Cytometric features of cellular immune compartment in participants of current military conflicts
https://doi.org/10.15789/1563-0625-CFO-2952
Abstract
Staying in a combat area is associated with a high risk of developing mental disorders. A significant knowledge has been accumulated concerning the mechanisms of immune-mediated mechanisms of neuropsychiatric pathologies, in particular, post-traumatic stress disorder (PTSD). Activated T regulatory cells play an important role in the development of neuroinflammation under stress conditions. Our purpose was to study the indices of blood system and cytometric features of immune cellular populations in the participants of current military conflicts in presence of stress-associated adaptation disorders. We examined 97 male veterans involved in modern military conflicts, 35 to 55 years old. The main group 35 included veterans of a special military operation in Ukraine (SVO), along with 42 veterans of the second Chechen military campaign (comparison group). Control group consisted of 20 healthy persons from military staff. All patients underwent pathopsychological examination in accordance with clinical recommendations. PTSD was diagnosed in 12% of SVO veterans, whereas 77% had various types of neurotic, stress-related and somatoform disorders. In the comparison group, 2% of combatants were diagnosed with chronic personality changes. A complete blood count was performed using a standardized technique with a hematological analyzer. Immunophenotyping of lymphocytes was performed by a Navios flow cytometer (Beckman Coulter, USA). In the group of SVO veterans, we have noted a decrease in RBC volume dispersion, reduced heterogeneity index and the average volume of platelets, as well as lymphopenia and monocytosis, thus reflecting the multidirectional effect of hematopoietic regulation factors on distinct differentiation lineages of mononuclear cells. Cytometric analysis of lymphocyte populations showed a decrease in T helper cells and mature NK cells in the group of SVO veterans which explains the presence of lymphopenia and may indicate a deficiency of adaptive and innate immune response upon prolonged response to stress. We have revealed an increased number of T NK and T regulatory lymphocytes which are suggested to prevent the development of autoimmune disorders. Under stress conditions, the FoxP3 transcription factor may upregulate the glucocorticoid-induced TNF receptor in the T regulatory cells thus potentiating their proliferative activity. We have also shown a decreased number of T helpers and T regulatory cells expressing markers of early and late positive activation, limiting the development of both autoimmune reactions and the development of stress-induced neuroinflammation. No significant differences were found between the indices control group and comparison group, thus indicating that the severity of stress-induced neuroimmune reactions leveled out over time. Hematopoiesis induction by stress mediators and indirect neuroimmune-mediated changes in the quantitative profile of lymphocyte subpopulations seem to be a consequence of a complex multi-level neuropsychodynamic process of the central nervous system associated with clinical forms of adaptation disorders.
About the Authors
S. L. PashninRussian Federation
Pashnin S.L., Neurosurgeon, Honored Physician of the Russian Federation, Head of the Department of Neurosurgery
70 Vorovsky St Chelyabinsk 454048
E. V. Davydova
Russian Federation
Davydova E.V., PhD, MD (Medicine), Associate Professor, Professor, Department of Medical Rehabilitation and Sports Medicine; Head, Department of Early Medical Rehabilitation
70 Vorovsky St Chelyabinsk 454048
D. Sh. Altman
Russian Federation
Altman D.Sh., PhD, MD (Medicine), Professor, Honored Physician of the Russian Federation, Chief Physician
70 Vorovsky St Chelyabinsk 454048
V. A. Zurochka
Russian Federation
Zurochka V.A., PhD, MD (Medicine), Senior Researcher, Laboratory of Immunopathophysiology, Institute of Immunology and Physiology; Senior Researcher, Laboratory of Immunobiotechnology, Russian-Chinese Center
Yekaterinburg;
Chelyabinsk
I. Yu. Zhuravlev
Russian Federation
Zhuravlev I.Yu., Neurosurgeon, Department of Neurosurgery
70 Vorovsky St Chelyabinsk 454048
Ya. T. Zhakupova
Russian Federation
Zhakupova Ya.T., PhD (Psychology), Associate Professor, Department of Psychology; Clinical Psychologist
Chelyabinsk
References
1. Vasilyeva A.V., Karavaeva T. A., Lukoshkina E. P. Diagnosis and therapy of posttraumatic stress disorder in the clinic of borderline disorders and somatic medicine. In: Semenova N.V. (comp.). Diagnosis and treatment of mental and narcological disorders: modern approaches. Collection of methodological recommendations. Issue 2. St. Petersburg: Publishing and printing company “COSTA”, 2019, pp. 300-324.
