Ferdowsi University of Mashhad

Document Type : Research Articles

Authors

1 Department of Biology, Faculty of Basic Sciences, Gonbad kavous University, Gonbad kavous, Golestan, Iran

2 Department of Plant Production, Collage of Agriculture Science and Natural Resource, Gonbad kavous University, Gonbad kavous, Golestan, Iran

Abstract

     Schizophrenia is an irritating mental disorder that affects around 1% of the world's population. The immune system contributes to the onset of the disease, particularly through production and secretion of some cytokines. In patients with schizophrenia, the balance of Th1 to Th2 ratio is often altered. In the present study, we investigated these changes by measuring the gene expression levels of IFN-γ and T-bet as Th1 indicators, as well as IL-4 and GATA-3 as representatives for Th2. Blood samples of schizophrenic patients (n=25) and healthy individuals (n=10) were obtained. Total RNA was extracted from leukocytes and cDNA synthesis was performed based on provided protocols. Real-time PCR technique was utilized for the assessment of gene expression levels. Results indicated a significant increase in the expression of IFN-γ and its transcription factor, T-bet, while IL-4 gene expression was reduced significantly. The expression level of GATA-3 gene revealed no meaningful changes. Altogether, results confirmed the relative shift of Th1 to Th2 status in the patient with schizophrenia and re-emphasize the importance of the inflammatory events in the incidence of the disease. Moreover, a new index was introduced based on the IFN-γ and T-bet genes expression, which can determine healthy condition with total accuracy of 79%.

