For years, veterans from the First Gulf War have suffered from a variety of psychological and physical symptoms that experts now call Gulf War illness, often referred to as Gulf War syndrome. The wide variety of ailments make finding a treatment difficult. A significant amount of these symptoms appears to be neurological. One of the most common symptoms relating to brain function is cognitive dysfunction and mood problems. Sufferers also may experience anxiety, depression, sleep problems and a reduced ability to concentrate.

So far, experts have been unable to identify the exact cause of Gulf War illness. However, they believe it is associated with veterans’ exposure to a variety of chemicals during the war coupled with war-related stress. Because approximately 700,000 United States troops were deployed during this war, and, thus, put at risk for Gulf War illness, a big concern grows about how to treat this seemingly untreatable illness.

The development of the study

Recently, a research team led by Ashok Shetty, PhD, professor with the Department of Molecular Medicine at the Texas A&M College of Medicine and associate director of the Institute for Regenerative Medicine, found some promising hints of a possible treatment for the chronic neuroinflammation and resulting brain dysfunction associated with Gulf War illness. The findings were recently published in Brain, Behavior and Immunity.

“We knew several of the wartime chemicals in question could enter the brain through a leaky blood-brain barrier, which caused a buildup of a neurotransmitter called acetylcholine,” Shetty said. “The acetylcholine typically excites neurons but can also make neurons sick or even die due to too much excitation, which creates the inflammation.” However, up until this point, the mechanisms underlying chronic brain inflammation in Gulf War illness are mostly unknown.

The study, funded by the U.S. Department of Defense, used animal models of Gulf War illness to recreate how the illness occurs and better inform experts on the mechanisms of inflammation. Researchers exposed the models to similar chemicals and waited 10 months, which is equivalent to 25 to 30 years in a human’s life—or roughly the length of time since the First Gulf War. In the models, they found elevated levels of HMBG1 (a protein called high mobility group box one), proinflammatory cytokines and complement activation in the cerebral cortex of the brain.

The role of HMBG1 and complement activation in the solution

“In a disease condition, HMBG1 can transport into the cytoplasm and leak into the extracellular space of a living cell,” Shetty said. “From there, the HMBG1 creates a chain reaction that ultimately releases toxic substances that can make neurons sick and die.” Firstly, the HMBG1 activates certain receptors on microglial cells found in the central nervous system. Those cells then release proinflammatory cytokines, which, when in too great of a quantity, can eventually deteriorate brain tissue and cause cognitive and mood problems.

“This chain reaction showed us that HMBG1 is one of the leading causes of the persistent cognitive dysfunction and chronic neuroinflammation associated with Gulf War illness,” said Madhu LN, PhD, postdoctoral fellow in the Department of Molecular and Cellular Medicine at the College of Medicine and the first author of this study. “After looking at our results, we decided to target the HMBG1 and the resulting complement system activation.”

As part of the immune system, the complement system increases the opportunity for antibodies to target invading cells by increasing inflammation. However, when the complement system is triggered by an injury or exposure to chemicals, it develops an autoimmune-type reaction that maintains a persistent inflammation within the body.

Presently, drugs do exist that neutralize or reduce HMGB1 and inhibit complement activation. Shetty said they may be useful for treating Gulf War illness after they are thoroughly tested.

A liquid biopsy approach to monitoring the neuroinflammation

“Next, we wanted to find a noninvasive way to measure the HMGB1, proinflammatory cytokines and complement system activation,” Shetty explained. “In our study, we found that we could reliably see those elevated biomarkers in the blood of our models of Gulf War illness.”

Tiny vesicles released from the neurons and astrocytes in the brain typically enter the circulating blood. “We characterized brain-derived vesicles in the blood and found higher levels of HMGB1 and other inflammatory proteins as seen in the brain,” Madhu said. The next step for the study is to perform what is called a “liquid biopsy,” or a study of the blood, of veterans with Gulf War illness. A liquid biopsy approach involving the characterization of brain-derived vesicles in the blood will be especially useful in clinical trials as it provides a minimally invasive way to monitor persistence or progression of brain inflammation in patients with Gulf War illness.

“We hope to collaborate with investigators that have a blood bank of samples taken from patients,” Shetty said. “We also hope to extend the current funding of this study through another grant from the Department of Defense.”

— Mary Leigh Meyer