DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Brain Immune Interactions as the Basis of Gulf War Illness: Gulf War Illness Consortium (GWIC)

Principal Investigator: SULLIVAN, KIMBERLY
Institution Receiving Award: BOSTON UNIVERSITY CHARLES RIVER CAMPUS
Program: GWIRP
Proposal Number: GW120037
Award Number: W81XWH-13-2-0072
Funding Mechanism: Consortium Award
Partnering Awards:
Award Amount: $4,784,133.00


PUBLIC ABSTRACT

Background: Gulf War (GW) veterans continue to report chronic health symptoms now 21 years following their return from the war including joint and muscle pain, sleepiness, problems with thinking, skin rash, and gastrointestinal problems. However, the physical cause for this chronic illness has remained a mystery. This has made identifying useful treatment strategies very difficult. New advances in the study of brain and immune system communication may provide important new clues to the physical cause of Gulf War Illness (GWI) that could lead to specific avenues of targeted treatment strategies. 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, called microglia. Microglia are able to detect foreign invaders to the brain such as bacteria that can cause infection. They also work by identifying damaged or dying cells inside us that release bits of blood or breakdown products that microglia see as dangerous to our survival and are called "endogenous danger signals" or "alarmins." Microglia react to these foreign invaders or alarmins by causing inflammation and other "sickness" behaviors, such as feeling tired and having an upset stomach or not being able to concentrate. This type of response can be quite helpful when we have an infection and our body needs rest to fight it off and 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" behaviors. GWI could be one of those types of chronic activation between the brain and the immune system, and some individuals may be more susceptible to this based on their genetic make-up. This might happen by alarmins from damaged brain cells (neurons) causing microglia to be continually activated and become oversensitive (creating chronic activation loops). The initial damage to brain cells is thought to be related to particular chemical exposures experienced by some GW veterans that initially stimulated this microglial response. Studies of GW veterans have shown that veterans exposed to certain chemicals during the war have lower amounts of white matter in the brain. White matter is a myelin sheath that wraps around neurons and is made by a different type of glia (oligodendrocytes). The breakdown bits of myelin and neurons could be activating microglia and causing chronic activation loops and inflammation.

This consortium study is designed to further probe these ideas (hypotheses) to test whether GWI is in fact related to chronic brain-immune activation and chronic inflammation. Studies that the consortium will perform include examining markers in the blood and brain fluid (cerebrospinal fluid) in addition to brain imaging (advanced magnetic resonance imaging [MRI], positron emission tomography, [PET] scans) and memory testing to try to identify this chronic activation and inflammation occurring in sick veterans. These studies are also planned in animal models and cell studies where brain cells can actually be studied under special microscopes. Identifying specifically where root causes of GWI is happening is very important because once identified, treatment options can be targeted to that specific problem and not to areas that are not affected.

The Brain-Immune Interaction Gulf War Illness Consortium (GWIC) will perform studies of microglial activation and neuroinflammation in GWI. The GWIC Coordinating Center will be located at Boston University School of Public Health and led by Dr. Kimberly Sullivan. Dr. Sullivan will take responsibility for scientific leadership and the day-to-day planning support for the proposed animal (preclinical) and human (clinical) research cores, working groups, and studies. Plans will be devised to coordinate all of the planned study data and analyses from multiple research sites into one location at Boston University. The GWI consortium will build upon the prior work of very experienced GWI researchers who have studied many different groups of GW veterans and experts in the fields of the proposed mechanisms of GWI. This will include experts in the immune system, brain structure, and signaling mechanisms and genetics. These consortium collaborators will come from government agencies, universities, and industry to help solve this problem by working together and learning from each other. Monthly webconference meetings of the consortium working groups and quarterly scientific meetings of all consortium members are planned to ensure research progress and sharing of results across individual studies and institutions. The approach of working together as a collaborative team will maximize research study funds and lead to faster translation of results from human, animal, and cell studies into effective and targeted human treatment trials of GWI. This could be particularly important because new treatments are currently available that specifically target brain-immune cross-talk pathways and reduce chronic inflammation. Initial studies with animals will be done to assess which treatments may be most promising for treating GWI and for identifying which may not be as effective without the high costs associated with human clinical treatment trials.