Gulf War Illness: Is there lasting damage to the endocrine-immune circuitry?

Abstract

We reported previously that the persistence of complex immune, endocrine and neurological symptoms that afflict up to one third of veterans from the 1990-91 Gulf War might be supported by a misdirected regulatory drive. Here we use a detailed model of immune signaling in concert with an overarching circuit model of known sex and stress hormone co-regulation to explore how the failure of regulatory elements may further establish a self-perpetuating imbalance that closely resembles Gulf War Illness (GWI). Defects to the model were imparted iteratively and the stable regulatory modes supported by these altered immune-endocrine circuits were identified using repeated simulation experiments. In each case the predicted homeostatic regimes were compared to experimental data collected in male GWI (n=20 ) and matched healthy veterans (n=22 ). We found that alignment of GWI with a new homeostatic regime improved significantly when cortisol's normal anti-inflammatory activity was interrupted. Alignment improved further when this cortisol insensitivity was compounded by the loss of the normal antagonistic effects of Th1 cytokines on Th2 lymphocyte activation. Together these simulation results suggest altered glucocorticoid gene regulation compounded by possible changes in IGF-1 regulation of Th1:Th2 immune balance may be key underlying features of GWI.

Keywords:

• Gulf War Illness
• mathematical immunology
• numerical simulation
• regulatory control
• regulatory logic

Disclosure of Potential Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This research was conducted in collaboration with the High Performance Computing team at the University of Miami Center for Computational Science (CCS) (http://ccs.miami.edu). The authors would also like to thank Dr. Andrée Gruslin for many helpful discussions regarding the many regulatory effects of insulin growth factor (IGF).

Funding

Funding was provided by US Department of Defense Congressionally Directed Medical Research Program (CDMRP) awards (http://cdmrp.army.mil/) GW093042 (Broderick - PI) and GW080152 (Klimas - PI) as well as Merit Awards from the US Veterans Affairs (Klimas - PI).

Supplemental Material

Supplemental data for this article can be accessed on the publisher's website.

Author Contributions

MAR, RMdR, TJAC, JZ and GB performed computational simulations and analysis of computational results. TJAC, NGK, MAF and GB, compiled physiological data and developed the immune-endocrine connectivity network. MAR, TJAC and GB performed comparisons between experimental and computational data and interpreted the results. MAF, NGK and ZB collected and analyzed the experimental data. TJAC, MAR, RMdR, and GB conceived of the discrete logical analysis algorithm. All authors contributed to the drafting of this article, and approve of its contents.