Patients with posttraumatic stress disorder exhibit an altered phenotype of regulatory T cells

Allergy, Asthma & Clinical Immunology

Mladen Jergović²  Krešo Bendelja⁴  Anđelko Vidović³  Ana Savić⁴  Valerija Vojvoda⁴  Neda Aberle⁵  Sabina Rabatić²  Tanja Jovanovic¹  Ante Sabioncello² 

[1] Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA, USA

[2] Department for Cellular Immunology, Institute of Immunology, Rockfellerova ulica 10, Zagreb, Croatia

[3] Department of Psychiatry, University Hospital Dubrava, Zagreb, Croatia

[4] Centre for research and knowledge transfer in biotechnology, University of Zagreb, Zagreb, Croatia

[5] General hospital “dr. Josip Benčević”, Slavonski Brod, Croatia

关键词: Autoimmunity;    Regulatory T cells;    Posttraumatic stress disorder;   

Others  :  1082135
DOI  :  10.1186/1710-1492-10-43

 received in 2014-05-08, accepted in 2014-08-07,  发布年份 2014

【 摘 要 】

Background

Regulatory T cells (Tregs) play a key role in immune homeostasis in vivo. Tregs have a critical role in preventing the development of autoimmune diseases and defects in Treg function are implicated in various autoimmune disorders. Individuals with posttraumatic stress disorder (PTSD) have higher prevalence of autoimmune disorders than the general population. We hypothesized that war veterans with PTSD would exhibit a decreased number and/or altered phenotype of Tregs.

Methods

We analyzed peripheral blood mononuclear cells (PBMCs) of patients with PTSD (N = 21) (mean age = 45.9) and age-matched healthy controls (N = 23) (mean age = 45.7) to determine the proportion of Tregs and their phenotype according to the expression of CD127 and HLA-DR markers which describe the differentiation stages of Tregs. In addition, we analyzed the expression of membrane ectoenzyme CD39 on Tregs of the study groups, an important component of the suppressive machinery of Tregs.

Results

We found no differences in the proportion of Tregs between PTSD patients and controls, but PTSD patients had a higher percentage of CD127^-HLA-DR^- Tregs and a lower percentage of CD127^loHLA-DR⁺ Tregs compared to controls. There was no difference in expression of CD39 on Tregs of the study groups.

Conclusions

Although the proportions of Tregs in PTSD patients were unchanged, we found that they exhibit a different phenotype of Tregs that might be less suppressive. Impaired differentiation and function of Tregs is likely involved in disruption of immune homeostasis in PTSD.