Keywords

Ajami A., Abedian F., Hosseini S. H., Akbarian E., Alizadeh-Navaei R. and Taghipour M. (2014) Serum TNF-α, IL-10 and IL-2 in Schizophrenic Patients Before and After Treatment with Risperidone and Clozapine. Iranian Journal of Immunology 11:200-209.
Al Awam K., Haussleiter I. S., Dudley E., Donev R., Brune M., Juckel G. and Thome J. (2015) Multiplatform metabolome and proteome profiling identifies serum metabolite and protein signatures as prospective biomarkers for schizophrenia. Journal of Neural Transmission (Vienna) 122 Suppl 1:S111-122.
Annunziato F., Cosmi L., Galli G., Beltrame C., Romagnani P., Manetti R., Romagnani S. and Maggi E. (1999) Assessment of chemokine receptor expression by human Th1 and Th2 cells in vitro and in vivo. Journal of Leukocyte Biology 65:691-699.
Ayalew M., Le-Niculescu H., Levey D. F., Jain N., Changala B., Patel S. D., Winiger E., Breier A., Shekhar A., Amdur R., Koller D., Nurnberger J. I., Corvin A., Geyer M., Tsuang M. T., Salomon D., Schork N. J., Fanous A. H., O'Donovan M. C. and Niculescu A. B. (2012) Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Molecular Psychiatry 17:887-905.
Bahn S. and Chan M. K. (2015) What Can We Learn About Depression from Gene Expression in Peripheral Tissues? Biological Psychiatry 77:207-209.
Benros M. E. and Mortensen P. B. (2020) Role of Infection, Autoimmunity, Atopic Disorders, and the Immune System in Schizophrenia: Evidence from Epidemiological and Genetic Studies. Current Topics in Behavioral Neurosciences 44:141-159.
Benros M. E., Nielsen P. R., Nordentoft M., Eaton W. W., Dalton S. O. and Mortensen P. B. (2011) Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. American Journal of Psychiatry 168:1303-1310.
Cardno A. G. and Gottesman, II. (2000) Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. American Journal of Medical Genetics 97:12-17.
Chakir H., Wang H., Lefebvre D. E., Webb J. and Scott F. W. (2003) T-bet/GATA-3 ratio as a measure of the Th1/Th2 cytokine profile in mixed cell populations: predominant role of GATA-3. Journal of Immunological Methods 278:157-169.
Chan M. K., Guest P. C., Levin Y., Umrania Y., Schwarz E., Bahn S. and Rahmoune H. (2011) Converging evidence of blood-based biomarkers for schizophrenia: an update. International Review of Neurobiology 101:95-144.
Chang H. R. and Bistrian B. (1998) The role of cytokines in the catabolic consequences of infection and injury. Journal of Parenteral and Enteral Nutrition 22:156-166.
Cox D., Chan M. K. and Bahn S. (2015) The potential of immune biomarkers to advance personalized medicine approaches for schizophrenia. Journal of Nervous and Mental Disease 203:393-399.
Dai J., Megjugorac N. J., Gallagher G. E., Yu R. Y. and Gallagher G. (2009) IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses Th2responses in human naive and memory T cells. Blood 113:5829-5838.
de Witte L., Tomasik J., Schwarz E., Guest P. C., Rahmoune H., Kahn R. S. and Bahn S. (2014) Cytokine alterations in first-episode schizophrenia patients before and after antipsychotic treatment. Schizophrenia Research 154:23-29.
Eaton W. W., Byrne M., Ewald H., Mors O., Chen C. Y., Agerbo E. and Mortensen P. B. (2006) Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. American Journal of Psychiatry 163:521-528.
He K., Guo C., Guo M., Tong S., Zhang Q., Sun H., He L. and Shi Y. (2019) Identification of serum microRNAs as diagnostic biomarkers for schizophrenia. Hereditas 156:23.
He X., Ma Q., Fan Y., Zhao B., Wang W., Zhu F., Ma X. and Zhou L. (2020) The Role of Cytokines in Predicting the Efficacy of Acute Stage Treatment in Patients with Schizophrenia. Neuropsychiatric Disease and Treatment 16:191-199.
Hosmer D. W., Lemeshow S. and Sturdivant R. X. 2013. Applied logistic regression. Wiley, Hoboken, New Jersey. xvi, 500 pages pp.
Kahn R. S. and Sommer I. E. (2015) The neurobiology and treatment of first-episode schizophrenia. Molecular Psychiatry 20:84-97.
