Immunomodulation in GWI
Abstract
Gulf War Illness (GWI) is a debilitating condition that is associated with a variety of symptoms including dysregulated immune system, fatigue, headache, memory problems, muscle and joint pain, gastrointestinal issues, neurological problems, hormonal imbalance, and immune dysfunction. Currently, little is known about what causes the onset and progression of the disease. Diagnosis is made based on a process of elimination, and treatment involves symptom management rather than targeting the underlying causes of the disease. While little is known about the inner workings of GWI, recent data have suggested that the condition is likely caused by a combination of factors including an individual’s genomic make-up and environmental exposures, such as toxic chemicals and/or pathogens. Further exacerbation or chronic stress exposure during and after wartime may also contribute to aggravation and persistence of GWI. The vast majority of genomic research in GWI has been done on peripheral blood mononuclear cells (PBMC), a mixture of lymphocytes with various immune functions, and showed significant immune dysregulation. When we compare gene expression or regulation of gene expression in the whole population of PBMC between GWI patients and healthy controls (HC), we receive “mixed” results from each of these different classes of immune cells. Some significant changes may be “diluted out” and lost. For example, if genomic DNA methylation of the particular gene is increased only in B cells of GWI patients, but not in other cell types, this increase could be undetectable when we measure DNA methylation in the whole PBMC mix. This is of relevance as the proportions and functions of the different types of immune cells change in GWI. Moreover, GWI patients have lower numbers of natural killer (NK) cells compared to HC, but elevated percentages of B cells and CD4:CD8 ratio in T cells. The goal of our research efforts is to determine changes in the transcriptional regulation in each of the four major subtypes of immune cells (helper T cells, cytotoxic T cells, B cells, and NK cells) caused by GWI and identify the role of cell-cell communication in pathobiology of GWI. Our studies will reveal potential therapeutic targets of GWI and provide insight into immune cell-specific disease onset and progression, with the goal of developing better diagnostics tools and therapeutic interventions. Specifically, more detailed understanding of the dysfunction involved in specific immune cell subtypes in GWI would greatly speed up the identification of promising immune cell-specific biomarkers to improve diagnosis and treatment. There are three components to our research efforts: (1) identification of the genes involved in the development of GWI in specific immune cell types, (2) uncovering the mechanisms that regulate gene expression response to GWI in specific immune cell types, and (3) determining differences in immune cell-to-cell communication. In an effort to understand what is occurring on a genomic level, we aim to understand the changes that occur in activation/deactivation RNA as well as in DNA in each of immune cell subtypes (helper T cells, cytotoxic T cells, B cells, and NK cells) of GWI patients as compared to their healthy counterparts exposed to similar wartime stressors. This will provide us with a better understanding of how changes in an individual’s genomic makeup cause them to develop the illness versus those who remain healthy today. While it is important to know what specific genes change their expression in the onset and progression of GWI, it is equally important to understand why these genes change their expression. Therefore, on a level of DNA, we want to understand how the changes in the DNA structure (specifically, methylation of DNA) can lead to the onset and progression of GWI as well as potentially alter specific mechanisms that are vital for cell survival, function, and immune defense. We will also evalu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810660
Entities
People
- Lubov Nathanson
Organizations
- Nova Southeastern University
- United States Army