2. Vasilyeva A.V., Karavaeva T.A., Neznanov N.G., Idrisov K.A., Kovlen D.V., Ponomarenko N.G., Radionov D.S., Starunskaya D.A., Shoigu Yu.S. Post-traumatic stress disorder in the paradigm of evidence-based medicine: pathogenesis, clinic, diagnosis and therapy. St. Petersburg: NMIC MON named after V.M. Bekhterev, 2022. 33 p. [Electronic resource]. Available at: https://bekhterev.ru/wpcontent/uploads/2023/02/metodicheskie-rekomendacii-ptsr_karavaeva-protokol-10-ot-22.12.2022g..pdf.
3. Verzakova Yu.A., Girshfeld V.A. Changes in the immune status under stress. Mezhdunarodnyy studencheskiy nauchnyy vestnik = International Student Scientific Bulletin, 2019, no. 3. [Electronic resource. Available at: https://eduherald.ru/article/view?id=19623. (In Russ.)
4. Zurochka A.V., Davydova E.V., Cytometric analysis of the spectrum subpopulation of T lymphocytes in the early forms of chronic brain ischemia veterans of modern wars. Meditsinskaya Immunologiya = Medical Immunology (Russia), 2015, Vol. 17, no. 1, pp. 33-38. (In Russ.) doi: 10.15789/1563-0625-2015-1-33-38.
5. Zurochka A.V., Khaidukov S.V., Kudryavtsev I.V., Chereshnev V.A. Flowcytometry in biomedical research. Yekaterinburg: RIO, Ural Branch of the Russian Academy of Sciences, 2018. 720 p.
6. Kiseleva N.M., Kuzmenko L.G., NkaneNzola M.M. Stress and lymphocytes. Pediatriya. Zhurnal im. G. N. Speranskogo = Pediatrics. Journal named after G.N. Speransky, 2012, no. 1, pp. 137-143. (In Russ.)
7. Komarova О.N., Khavkin A.I. Correlation Between Stress, Immunity and Intestinal Microbiota. Pediatricheskaya farmakologiya = Pediatric Pharmacology, 2020. Vol. 17, no. 1, рр. 18-24. (In Russ.)
8. Kryukov E.V., Shamrey V.K. Military psychiatry in the XXI century: modern problems and prospects of development. St. Petersburg: SpetsLit, 2022. 367 p.
9. Reznik A.M. Mental disorders in veterans of local wars who suffered a traumatic brain injury. Health, Food and Biotechnology = Health, Food and Biotechnology, 2020, Vol. 2, no. 1, pp. 11-23. (In Russ.)
10. Smirnova A.V., Koryagina O.A. Stress and the physiological response of the body. Exam stress among students. Mezhdunarodnyy studencheskiy nauchnyy vestnik = International Student Scientific Bulletin, 2019, no. 2. [Electronic resource]. Available at: https://eduherald.ru/ru/article/view?id=19612. (In Russ.)
11. Senyavskaya E.S. Frontline life of the Great Patriotic War: structure and features. Vestnik antropologii = Bulletin of Anthropology, 2021, no. 2. pp. 7-25. (In Russ.)
12. Tokarev A.R. Neuro-cytokine mechanisms of acute stress (literature review). Vestnik novykh meditsinskikh tekhnologiy. Elektronnoe izdanie = Journal of New Medical Technologies. eEdition, 2019, no. 3, pp. 194-204. [Electronic resource]. Available at: https://elibrary.ru/zrwozp. (In Russ.)
13. Troitskiy M.S. Stress and psychopathology. Vestnik novykh meditsinskikh tekhnologiy = Journal of New Medical Technologies, 2016, no. 4, pp. 343-352. (In Russ.)
14. Tuchina O.P., Sidorova M.V., Turkin A.V., Shvayko D.A., Shalaginova I.G., Vakolyuk I.A. Molecular mechanisms of initiation and development of neuroinflammation in the model of posttraumatic stress disorder. Geny i kletki = Genes and Cells. 2018, Vol. 13, no. 2, pp. 47-55. (In Russ.)
15. Bam M., Yang X., Busbee B.P., Aiello A.E., Uddin M., Ginsberg J.P., Galea S., Nagarkatti P.S., Nagarkatti M. Increased H3K4me3 methylation and decreased miR-7113-5p expression lead to enhanced Wnt/β-catenin signaling in immune cells from PTSD patients leading to inflammatory phenotype. Mol. Med., 2020, Vol. 26, 110. doi: 10.1186/s10020-020-00238-3.