Kanhere A., Hertweck A., Bhatia U., Gökmen M. R., Perucha E., Jackson I., Lord G. M. and Jenner R. G. (2012) T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nature Communications 3:1268.
Katsikis P. D., Cohen S. B., Londei M. and Feldmann M. (1995) Are CD4+ Th1 cells pro-inflammatory or anti-inflammatory? The ratio of IL-10 to IFN-gamma or IL-2 determines their function. International Immunology 7:1287-1294.
Kelsven S., de la Fuente-Sandoval C., Achim C. L., Reyes-Madrigal F., Mirzakhanian H., Domingues I. and Cadenhead K. (2020) Immuno-inflammatory changes across phases of early psychosis: The impact of antipsychotic medication and stage of illness. Schizophrenia Research.
Khandaker G. M., Cousins L., Deakin J., Lennox B. R., Yolken R. and Jones P. B. (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry 2:258-270.
Kidd P. (2003) Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alternative Medicine Review 8:223-246.
Kim Y. K., Myint A. M., Lee B. H., Han C. S., Lee H. J., Kim D. J. and Leonard B. E. (2004) Th1, Th2 and Th3 cytokine alteration in schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry 28:1129-1134.
Kumar A., Pareek V., Singh H. N., Faiq M. A., Narayan R. K., Raza K. and Kumar P. (2019) Altered Expression of a Unique Set of Genes Reveals Complex Etiology of Schizophrenia. Frontiers in Psychiatry 10:906.
Lai C. Y., Scarr E., Udawela M., Everall I., Chen W. J. and Dean B. (2016) Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics. World Journal of Psychiatry 6:102-117.
Lazarevic V., Glimcher L. H. and Lord G. M. (2013) T-bet: a bridge between innate and adaptive immunity. Nature Reviews Immunology 13:777-789.
Li Y., Zhou K., Zhang Z., Sun L., Yang J., Zhang M., Ji B., Tang K., Wei Z., He G., Gao L., Yang L., Wang P., Yang P., Feng G., He L. and Wan C. (2012) Label-free quantitative proteomic analysis reveals dysfunction of complement pathway in peripheral blood of schizophrenia patients: evidence for the immune hypothesis of schizophrenia. Molecular BioSystems 8:2664-2671.
Liu S., Zhang F., Shugart Y. Y., Yang L., Li X., Liu Z., Sun N., Yang C., Guo X., Shi J., Wang L., Cheng L., Zhang K., Yang T. and Xu Y. (2017) The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring. Translational Psychiatry 7:e998.
Macedo D. (2019) 37. NEUROIMMUNE DYSFUNCTION IN SCHIZOPHRENIA: FROMBIOMARKERS TO DRUG REPURPOSING. Schizophrenia Bulletin 45:S147-S147.
Mansur R. B., Zugman A., Asevedo E. M., da Cunha G. R., Bressan R. A. and Brietzke E. (2012) Cytokines in schizophrenia: possible role of anti-inflammatory medications in clinical and preclinical stages. Psychiatry and Clinical Neurosciences 66:247-260.
Metz C. E. (1978) Basic principles of ROC analysis. Seminars in Nuclear Medicine 8:283-298.
Modai S. and Shomron N. (2016) Molecular Risk Factors for Schizophrenia. Trends in Molecular Medicine 22:242-253.
Momtazmanesh S., Zare-Shahabadi A. and Rezaei N. (2019) Cytokine Alterations in Schizophrenia: An Updated Review. Frontiers in Psychiatry 10:892.
Muller N., Weidinger E., Leitner B. and Schwarz M. J. (2015) The role of inflammation in schizophrenia. Frontiers in Neuroscience 9:372.
Myles A., Gearhart P. J. and Cancro M. P. (2017) Signals that drive T-bet expression in B cells. Cellular Immunology 321:3-7.
Na K. S. and Kim Y. K. (2007) Monocytic, Th1 and th2 cytokine alterations in the pathophysiology of schizophrenia. Neuropsychobiology 56:55-63.
Nagelkerke N. J. D. (1991) A Note on a General Definition of the Coefficient of Determination. Biometrika 78:691-692.
Noto C., Maes M., Ota V. K., Teixeira A. L., Bressan R. A., Gadelha A. and Brietzke E. (2015) High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World Journal of Biological Psychiatry 16:422-429.
Potvin S., Stip E., Sepehry A. A., Gendron A., Bah R. and Kouassi E. (2008) Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biological Psychiatry 63:801-808.
Rajasekaran A., Shivakumar V., Kalmady S. V., Narayanaswamy J. C., Subbana M., Venugopal D., Amaresha A. C., Venkatasubramanian G. and Debnath M. (2016) The impact of IL10 polymorphisms and sHLA-G levels on the risk of schizophrenia. Asian Journal of Psychiatry 23:39-43.
