Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2004 Jun;112(8):840–846. doi: 10.1289/ehp.6881

Cellular and humoral immune abnormalities in Gulf War veterans.

Aristo Vojdani 1, Jack D Thrasher 1
PMCID: PMC1242010  PMID: 15175170

Abstract

We examined 100 symptomatic Gulf War veterans (patients) and 100 controls for immunologic assays. The veterans and controls were compared for the percentage of T cells (CD3); B cells (CD19); helper:suppressor (CD4:CD8) ratio; natural killer (NK) cell activity; mitogenic response to phytohemagglutin (PHA) and pokeweed mitogen (PWM); level of immune complexes; myelin basic protein (MBP) and striated and smooth muscle autoantibodies; and antibodies against Epstein-Barr virus, cytomegalovirus, herpes simplex virus type 1 (HSV-1), HSV-2, human herpes Type 6 (HHV-6), and Varicella zoster virus (VZV). The percentage of T cells in patients versus controls was not significantly different, whereas a significantly higher proportion of patients had elevated T cells compared with controls. The percentage of B cells was significantly elevated in the patients versus the controls. The NK cell (NK) activity was significantly decreased in the patients (24.8 +/- 16.5 lytic units) versus the controls (37.3 +/- 26.4 lytic units). The percentage of patients with lower than normal response to PHA and PWM was significantly different from controls. Immune complexes were significantly increased in the patients (53.1 +/- 18.6, mean +/- SD) versus controls (34.6 +/- 14.3). Autoantibody titers directed against MBP and striated or smooth muscle were significantly greater in patients versus controls. Finally, the patients had significantly greater titers of antibodies to the viruses compared with the controls (p < 0.001). These immune alterations were detected 2-8 years after participation in the Gulf War. The immune alterations are consistent with exposure to different environmental factors. We conclude that Gulf War syndrome is a multifaceted illness with immune function alterations that may be induced by various factors and are probably associated with chronic fatigue syndrome.

Full Text

The Full Text of this article is available as a PDF (145.2 KB).