【 授权许可】

   
2014 Jergovic et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Pillars article: immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 1995. J Immunol 2011, 186:3808-3821.
• [2]Fontenot JD, Gavin MA, Rudensky AY: Foxp3 programs the development and function of CD4 + CD25+ regulatory T cells. Nat Immunol 2003, 4:330-336.
• [3]Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057-1061.
• [4]Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM: JM2, encoding a fork head – related protein, is mutated in X-linked autoimmunity – allergic disregulation syndrome. J Clin Invest 2000, 106:75-81.
• [5]Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001, 27:20-21.
• [6]Ziegler SF: FOXP3: of mice and men. Annu Rev Immunol 2006, 24:209-226.
• [7]Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA: CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006, 203:1701-1711.
• [8]Povoleri GAM, Scottà C, Nova-Lamperti EA, John S, Lombardi G, Afzali B: Thymic versus induced regulatory T cells - who regulates the regulators? Front Immunol 2013, 4:169.
• [9]Long SA, Buckner JH: CD4 + FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game. J Immunol 2011, 187:2061-2066.
• [10]Costantino CM, Baecher-Allan CM, Hafler DA: Human regulatory T cells and autoimmunity. Eur J Immunol 2009, 38:921-924.
• [11]Baecher-Allan C, Wolf E, Hafler DA: MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol 2006, 176:4622-4631.
• [12]Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B: Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006, 203:1693-1700.
• [13]Michel L, Berthelot L, Pettré S, Wiertlewski S, Lefrère F, Braudeau C, Brouard S, Soulillou J, Laplaud D: Patients with relapsing-remitting multiple sclerosis have normal Treg function when cells expressing IL-7 receptor α-chain are excluded from the analysis. J Clin Invest 2008, 118:3411-3419.
• [14]Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, Rossini PM, Battistini L, Rötzschke O, Falk K: Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 2007, 110:1225-1232.
• [15]Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, Tubridy N, Mills KHG: CD39 + Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009, 183:7602-7610.
• [16]American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 5th edition. Arlington, VA: American Psychiatric Publishing; 2013.
• [17]Vieweg WVR, Julius DA, Fernandez A, Beatty-Brooks M, Hettema JM, Pandurangi AK: Posttraumatic stress disorder: clinical features, pathophysiology, and treatment. Am J Med 2006, 119:383-390.
• [18]Yehuda R, LeDoux J: Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 2007, 56:19-32.
• [19]Sundin J, Fear NT, Iversen A, Rona RJ, Wessely S: PTSD after deployment to Iraq: conflicting rates, conflicting claims. Psychol Med 2010, 40:367-382.
• [20]Barrett DH, Doebbeling CC, Schwartz DA, Voelker MD, Falter KH, Woolson RF, Doebbeling BN: Posttraumatic stress disorder and self-reported physical health status among U.S. Military personnel serving during the Gulf War period: a population-based study. Psychosomatics 2002, 43:195-205.
• [21]Boscarino JA: A prospective study of PTSD and early-age heart disease mortality among Vietnam veterans: implications for surveillance and prevention. Psychosom Med 2008, 70:668-676.
• [22]Qureshi S, Pyne J, Magruder K, Schulz P, Kunik M: The link between post-traumatic stress disorder and physical comorbidities: a systematic review. Psychiatr Q 2009, 80:87-97.
• [23]Boscarino JA: Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann N Y Acad Sci 2004, 1032:141-153.
• [24]Baker DG, Nievergelt CM, O’Connor DT: Biomarkers of PTSD: neuropeptides and immune signaling. Neuropharmacology 2012, 62:663-673.
• [25]Pace TWW, Heim CM: A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun 2011, 25:6-13.
• [26]Sommershof A, Aichinger H, Engler H, Adenauer H, Catani C, Boneberg E-M, Elbert T, Groettrup M, Kolassa I-T: Substantial reduction of naïve and regulatory T cells following traumatic stress. Brain Behav Immun 2009, 23:1117-1124.
• [27]Freier E, Weber CS, Nowottne U, Horn C, Bartels K, Meyer S, Hildebrandt Y, Luetkens T, Cao Y, Pabst C, Muzzulini J, Schnee B, Brunner-Weinzierl MC, 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, 35:663-673.
• [28]Schmidt D, Reber SO, Botteron C, Barth T, Peterlik D, Uschold N, Männel DN, Lechner A: Chronic psychosocial stress promotes systemic immune activation and the development of inflammatory Th cell responses. Brain Behav Immun 2010, 24:1097-1104.
• [29]World Health Organisation: ICD-10, International Statistical Classification of Diseases and Health Related Problems, 10th Revision. 1st edition. Geneva: World Health Organisation; 1992.