16. Bujko K., Kucia M., Ratajczak J., Ratajczak M.Z. Hematopoietic Stem and Progenitor Cells (HSPCs). Adv. Exp. Med. Biol., 2019, Vol. 1201, рр. 49-77.
17. Busbee P.B., Bam M., Yang X., Abdulla O.A., Zhou J., Ginsberg J.P., Aiello A.E., Uddin M., Nagarkatti M., Nagarkatti P.S. Dysregulated TP53 among PTSD patients leads to downregulation of miRNA let-7a and promotes an inflammatory Th17 phenotype. Front. Immunol., 2022, Vol. 12, 815840. doi: 10.3389/fimmu.2021.815840.
18. Chen Y., An Q., Yang S.T., Chen Y.L., Tong L., Ji L.L. MicroRNA-124 attenuates PTSD-like behaviors and reduces the level of inflammatory cytokines by downregulating the expression of TRAF6 in the hippocampus of rats following single-prolonged stress. Exp. Neurol., 2022, Vol. 356, 114154. doi: 10.1016/j.expneurol.2022.114154.
19. Dantzer R. Role of the kynurenine metabolism pathway in inflammation-induced depression: preclinical approaches. Curr. Top. Behav. Neurosci., 2017, Vol. 31, рр. 117-138.
20. Freier E., Weber C.S., Nowottne U., Horn C., Bartels K., Meyer S., Hildebrandt Y., Luetkens T., Cao Y., Pabst C., Muzzulini J., Schnee B., Brunner-Weinzierl M.C., Marangolo M., Bokemeyer C., Deter H.C., Atanackovic D. Decrease of CD4(+)FOXP3(+) T regulatory cells in the peripheral blood of human subjects undergoing a mental stressor. Psychoneuroendocrinology, 2010, Vol. 35, no. 5, рр. 663-673.
21. Gelernter J., Sun N., Polimanti R., Pietrzak R., Levey D.F., Bryois J., Lu Q., Hu Y., Li B., Radhakrishnan K., Aslan M., Cheung K.H., Li Y., Rajeevan N., Sayward F., Harrington K., Chen Q., Cho K., Pyarajan S., Sullivan P.F., Quaden R., Shi Y., Hunter-Zinck H., Gaziano J.M., Concato J., Zhao H., Stein M.B.; Department of Veterans Affairs Cooperative Studies Program (#575B) and Million Veteran Program. Genome-wide association study of posttraumatic stress disorder reexperiencing symptoms in >165,000 US veterans. Nat. Neurosci., 2019, Vol. 22, no. 9, рр. 1394-1401.
22. Gerondakis S., Fulford T.S., Messina N.L., Grumont R.J. Corrigendum: NF-κB control of T cell development. Nat. Immunol., 2017, Vol. 18, no. 10, 1173. doi: 10.1038/ni1017-1173a.
23. Giotakos O. Neurobiology of emotional trauma. Psychiatriki, 2020, Vol. 31, no. 2, рр. 162-171.
24. Iqbal J., Huang G.D., Xue Y.X., Yang M., Jia X.J. The neural circuits and molecular mechanisms underlying fear dysregulation in posttraumatic stress disorder. Front. Neurosci., 2023, Vol. 17, 1281401. doi: 10.3389/fnins.2023.1281401.
25. Jenne C.N., Lee W-Y., Léger C., Kubes P. Functional innervation of hepatic iNKT cells is immunosuppressive following stroke. Science, 2011, Vol 334, no. 6052, pp. 101-105.
26. Krabbe S., Grundemann J., Luthi A. Amygdala inhibitory circuits regulate associative fear conditioning. Biol. Psychiatry, 2018, Vol. 83, no. 10, рр. 800-809.
27. Li Y., Duan W., Chen Z. Latent profiles of the comorbidity of the symptoms for posttraumatic stress disorder and generalized anxiety disorder among children and adolescents who are susceptible to COVID-19. Child Youth Serv. Rev., 2020, Vol. 116, 105235. doi: 10.1016/j.childyouth.2020.105235.
28. O’Farrell K., Harkin A. Stress-related regulation of the kynurenine pathway: Relevance to neuropsychiatric and degenerative disorders. Neuropharmacology, 2017, Vol. 112, Pt B, рр. 307-323.
