cell subpopulations. J Immunol 134:2989–2994, 1985Google Scholar
  45. 45.
    Akbar A, Terry L, Timms A, Beverley PCL, Janossy G: Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol 140:2171–2178, 1988Google Scholar
  46. 46.
    Clement LT, Yamoshita N, Martin AM: The functionally distinct subpopulations of human CD4+ helper/inducer T lymphocytes defined by anti-CD45R antibodies derive sequentially from a differentiation pathway that is regulated by activation-dependent post-thymic differentiation. J Immunol 141:1464–1470, 1988Google Scholar
  47. 47.
    Morimoto C, Letvin NL, Distaso JA, Aldrich WR, Schlossman SF: The isolation and characterization of the human suppressor inducer T cell subset. J Immunol 134:1508–1515, 1985Google Scholar
  48. 48.
    Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young JA, Shaw S: Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-γ production. J Immunol 140:1401–1407, 1988Google Scholar
  49. 49.
    Schleifer SJ, Keller SE, Meyerson AT, Raskin MJ, Davis KL, Stein M: Lymphocyte function in major depressive disorder. Arch Gen Psych 41:484–486, 1984Google Scholar
  50. 50.
    Denney DI, Stephenson LA, Penick EC, Weller RA: Lymphocyte subclasses and depression. J Abnorm Psychol 97:499–502, 1988Google Scholar
  51. 51.
    Maes M, Lambrechts J, Bosmans E, Jacobs J, Suy E, Vandervorst C, De Jonckheere C, Minner B, Raus J: Evidence for a systemic immune activation during depression: Results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med 22:45–53, 1992Google Scholar
  52. 52.
    Joseph-Vanderpool JR, Rosenthal NE, Chrousos GP, Wehr TA, Skwerer R, Kasper S, Gold PW: Abnormal pituitary-adrenal responses to oCRH in patients with seasonal affective disorder. Clinical and pathophysiological implications. J Clin Endocrin Metab 72:1382–1387, 1991Google Scholar
  53. 53.
    Kling MA, Roy A, Doran AR,et al.: Cerebrospinal fluid immunoreactive CRH and ACTH secretion in Cushing's disease and major depression: Potential clinical implications. J Clin Endocrin Metab 72:260–271, 1991Google Scholar
  54. 54.
    Kamilaris TC, DeBold CR, Pavlou SN, Island DP, Hoursandis A, Orth DN: Effect of altered thyroid hormone levels on hypothalamic-pituitary-adrenal function. J Clin Endocrin Metab 65:994–999, 1987Google Scholar

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Stephen E. Straus
    • 1
  • Scott Fritz
    • 3
  • Janet K. Dale
    • 1
  • Barbara Gould
    • 3
  • Warren Strober
    • 2
  1. 1.Medical Virology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesda
  2. 2.Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesda
  3. 3.Clinical Immunology Services, Program Resources Inc./DynCorpNational Cancer Institute, Frederick Cancer Research and Development CenterFrederick
  4. 4.Laboratory of Clinical Investigation/NIAIDNational Institutes of HealthBethesda

Personalised recommendations