Selected References

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

  1. Abou-Donia M. B., Goldstein L. B., Jones K. H., Abdel-Rahman A. A., Damodaran T. V., Dechkovskaia A. M., Bullman S. L., Amir B. E., Khan W. A. Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination. Toxicol Sci. 2001 Apr;60(2):305–314. doi: 10.1093/toxsci/60.2.305. [DOI] [PubMed] [Google Scholar]
  2. Babcock G. F., Taylor A. F., Hynd B. A., Sramkoski R. M., Alexander J. W. Flow cytometric analysis of lymphocyte subset phenotypes comparing normal children and adults. Diagn Clin Immunol. 1987;5(4):175–179. [PubMed] [Google Scholar]
  3. Baj Z., Majewska E., Zeman K., Pokoca L., Dworniak D., Paradowski M., Tchórzewski H. The effect of chronic exposure to formaldehyde, phenol and organic chlorohydrocarbons on peripheral blood cells and the immune system in humans. J Investig Allergol Clin Immunol. 1994 Jul-Aug;4(4):186–191. [PubMed] [Google Scholar]
  4. Cherry N., Creed F., Silman A., Dunn G., Baxter D., Smedley J., Taylor S., Macfarlane G. J. Health and exposures of United Kingdom Gulf war veterans. Part I: The pattern and extent of ill health. Occup Environ Med. 2001 May;58(5):291–298. doi: 10.1136/oem.58.5.291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Christenson B., Böttiger M., Svensson A., Jeansson S. A 15-year surveillance study of antibodies to herpes simplex virus types 1 and 2 in a cohort of young girls. J Infect. 1992 Sep;25(2):147–154. doi: 10.1016/0163-4453(92)93943-k. [DOI] [PubMed] [Google Scholar]
  6. Cooper Glinda S., Miller Frederick W., Germolec Dori R. Occupational exposures and autoimmune diseases. Int Immunopharmacol. 2002 Feb;2(2-3):303–313. doi: 10.1016/s1567-5769(01)00181-3. [DOI] [PubMed] [Google Scholar]
  7. Deibler G. E., Martenson R. E., Kies M. W. Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem. 1972;2(2):139–165. doi: 10.1080/00327487208061467. [DOI] [PubMed] [Google Scholar]
  8. Ferguson E., Cassaday H. J. Theoretical accounts of Gulf War Syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration. Behav Neurol. 2001;13(3-4):133–147. doi: 10.1155/2002/418758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gray Gregory C., Reed Robert J., Kaiser Kevin S., Smith Tyler C., Gastañaga Victor M. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: the Seabee Health Study. Am J Epidemiol. 2002 Jun 1;155(11):1033–1044. doi: 10.1093/aje/155.11.1033. [DOI] [PubMed] [Google Scholar]
  10. Griem P., Wulferink M., Sachs B., González J. B., Gleichmann E. Allergic and autoimmune reactions to xenobiotics: how do they arise? Immunol Today. 1998 Mar;19(3):133–141. doi: 10.1016/s0167-5699(97)01219-x. [DOI] [PubMed] [Google Scholar]
  11. Haley R. W., Billecke S., La Du B. N. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol. 1999 Jun 15;157(3):227–233. doi: 10.1006/taap.1999.8703. [DOI] [PubMed] [Google Scholar]
  12. Haley R. W., Kurt T. L. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. JAMA. 1997 Jan 15;277(3):231–237. [PubMed] [Google Scholar]
  13. Haley R. W., Marshall W. W., McDonald G. G., Daugherty M. A., Petty F., Fleckenstein J. L. Brain abnormalities in Gulf War syndrome: evaluation with 1H MR spectroscopy. Radiology. 2000 Jun;215(3):807–817. doi: 10.1148/radiology.215.3.r00jn48807. [DOI] [PubMed] [Google Scholar]
  14. Haley Robert W. Excess incidence of ALS in young Gulf War veterans. Neurology. 2003 Sep 23;61(6):750–756. doi: 10.1212/wnl.61.6.750. [DOI] [PubMed] [Google Scholar]
  15. Hallman William K., Kipen Howard M., Diefenbach Michael, Boyd Kendal, Kang Han, Leventhal Howard, Wartenberg Daniel. Symptom patterns among Gulf War registry veterans. Am J Public Health. 2003 Apr;93(4):624–630. doi: 10.2105/ajph.93.4.624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Heuser G., Vojdani A. Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C. Immunopharmacol Immunotoxicol. 1997 Aug;19(3):291–312. doi: 10.3109/08923979709046977. [DOI] [PubMed] [Google Scholar]