29. Pasciuto E., Burton O.T., Roca C.P., Lagou V., Rajan W.D., Theys T., Mancuso R., Tito R.Y., Kouser L., Callaerts-Vegh Z., De La Fuente A.G., Prezzemolo T., Mascali L.G., Brajic A., Whyte C.E., Yshii L., MartinezMuriana A., Naughton M., Young A., Moudra A., Lemaitre P., Poovathingal S., Raes J., de Strooper B., Fitzgerald D.C., Dooley J., Liston A. Microglia require CD4 T cells to complete the fetal-to-adult transition. Cell, 2020, Vol. 182, pp. 625-640.e24.
30. Rosen V., Ayers G. An update on the complexity and importance of accurately diagnosing post-traumatic stress disorder and comorbid traumatic brain injury. Neurosci. Insights, 2020, Vol. 15, 2633105520907895. doi: 10.1177/2633105520907895.
31. Satoh M., Iwabuchi K. Immunomodulatory functions of α-GalCer and a Derivative, α-Carba-GalCer. Methods Mol. Biol., 2023, Vol. 2613, рр. 1-11.
32. Stein M.B., Levey D.F., Cheng Z., Wendt F.R., Harrington K., Pathak G.A., Cho K., Quaden R., Radhakrishnan K., Girgenti M.J., Ho Y.A., Posner D., Aslan M., Duman R.S., Zhao H. Department of Veterans Affairs Cooperative Studies Program (no. 575B); VA Million Veteran Program; Polimanti R., Concato J., Gelernter J. Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program. Nat. Genet., 2021, Vol. 53, no. 2, рр. 174-184.
33. Tang W., Wang Y., Lu L., Lu Y., Xu J. Post-traumatic growth among 5195 adolescents at 8.5 years after exposure to the Wenchuan earthquake: roles of post-traumatic stress disorder and self-esteem. J. Health Psychol., 2021, Vol. 26, рр. 2450-2459.
34. Xu Z., Zhang X., Chang H., Kong Y., Ni Y., Liu R., Zhang X., Hu Y., Yang Z., Hou M., Mao R., Liu W.T., Du Y., Yu S., Wang Z., Ji M., Zhou Z. Rescue of maternal immune activation-induced behavioral abnormalities in adult mouse offspring by pathogen-activated maternal Treg cells Nat. Neurosci., 2021, Vol. 24, pp. 818-830.
35. Yan Y., Ramanan D., Rozenberg M., McGovern K., Rastelli D., Vijaykumar B., Yaghi O., Voisin T., Mosaheb M., Chiu I., Itzkovitz S., Rao M., Mathis D., Benoist C. Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gute. Immunity, 2021, Vol. 54, no. 3, pp. 499-513.e5.
36. Yuan M., Liu B., Yang B., Dang W., Xie H., Lui S., Qiu C., Zhu H., Zhang W. Dysfunction of default mode network characterizes generalized anxiety disorder relative to social anxiety disorder and post-traumatic stress disorder. J. Affect. Disord., 2023, Vol. 334, рр. 35-42.
37. Yshii L., Pasciuto E., Bielefeld P., Mascali L., Lemaitre P., Marino M., Dooley J., Kouser L., Verschoren S., Lagou V., Kemps H., Gervois P., de Boer A., Burton O.T., Wahis J., Verhaert J., Tareen S.H.K., Roca C.P., Singh K., Whyte C.E., Kerstens A., CallaertsVegh Z., Poovathingal S., Prezzemolo T., Wierda K., Dashwood A., Xie J., vanWonterghem E., Creemers E., Aloulou M., Gsell W., Abiega O., Munck S., Vandenbroucke R.E., Bronckaers A., Lemmens R., De Strooper B., Van Den Bosch L., Himmelreich U., Fitzsimons C.P., Holt M.G., Liston A. Astrocytetargeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. Nat. Immunol., 2022, Vol. 23, no. 6, pp. 878-891.
38. Zhao J.L., Baltimore D. Regulation of stress-induced hematopoiesis. Curr. Opin. Hematol., 2015, Vol. 22, no. 4, рp. 286-292.
39. Zhao J.L., Ma C., O’Connell R.M., Mehta A., diLoreto R., Heath J.R., Baltimore D. Conversion of danger signals into cytokine signals by hematopoietic stem and progenitor cells for regulation of stress-induced hematopoiesis. Cell Stem Cell, 2014, Vol. 14, no. 4, рр. 445-459.
Supplementary files
Review
For citations:
Pashnin S.L., Davydova E.V., Altman D.Sh., Zurochka V.A., Zhuravlev I.Yu., Zhakupova Ya.T. Cytometric features of cellular immune compartment in participants of current military conflicts. Medical Immunology (Russia). 2025;27(5):1087-1098. (In Russ.) https://doi.org/10.15789/1563-0625-CFO-2952