Rosenblat J. D. (2019) Targeting the immune system in the treatment of bipolar disorder. Psychopharmacology (Berl) 236:2909-2921.
Schmittgen T. D. and Livak K. J. (2008) Analyzing real-time PCR data by the comparative CT method. Nature Protocols 3:1101-1108.
Shi J., Levinson D. F., Duan J., Sanders A. R., Zheng Y., Pe'er I., Dudbridge F., Holmans P. A., Whittemore A. S., Mowry B. J., Olincy A., Amin F., Cloninger C. R., Silverman J. M., Buccola N. G., Byerley W. F., Black D. W., Crowe R. R., Oksenberg J. R., Mirel D. B., Kendler K. S., Freedman R. and Gejman P. V. (2009) Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460:753-757.
Solek C. M., Farooqi N., Verly M., Lim T. K. and Ruthazer E. S. (2018) Maternal immune activation in neurodevelopmental disorders. Developmental Dynamics 247:588-619.
Sonti G., Ilyin S. E. and Plata-Salaman C. R. (1996) Anorexia induced by cytokine interactions at pathophysiological concentrations. American Journal of Physiology 270:R1394-1402.
Srinivasan S., Bettella F., Mattingsdal M., Wang Y., Witoelar A., Schork A. J., Thompson W. K., Zuber V., Schizophrenia Working Group of the Psychiatric Genomics Consortium T. I. H. G. C., Winsvold B. S., Zwart J. A., Collier D. A., Desikan R. S., Melle I., Werge T., Dale A. M., Djurovic S. and Andreassen O. A. (2016) Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biological Psychiatry 80:284-292.
Stolz P. A., Wehring H. J., Liu F., Love R. C., Ellis M., DiPaula B. A. and Kelly D. L. (2019) Effects of Cigarette Smoking and Clozapine Treatment on 20-Year All-Cause & Cardiovascular Mortality in Schizophrenia. Psychiatric Quarterly 90:351-359.
Sun X. Y., Lu J., Zhang L., Song H. T., Zhao L., Fan H. M., Zhong A. F., Niu W., Guo Z. M., Dai Y. H., Chen C., Ding Y. F. and Zhang L. Y. (2015)Aberrant microRNA expression in peripheral plasma and mononuclear cells as specific blood-based biomarkers in schizophrenia patients. Journal of Clinical Neuroscience 22:570-574.
Tasic L., Larcerda A. L. T., Pontes J. G. M., da Costa T., Nani J. V., Martins L. G., Santos L. A., Nunes M. F. Q., Adelino M. P. M., Pedrini M., Cordeiro Q., Bachion de Santana F., Poppi R. J., Brietzke E. and Hayashi M. A. F. (2019) Peripheral biomarkers allow differential diagnosis between schizophrenia and bipolar disorder. Journal of Psychiatric Research 119:67-75.
Tomasik J., Rahmoune H., Guest P. C. and Bahn S. (2016) Neuroimmune biomarkers in schizophrenia. Schizophrenia Research 176:3-13.
Trovao N., Prata J., VonDoellinger O., Santos S., Barbosa M. and Coelho R. (2019) Peripheral Biomarkers for First-Episode Psychosis-Opportunities from the Neuroinflammatory Hypothesis of Schizophrenia. Psychiatry Investigation 16:177-184.
Tullius S. G., Biefer H. R. C., Li S., Trachtenberg A. J., Edtinger K., Quante M., Krenzien F., Uehara H., Yang X., Kissick H. T., Kuo W. P., Ghiran I., de la Fuente M. A., Arredouani M. S., Camacho V., Tigges J. C., Toxavidis V., El Fatimy R., Smith B. D., Vasudevan A. and ElKhal A. (2014) NAD+ protects against EAE by regulating CD4+ T-cell differentiation. Nature Communications 5:5101.
Upthegrove R. and Khandaker G. M. (2020) Cytokines, Oxidative Stress and Cellular Markers of Inflammation in Schizophrenia. Current Topics in Behavioral Neurosciences 44:49-66.
Vatankhah V., Mirabzadeh A., Iranpour H., Dieji B., Norouzi M., Karimipour M., Nobakht J., Esmaeili E. and Ayazi M. (2019) Determination of Changes in Blood Biomarker Levels in Antipsychotic Polypharmacy and Aripiprazole Monotherapy in Patients With Long-term Schizophrenia. Iranian-Rehabilitation-Journal 17:369-376.
Wang T., Holland J. W., Martin S. A. M. and Secombes C. J. (2010) Sequence and expression analysis of two T helper master transcription factors, T-bet and GATA3, in rainbow trout Oncorhynchus mykiss and analysis of their expression during bacterial and parasitic infection. Fish & Shellfish Immunology 29:705-715.
CAPTCHA Image