  17. Horner R. D., Kamins K. G., Feussner J. R., Grambow S. C., Hoff-Lindquist J., Harati Y., Mitsumoto H., Pascuzzi R., Spencer P. S., Tim R. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003 Sep 23;61(6):742–749. doi: 10.1212/01.wnl.0000069922.32557.ca. [DOI] [PubMed] [Google Scholar]
  18. Imai K., Matsuyama S., Miyake S., Suga K., Nakachi K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet. 2000 Nov 25;356(9244):1795–1799. doi: 10.1016/S0140-6736(00)03231-1. [DOI] [PubMed] [Google Scholar]
  19. Kang Han K., Mahan Clare M., Lee Kyung Y., Murphy Frances M., Simmens Samuel J., Young Heather A., Levine Paul H. Evidence for a deployment-related Gulf War syndrome by factor analysis. Arch Environ Health. 2002 Jan-Feb;57(1):61–68. doi: 10.1080/00039890209602918. [DOI] [PubMed] [Google Scholar]
  20. Kroenke K., Koslowe P., Roy M. Symptoms in 18,495 Persian Gulf War veterans. Latency of onset and lack of association with self-reported exposures. J Occup Environ Med. 1998 Jun;40(6):520–528. doi: 10.1097/00043764-199806000-00004. [DOI] [PubMed] [Google Scholar]
  21. Kurt T. L. Epidemiological association in US veterans between Gulf War illness and exposures to anticholinesterases. Toxicol Lett. 1998 Dec 28;102-103:523–526. doi: 10.1016/s0378-4274(98)00259-8. [DOI] [PubMed] [Google Scholar]
  22. La Du B. N., Billecke S., Hsu C., Haley R. W., Broomfield C. A. Serum paraoxonase (PON1) isozymes: the quantitative analysis of isozymes affecting individual sensitivity to environmental chemicals. Drug Metab Dispos. 2001 Apr;29(4 Pt 2):566–569. [PubMed] [Google Scholar]
  23. Lashof J. C., Cassells J. S. Illness among Gulf War veterans: risk factors, realities, and future research. JAMA. 1998 Sep 16;280(11):1010–1011. doi: 10.1001/jama.280.11.1010. [DOI] [PubMed] [Google Scholar]
  24. Levine P. H., Whiteside T. L., Friberg D., Bryant J., Colclough G., Herberman R. B. Dysfunction of natural killer activity in a family with chronic fatigue syndrome. Clin Immunol Immunopathol. 1998 Jul;88(1):96–104. doi: 10.1006/clin.1998.4554. [DOI] [PubMed] [Google Scholar]
  25. Loewenstein-Lichtenstein Y., Schwarz M., Glick D., Nørgaard-Pedersen B., Zakut H., Soreq H. Genetic predisposition to adverse consequences of anti-cholinesterases in 'atypical' BCHE carriers. Nat Med. 1995 Oct;1(10):1082–1085. doi: 10.1038/nm1095-1082. [DOI] [PubMed] [Google Scholar]
  26. Luster M. I., Munson A. E., Thomas P. T., Holsapple M. P., Fenters J. D., White K. L., Jr, Lauer L. D., Germolec D. R., Rosenthal G. J., Dean J. H. Development of a testing battery to assess chemical-induced immunotoxicity: National Toxicology Program's guidelines for immunotoxicity evaluation in mice. Fundam Appl Toxicol. 1988 Jan;10(1):2–19. doi: 10.1016/0272-0590(88)90247-3. [DOI] [PubMed] [Google Scholar]
  27. Luster M. I., Portier C., Pait D. G., Rosenthal G. J., Germolec D. R., Corsini E., Blaylock B. L., Pollock P., Kouchi Y., Craig W. Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests. Fundam Appl Toxicol. 1993 Jul;21(1):71–82. doi: 10.1006/faat.1993.1074. [DOI] [PubMed] [Google Scholar]
  28. Maino V. C., Suni M. A., Ruitenberg J. J. Rapid flow cytometric method for measuring lymphocyte subset activation. Cytometry. 1995 Jun 1;20(2):127–133. doi: 10.1002/cyto.990200205. [DOI] [PubMed] [Google Scholar]
  29. Matheson B. A., Chisholm S. M., Ho-Yen D. O. Assessment of rapid ELISA test for detection of Epstein-Barr virus infection. J Clin Pathol. 1990 Aug;43(8):691–693. doi: 10.1136/jcp.43.8.691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. McConnachie P. R., Zahalsky A. C. Immune alterations in humans exposed to the termiticide technical chlordane. Arch Environ Health. 1992 Jul-Aug;47(4):295–301. doi: 10.1080/00039896.1992.9938365. [DOI] [PubMed] [Google Scholar]
