THE INSPIRED RESEARCH
As many as 50-90% of the U.S. general population experiences a traumatic event that has the potential to result in Post-Traumatic Stress Disorder (PTSD) 1-2. The discovery of a clear biomarker for PTSD is urgently needed, as this disorder affects 7-8% of the general population and as many as 20% of returning combat veterans 3. The economic impact of PTSD related to military personnel deployed to Iraq and Afghanistan is estimated at $2-3 billion per year. According to the Sidran Institute PTSD statistics, people with PTSD have among the highest rates of healthcare service use. Individuals with PTSD have symptoms such as chronic hyperarousal, heightened startle reactions, depression, numbed emotions, anxiety, and social withdrawal 4. Furthermore, they are also considerably more likely to have health problems related to inflammation and autoimmune disease 5-6. Given that the chronic stress typical of this condition affects the immune system, individual genetic biomarkers that indicate risk and resilience to PTSD may exist 7,8. With this view, past studies have examined PTSD in relation to altered gene expression 9-11, the stress-response hormone system12, gene networks underlying the innate immune system 13, and the adaptive immune system’s T cell number and ratio 14. Taken together, these studies suggest that the comorbid health problems observed in individuals with PTSD are moderated by dysregulated immune function.
iXpressGenes has conducted preliminary studies of T cell receptor transcriptome sequences that offer an unprecedented analysis of linking an immune repertoire to sensitivity or resilience to PTSD. The T-cell receptor is a protein molecule found on the surface of T cell lymphocytes, a type of white blood cell that forms part of a body’s defense system against pathogens. Any individual will have hundreds of thousands of different shape T-cell receptors based on environmental exposure. The transcriptome sequences refer to the collection of all the gene readouts corresponding to different T-cell receptor shapes. Thus the unique library collection of an individual’s transcriptome sequences is referred to as the immune repertoire.
Our preliminary data suggest there may be distinguishing immune repertoire associated with those who have PTSD. Further study of our preliminary finding, that people with PTSD have unique immune repertoire sequences, is critical to the understanding of why certain immune problems are more common in people with PTSD, how these differences can serve as biomarkers, and what may serve as targeted therapy for this condition. While our preliminary study findings are encouraging and provide strong support for the proposed study, they cannot stand alone due to the size of the participant pool. We seek funding to expand our preliminary findings by collecting immune repertoire data for a thousand or more soldiers who have been trauma exposed with and without PTSD symptoms. Our goal is to establish a secure and intelligent database for analyses and data mining in the search for predictive markers. Once the markers have been identified and verified, intervention strategies can be recommended.
References
1. Yehuda, R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann. NY Acad. Sci. 1179, 56–69 (2009)
2. Wessa, M., Rohleder, N. Endocrine and inflammatory alterations in posttraumatic stress disorder. Expert Rev. Endocrinol. Metab. 2, 91–122 (2007)
3. Heim, C., Mletzko, T., Purselle, D., Musselman, D.L., Nemeroff, C.B. The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol. Psychiatry 63, 398–405 (2008)
4.Iwata M, Ota KT, Duman RS. The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun 31, 105–114(2012)
5. Jessica M. Gill, PhD, RN, Leo Saligan, PhD, RN, Stephanie Woods, PhD, RN, and Gayle Page, DNSc, RN. PTSD is Associated with an Excess of Inflammatory Immune Activities. Perspectives in Psychiatric Care 4, (2009)
6. Eric S. Wohleb, Daniel B. McKim, Daniel T. Shea, Nicole D. Powell, Andrew J. Tarr,
John F. Sheridan, and Jonathan P. Godbout. Re-establishment of Anxiety in Stress-Sensitized Mice Is Caused by Monocyte Trafficking from the Spleen to the Brain. BIOL PSYCHIATRY 75, 970–981 (2014)
7. Thomas, J.L., Wilk, J.E., Riviere, L.A., McGurk, D., Castro, C.A., Hoge, C.W. Prevalence of Mental Health Problems and Functional Impairment among Active Component and National Guard Soldiers 3 and 12 Months Following Combat in Iraq. Arch. Gen. Psychiatry 67, 614-623 (2010)
8. Tanielian, T. & Jaycox, L. (Eds.). Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery. Santa Monica, CA: RAND Corporation (2008)
9. Lisa K. Richardson, Christopher Frueh, and Ronald Acierno. Prevalence Estimates of Combat-Related PTSD: A Critical Review. Aust N Z J Psychiatry 44, 4–19, (2010)
10. Heim, C., Nemeroff, C.B. Neurobiology of posttraumatic stress disorder. CNS Spectr. 14, 13–24 (2009)
11. Van Wingen, G.A., Geuze, E., Vermetten, E., Fernandez, G. The Neural Consequences of Combat Stress: Long-term Follow-up. Mol. Psychiatry 17, 116-118 (2012)
12. Van Zuiden, M., Geuze, E., Willemen, H.L.D.M., Vermetten, E., Maas, M., Amarouchi, K., Kavelaars, A., Heijnen, C.J. Glucocorticoid receptor pathway components predict PTSD symptom development: a prospective study. Biol. Psychiatry 71, 309-316 (2012)
13. Elbert Geuze, Guido A. van Wingen, Mirjam van Zuiden, Arthur R. Rademaker, Eric Vermetten, Annemieke Kavelaars, Guille´n Ferna´ndez, Cobi J. Heijnen. Glucocorticoid receptor number predicts increase in amygdala activity after severe stress. Psychoneuroendocrinology 37, 1837-1844 (2012)
14. MARGARET ALTEMUS,a FIRDAUS S. DHABHAR, AND RUIRONG YANG, Immune Function in PTSD. Ann. N.Y. Acad. Sci. 1071, 167–183 (2006)
15. Hannah Gola, Harald Engler, Annette Sommershof, Hannah Adenauer, Stephan Kolassa, Manfred Schedlowski, Marcus Groettrup, Thomas Elbert and Iris-Tatjana Kolassa. Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. BMC Psychiatry 13, 40-48 (2013)
16. Qiong Wu, Anne M. Pesenacker, Alka Stansfield, Douglas King, Dawn Barge, Helen E. Foster, Mario Abinun and Lucy R. Wedderburn. Immunological characteristics and T-cell receptor clonal diversity in children with systemic juvenile idiopathic arthritis undergoing T-cell-depleted autologous stem cell transplantation. Immunology 142, 227–236 (2014)
17. Ying Xiong; Yan Tan; Yu Guo Song. Analysis of T Cell Receptor Vβ Diversity in Peripheral CD4+ and CD8+ T Lymphocytes Obtained From Patients With Chronic Severe Hepatitis B. Hepat Mon. 14, e15900-e15905 (2014)
18. Sainz-Perez A1, Lim A, Lemercier B, Leclerc C. The T-cell receptor repertoire of tumor-infiltrating regulatory T lymphocytes is skewed toward public sequences. Cancer Res. 72, 3557-69 (2012)
19. Wang C1, Sanders CM, Yang Q, Schroeder HW Jr, Wang E, Babrzadeh F, Gharizadeh B, Myers RM, Hudson JR Jr, Davis RW, Han J. High throughput sequencing reveals a complex pattern of dynamic interrelationships among human T cellsubsets. Proc Natl Acad Sci U S A 107, 1518-23 (2010)
20. Jane A. Foster and Karen-Anne McVey Neufeld. Gut–brain axis: how the microbiome influences anxiety and depression. Trends in Neurosciences 36, 305-312 (2013)