Gulf War Illness (GWI) is a chronic disorder with symptoms including joint pain, fatigue, and cognitive problems that affects approximately 30% of the 697,000 Veterans who served in the 1991 Gulf War. It has long been suspected that GWI was caused by exposures to similarly acting pesticides, sarin nerve gas, and anti-nerve gas pills during the war. Our prior study with pesticide applicators from the Gulf War called "The Pesticide MRI study," showed that GW Veterans with pesticide exposures had lower brain volumes on brain imaging that was associated with worse performance on memory testing. This suggested that exposed GW Veterans had differences on brain imaging, but at that time there was no simple test to diagnose their exposures or their illness. There were no reliable blood tests that could be used as markers to identify those previous exposures to these types of toxicants or to identify damage to brain cells from these exposures. However, cutting-edge blood tests have recently been identified that are sensitive to individuals with similar types of pesticide exposures and chronic health symptoms. In fact, we used these same blood tests in a small number of stored blood samples from Veterans with GWI from our prior studies, and we found an eightfold increase in a particular marker associated with brain signaling (glial fibrillary acidic protein) as well as other increased markers in the blood samples of these Veterans. It is now necessary to do a larger, more conclusive study to determine whether these blood markers are present in all Veterans with GWI and/or whether they are higher in those Veterans with specific exposures to GW-related toxins or with a history of mild traumatic brain injury (mTBI). We have recently found higher-than-expected rates of mTBI in GW deployed Veterans in our other studies.

GWI may reflect a process of "brain inflammation" due to exposure to toxicants during the war that resulted in damage to brain cells. These damaged brain cells can result in bits of damaged or dying cells inside us that release bits of blood or breakdown products (proteins) that brain immune cells see as dangerous to our survival. These damaged brain cells send "damage" signals to the immune cells of the brain that can cause openings in the blood-brain barrier. This barrier usually prevents these bits of damaged cells from being released into the blood circulation; however, if it becomes "leaky," it could cause the release of some of these damage signals that can activate the immune cells in the rest of the body and result in autoantibodies to these damage signaling proteins. Our study hypothesis (idea) is that following nervous system damage in GWI, there is loss of these cells, breakdown of the blood-brain barrier leading to leakage of specific brain cell proteins (neuronal and glial) into circulation, with subsequent formation of their autoantibodies; such antibodies can be measured and used as sensitive biomarkers for nervous system injury.

Only recently has the importance of brain-immune system cross-talk been recognized and it appears to work through the immune cells of the brain. These brain-immune cells react to foreign invaders or damage signals by causing inflammation and other "sickness" symptoms such as feeling tired and achy or not being able to concentrate. This type of response is helpful when we have an infection and our body needs rest to get better. However, there appears to be times when this system gets caught in a loop of continuous activation resulting in long-lasting or chronic "sickness" symptoms. It appears that GWI could be one of those types of chronic activation between the brain and the immune system caused by this initial damage to the nervous system.

In this study, we will compare autoantibodies against brain proteins in the stored blood samples from Veterans with GWI compared with healthy GW Veteran controls. As a second comparison group, we will also study individuals with either irritable bowel syndrome or chronic fatigue syndrome, two chronic disorders that also occur in GW Veterans and with similarities to GWI. In this study, we will determine whether Veterans with GWI have higher levels of blood autoantibodies than healthy Veterans or disease controls and whether the pattern or levels of autoantibodies are associated with exposures during the war, including pesticides, sarin nerve gas, anti-nerve gas pills, or prior mild traumatic brain injuries in GW Veterans.

The results from this study may help Veterans with GWI in multiple ways. First, our study may change the way GWI and other similar disorders are diagnosed by using a simple blood test for immune system activation of brain proteins. Second, it may change the way that GWI and other similar disorders are treated if it is shown that a particular pattern of brain autoantibodies are associated with GWI. This could result in utilizing currently available medicines to alter specific brain proteins and treat the symptoms of GWI. Third, it could provide savings in time and expensive tests to diagnose and monitor the progression of the disorder. This could help Department of Veterans Affairs and private doctors to better diagnose and treat ill GW Veterans.