  31. McConnachie P. R., Zahalsky A. C. Immunological consequences of exposure to pentachlorophenol. Arch Environ Health. 1991 Jul-Aug;46(4):249–253. doi: 10.1080/00039896.1991.9937456. [DOI] [PubMed] [Google Scholar]
  32. Moss J. I. Many Gulf War illnesses may be autoimmune disorders caused by the chemical and biological stressors pyridostigmine bromide, and adrenaline. Med Hypotheses. 2001 Feb;56(2):155–157. doi: 10.1054/mehy.2000.1129. [DOI] [PubMed] [Google Scholar]
  34. Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y Acad Sci. 2001 Mar;933:185–200. doi: 10.1111/j.1749-6632.2001.tb05824.x. [DOI] [PubMed] [Google Scholar]
  35. Racciatti D., Vecchiet J., Ceccomancini A., Ricci F., Pizzigallo E. Chronic fatigue syndrome following a toxic exposure. Sci Total Environ. 2001 Apr 10;270(1-3):27–31. doi: 10.1016/s0048-9697(00)00777-4. [DOI] [PubMed] [Google Scholar]
  36. Rogers S. W., Twyman R. E., Gahring L. C. The role of autoimmunity to glutamate receptors in neurological disease. Mol Med Today. 1996 Feb;2(2):76–81. doi: 10.1016/1357-4310(96)88742-9. [DOI] [PubMed] [Google Scholar]
  37. Rook G. A., Zumla A. Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile? Lancet. 1997 Jun 21;349(9068):1831–1833. doi: 10.1016/S0140-6736(97)01164-1. [DOI] [PubMed] [Google Scholar]
  38. Schumm Walter R., Reppert Earl J., Jurich Anthony P., Bollman Stephan R., Webb Farrell J., Castelo Carlos S., Stever James C., Kaufman Mark, Deng Liang-Yu, Krehbiel Michelle. Pyridostigmine bromide and the long-term subjective health status of a sample of over 700 male Reserve Component Gulf War era veterans. Psychol Rep. 2002 Jun;90(3 Pt 1):707–721. doi: 10.2466/pr0.2002.90.3.707. [DOI] [PubMed] [Google Scholar]
  39. Sharabi Y., Danon Y. L., Berkenstadt H., Almog S., Mimouni-Bloch A., Zisman A., Dani S., Atsmon J. Survey of symptoms following intake of pyridostigmine during the Persian Gulf war. Isr J Med Sci. 1991 Nov-Dec;27(11-12):656–658. [PubMed] [Google Scholar]
  40. Shearer William T., Rosenblatt Howard M., Gelman Rebecca S., Oyomopito Rebecca, Plaeger Susan, Stiehm E. Richard, Wara Diane W., Douglas Steven D., Luzuriaga Katherine, McFarland Elizabeth J. Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003 Nov;112(5):973–980. doi: 10.1016/j.jaci.2003.07.003. [DOI] [PubMed] [Google Scholar]
  41. Shehab Z., Brunell P. A. Enzyme-linked immunosorbent assay for susceptibility to varicella. J Infect Dis. 1983 Sep;148(3):472–476. doi: 10.1093/infdis/148.3.472. [DOI] [PubMed] [Google Scholar]
  42. Shen Z. X. Pyridostigmine bromide and Gulf War syndrome. Med Hypotheses. 1998 Sep;51(3):235–237. doi: 10.1016/s0306-9877(98)90081-0. [DOI] [PubMed] [Google Scholar]
  43. Sorensen Bristol, Streib Joanne E., Strand Matthew, Make Barry, Giclas Patricia C., Fleshner Monika, Jones James F. Complement activation in a model of chronic fatigue syndrome. J Allergy Clin Immunol. 2003 Aug;112(2):397–403. doi: 10.1067/mai.2003.1615. [DOI] [PubMed] [Google Scholar]
  44. Terryberry J. W., Thor G., Peter J. B. Autoantibodies in neurodegenerative diseases: antigen-specific frequencies and intrathecal analysis. Neurobiol Aging. 1998 May-Jun;19(3):205–216. doi: 10.1016/s0197-4580(98)00049-9. [DOI] [PubMed] [Google Scholar]
  45. Thrasher J. D., Broughton A., Madison R. Immune activation and autoantibodies in humans with long-term inhalation exposure to formaldehyde. Arch Environ Health. 1990 Jul-Aug;45(4):217–223. doi: 10.1080/00039896.1990.9940805. [DOI] [PubMed] [Google Scholar]
