Elsevier

The Lancet

Volume 349, Issue 9068, 21 June 1997, Pages 1831-1833
The Lancet

Hypothesis
Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile?

https://doi.org/10.1016/S0140-6736(97)01164-1Get rights and content

Summary

The symptoms of Gulf War syndrome are compatible with the hypothesis that the immune system of affected individuals is biased towards a Th2-cytokine pattern. Factors that could lead to a Th2 shift among Gulf War veterans include exposure to multiple Th2-inducing vaccinations under stressful circumstances and the way in which such vaccinations were administered, which would be expected to maximise Th2 immunogenicity. These factors may have led to a long-term systemic shift towards a Th2-cytokine balance and to mood changes related to the immunoendocrine state. Other vaccines that lead to similar long-term, non-specific shifts in cytokine balance are well-established. If our hypothesis is proven, treatment may be possible with regimens that induce a systemic Th1 bias.

Section snippets

Non-specific effects of vaccination

Potent immunogens can have systemic long-lasting, non-specific effects on the nature of the immune response to unrelated antigens. For example, the prevalence of atopy and of allergic reactions to housedust mite are lower in people who have been exposed to measles infection4 and in members of large families in which there is a greater likelihood of exposure to childhood infections.5 Similarly, Japanese children who are tuberculin skin-test positive are less likely to be atopic and have a higher

Stress, the endocrine system, and immunity

The innate tendency of the vaccines used in the Gulf War to drive a systemic Th2 response will have been greatly enhanced by endocrine factors secondary to stress at the time of vaccination. Several steroid hormones modulate T-cell responses. DHEA, or unknown metabolites of this hormone, tend to promote a Th1 pattern. Thus, DHEA restores immune functions in old mice and corrects the deregulated, spontaneous release of cytokine in old animals.20, 21, 22 This adrenal steroid has been tested for

Mood changes

The mood changes and depression that commonly accompany Gulf War syndrome can also be accounted for by our hypothesis. There is convincing evidence that depression can be associated with excessive cortisol-mediated effects,36 and that stress can lead to depression. Thus, depression tends to be associated with Th2- mediated disorders, or disorders that result from a lack of Th1. Some endocrine changes are also common to Th2 disorders and to depression.37, 38 Studies of metyrapone, an endocrine

Possible role of carbamate and organophosphate insecticides

The combination of stress and of a large Th2-inducing vaccination schedule would be expected to cause a systemic Th1 to Th2 shift in cytokine balance. These effects were possibly exacerbated in the Gulf War veterans by exposure to carbamate and organophosphate insecticides that are known to inhibit important functions of interleukin-2,15 a cytokine that is pivotal to the role of Th1 lymphocytes. Reports have suggested that many of the insecticides were obtained from local sources in the Gulf,

Conclusion

Our hypothesis provides an explanation for the diversity of symptoms as seen in Gulf War syndrome and chronic fatigue syndrome. A systemic shift in the Th1/Th2 balance towards Th2 will lead to an increase in: diseases that are exacerbated by diminished Th1; diseases mediated by increased Th2; and mood disorders attributable to neuroendocrine changes. These effects can explain the diverse nature of Gulf War syndrome, because the signs of the syndrome will vary between individuals and will also

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