• [30]King LA, King DW, Leskin G, Foy DW: The Los Angeles symptom checklist: a self report measure of posttraumatic stress disorder. Assessment 1995, 2:1-17.
• [31]Beck AT, Steer RA, Carbin MG: Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 1988, 8:77-100.
• [32]Spielberger CD, Gorsuch RL, Lushene RE: Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press; 1970.
• [33]Weinberg A, Song L-Y, Wilkening C, Sevin A, Blais B, Louzao R, Stein D, Defechereux P, Durand D, Riedel E, Raftery N, Jesser R, Brown B, Keller MF, Dickover R, McFarland E, Fenton T: Optimization and limitations of use of cryopreserved peripheral blood mononuclear cells for functional and phenotypic T-cell characterization. Clin Vaccine Immunol 2009, 16:1176-1186.
• [34]Van Hemelen D, Oude Elberink JNG, Heimweg J, van Oosterhout AJM, Nawijn MC: Cryopreservation does not alter the frequency of regulatory T cells in peripheral blood mononuclear cells. J Immunol Methods 2010, 353:138-140.
• [35]Spitzer C, Barnow S, Völzke H, Wallaschofski H, John U, Freyberger HJ, Löwe B, Grabe HJ: Association of posttraumatic stress disorder with low-grade elevation of C-reactive protein: evidence from the general population. J Psychiatr Res 2010, 44:15-21.
• [36]Vaccarino V, Bremner JD, Afzal N, Veledar E, Goldberg J: Posttraumatic stress disorder is associated with higher c-reactive protein levels. J Am Coll Cardiol 2010, 55:A176.E1656.
• [37]Kawamura N, Kim Y, Asukai N: Suppression of cellular immunity in men with a past history of posttraumatic stress disorder. Am J Psychiatry 2001, 158:484-486.
• [38]Vidović A, Vilibić M, Sabioncello A, Gotovac K, Rabatić S, Folnegović-Smalc V, Dekaris D: Circulating lymphocyte subsets, natural killer cell cytotoxicity, and components of hypothalamic-pituitary-adrenal axis in Croatian war veterans with posttraumatic stress disorder: cross-sectional study. Croat Med J 2007, 48:198-206.
• [39]Boscarino JA, Chang J: Higher abnormal leukocyte and lymphocyte counts 20 years after exposure to severe stress: research and clinical implications. Psychosom Med 1999, 61:378-386.
• [40]Ironson G, Wynings C, Schneiderman N, Baum A, Rodriguez M, Greenwood D, Benight C, Antoni M, LaPerriere A, Huang HS, Klimas N, Fletcher MA: Posttraumatic stress symptoms, intrusive thoughts, loss, and immune function after Hurricane Andrew. Psychosom Med 1997, 59:128-141.
• [41]Altemus M, Dhabhar FS, Yang R: Immune function in PTSD. Ann N Y Acad Sci 2006, 1071:167-183.
• [42]Wang J, Ioan-Facsinay A, van der Voort EIH, Huizinga TWJ, Toes REM: Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007, 37:129-138.
• [43]Aerts NE, Dombrecht EJ, Ebo DG, Bridts CH, Stevens WJ, De Clerck LS: Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis. Cell Immunol 2008, 251:109-115.
• [44]Baecher-Allan CM, Costantino CM, Cvetanovich GL, Ashley CW, Beriou G, Dominguez-Villar M, Hafler DA: CD2 costimulation reveals defective activity by human CD4 + CD25(hi) regulatory cells in patients with multiple sclerosis. J Immunol 2011, 186:3317-3326.
• [45]Jergović M, Tomičević M, Vidović A, Bendelja K, Savić A, Vojvoda V, Rac D, Lovrić-Čavar D, Rabatić S, Jovanovic T, Sabioncello A: Telomere shortening and immune activity in war veterans with posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2014, 54C:275-283.
• [46]Sakaguchi S, Wing K, Onishi Y, Prieto-martin P, Yamaguchi T: Regulatory T cells: how do they suppress immune responses? Int Immunol 2009, 21:1105-1111.
• [47]Niedbala W, Wei X-Q, Cai B, Hueber AJ, Leung BP, McInnes IB, Liew FY: IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol 2007, 37:3021-3029.
• [48]Tiemessen MM, Jagger AL, Evans HG, Van Herwijnen MJC, John S, Taams LS: CD4 + CD25 + Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 2007, 104(49):19446-19451.
• [49]Zheng SG: Regulatory T cells vs Th17: differentiation of Th17 versus Treg, are the mutually exclusive? Am J Clin Exp Immunol 2013, 2:94-106.
• [50]Adalid-Peralta L, Fragoso G, Fleury A, Sciutto E: Mechanisms underlying the induction of regulatory T cells and its relevance in the adaptive immune response in parasitic infections. Int J Biol Sci 2011, 7(9):1412-1426.
• [51]Gotovac K, Sabioncello A, Rabatic S, Berki T, Dekaris D: Flow cytometric determination of glucocorticoid receptor (GCR) expression in lymphocyte subpopulations: lower quantity of GCR in patients with post-traumatic stress disorder (PTSD). Clin Exp Immunol 2003, 131:335-339.
• [52]Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, Keane TM: The development of a clinician-administered PTSD scale. J Trauma Stress 1995, 8:75-90.
• [53]Keane TM, Newman E, Orsillo SM: The assessment of military-related PTSD. In Assessing Psychological Trauma and PTSD. 1st edition. Edited by Wilson JP, Keane TM. New York: The Guilford Press; 1996:267-290.