  46. Thrasher J. D., Madison R., Broughton A. Immunologic abnormalities in humans exposed to chlorpyrifos: preliminary observations. Arch Environ Health. 1993 Mar-Apr;48(2):89–93. doi: 10.1080/00039896.1993.9938400. [DOI] [PubMed] [Google Scholar]
  47. Thrasher J. D., Wojdani A., Cheung G., Heuser G. Evidence for formaldehyde antibodies and altered cellular immunity in subjects exposed to formaldehyde in mobile homes. Arch Environ Health. 1987 Nov-Dec;42(6):347–350. doi: 10.1080/00039896.1987.9934357. [DOI] [PubMed] [Google Scholar]
  48. Thrasher Jack D., Heuser Gunnar, Broughton Alan. Immunological abnormalities in humans chronically exposed to chlorpyrifos. Arch Environ Health. 2002 May-Jun;57(3):181–187. doi: 10.1080/00039890209602934. [DOI] [PubMed] [Google Scholar]
  49. Urnovitz H. B., Tuite J. J., Higashida J. M., Murphy W. H. RNAs in the sera of Persian Gulf War veterans have segments homologous to chromosome 22q11.2. Clin Diagn Lab Immunol. 1999 May;6(3):330–335. doi: 10.1128/cdli.6.3.330-335.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vojdani A., Campbell A. W., Anyanwu E., Kashanian A., Bock K., Vojdani E. Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol. 2002 Aug;129(1-2):168–177. doi: 10.1016/s0165-5728(02)00180-7. [DOI] [PubMed] [Google Scholar]
  51. Vojdani A., Campbell A., Brautbar N. Immune functional impairment in patients with clinical abnormalities and silicone breast implants. Toxicol Ind Health. 1992 Nov-Dec;8(6):415–429. [PubMed] [Google Scholar]
  52. Vojdani A., Ghoneum M., Brautbar N. Immune alteration associated with exposure to toxic chemicals. Toxicol Ind Health. 1992 Sep-Oct;8(5):239–254. [PubMed] [Google Scholar]
  53. Vojdani A., Vojdani E., Cooper E. Antibodies to myelin basic protein, myelin oligodendrocytes peptides, alpha-beta-crystallin, lymphocyte activation and cytokine production in patients with multiple sclerosis. J Intern Med. 2003 Oct;254(4):363–374. doi: 10.1046/j.1365-2796.2003.01203.x. [DOI] [PubMed] [Google Scholar]
  54. Whiteside T. L., Bryant J., Day R., Herberman R. B. Natural killer cytotoxicity in the diagnosis of immune dysfunction: criteria for a reproducible assay. J Clin Lab Anal. 1990;4(2):102–114. doi: 10.1002/jcla.1860040207. [DOI] [PubMed] [Google Scholar]
  55. Whiteside T. L., Friberg D. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. Am J Med. 1998 Sep 28;105(3A):27S–34S. doi: 10.1016/s0002-9343(98)00155-7. [DOI] [PubMed] [Google Scholar]
  56. Whyatt R. M., Perera F. P., Jedrychowski W., Santella R. M., Garte S., Bell D. A. Association between polycyclic aromatic hydrocarbon-DNA adduct levels in maternal and newborn white blood cells and glutathione S-transferase P1 and CYP1A1 polymorphisms. Cancer Epidemiol Biomarkers Prev. 2000 Feb;9(2):207–212. [PubMed] [Google Scholar]
  57. Willison Hugh J., Yuki Nobuhiro. Peripheral neuropathies and anti-glycolipid antibodies. Brain. 2002 Dec;125(Pt 12):2591–2625. doi: 10.1093/brain/awf272. [DOI] [PubMed] [Google Scholar]
  58. Wilson S. D., McCay J. A., Butterworth L. F., Munson A. E., White K. L., Jr Correlation of suppressed natural killer cell activity with altered host resistance models in B6C3F1 mice. Toxicol Appl Pharmacol. 2001 Dec 15;177(3):208–218. doi: 10.1006/taap.2001.9298. [DOI] [PubMed] [Google Scholar]
  59. Winrow Christopher J., Hemming Matthew L., Allen Duane M., Quistad Gary B., Casida John E., Barlow Carrolee. Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity. Nat Genet. 2003 Mar 17;33(4):477–485. doi: 10.1038/ng1131. [DOI] [PubMed] [Google Scholar]
  60. Zhang Q., Zhou X. D., Denny T., Ottenweller J. E., Lange G., LaManca J. J., Lavietes M. H., Pollet C., Gause W. C., Natelson B. H. Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999 Jan;6(1):6–13. doi: 10.1128/cdli.6.1.6-13.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES