The Role of Innate and Adaptive Immune System in the Pathogenesis of Schizophrenia
-
Marziyeh Soltani
,
Yousef Mirzaei
,
Ali Hussein Mer
,
Mina Mohammad-Rezaei
,
Zahra Shafaghat
,
Soheila Fattahi
,
Fatemeh Azadegan-Dehkordi
,
Meghdad Abdollahpour-Alitappeh
,
Nader Bagheri
Abstract
Schizophrenia is one of the most severely debilitating mental disorders that affects 1.1% of the world's population. The exact cause of the disease is not known, but genetics, environmental factors (such as infectious agents, season and region of birth, exposure to viruses, low birth weight, advanced paternal age, and tobacco), and immune system dysfunction can all contribute to the development of schizophrenia. Recently, the role of the immune system in schizophrenia has received much attention. Both acquired and innate immune systems are involved in the pathogenesis of schizophrenia and facilitate the disease's progression. Almost all cells of the immune system including microglia, B cells, and T cells play an important role in the blood-brain barrier damage, inflammation, and in the progression of this disease. In schizophrenia, the integrity of the blood-brain barrier is reduced and then the immune cells are recruited into the endothelium following an increase in the expression of cell adhesion molecules. The entry of immune cells and cytokines leads to inflammation and antibody production in the brain. Accordingly, the results of this study strengthen the hypothesis that the innate and acquired immune systems are involved in the pathogenesis of schizophrenia.
1. Li C, Whelan R, Yang H, Jiang Y, Qiu C, Meng Q, et al. Anti-TSNARE1 IgG plasma levels differ by sex in patients with schizophrenia in a Chinese population. FEBS Open Bio. 2019;9(10):1705-12.
2. Nakazawa K, Sapkota K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther. 2020;205:107426.
3. Severance EG, Dickerson FB, Yolken RH. Autoimmune phenotypes in schizophrenia reveal novel treatment targets. Pharmacol Ther. 2018;189:184-98.
4. Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, et al. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018;44(6):1195-203.
5. Zhang W, Amos TB, Gutkin SW, Lodowski N, Giegerich E, Joshi K. A systematic literature review of the clinical and health economic burden of schizophrenia in privately insured patients in the United States. Clinicoecon Outcomes Res. 2018;10:309-20.
6. Marcellusi A, Fabiano G, Viti R, Francesa Morel PC, Nicolò G, Siracusano A, et al. Economic burden of schizophrenia in Italy: a probabilistic cost of illness analysis. BMJ Open. 2018;8(2):e018359.
7. Fond G, Lançon C, Korchia T, Auquier P, Boyer L. The Role of Inflammation in the Treatment of Schizophrenia. Front Psychiatry. 2020;11:160.
8. Mohebbi A, Yasaghi M, Mamizadeh Z, Salehnia A, Lorestani N, Tabarraei A. Risk of Borna Disease Virus among Asian Psychiatric Patients: A Systematic Review and Meta-Analysis. Iran J Virol. 2018;12(1):6-19.
9. van Mierlo HC, Broen JCA, Kahn RS, de Witte LD. B-cells and schizophrenia: A promising link or a finding lost in translation? Brain Behav Immun. 2019;81:52-62.
10. Whelan R, St Clair D, Mustard CJ, Hallford P, Wei J. Study of Novel Autoantibodies in Schizophrenia. Schizophr Bull. 2018;44(6):1341-9.
11. Momtazmanesh S, Zare-Shahabadi A, Rezaei N. Cytokine Alterations in Schizophrenia: An Updated Review. Front Psychiatry. 2019;10:892.
12. Comer AL, Carrier M, Tremblay M, Cruz-Martín A. The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation. Front Cell Neurosci. 2020;14:274.
13. Shalev H, Serlin Y, Friedman A. Breaching the blood-brain barrier as a gate to psychiatric disorder. Cardiovasc Psychiatry Neurol. 2009;2009:278531.
14. Sæther SG, Rø ADB, Larsen JB, Vaaler A, Kondziella D, Reitan SK. Biomarkers of Autoimmunity in Acute Psychiatric Disorders. J Neuropsychiatry Clin Neurosci. 2019;31(3):246-53.
15. Fatani BZ, Aldawod R, Alhawaj A, Alsadah S, Slais FR, Alyaseen EN, et al. Schizophrenia: etiology, pathophysiology and management-a review. The Egyptian Journal of Hospital Medicine. 2017;69(6):2640-6.
16. Tamminga CA, Medoff DR. The biology of schizophrenia. Dialogues in clinical neuroscience. 2022.
17. Arab A, Mohebbi A, Afshar H, Moradi A. Multi-factorial Etiology of Bipolar Disorder and Schizophrenia in Iran: No Evidence of Borna Disease Virus Genome. Med Laboratory J. 2018;12(5):42-9.
18. McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry. 2020;19(1):15-33.
19. Sonnenschein SF, Gomes FV, Grace AA. Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia. Front Psychiatry. 2020;11:613.
20. Zamanpoor M. Schizophrenia in a genomic era: a review from the pathogenesis, genetic and environmental etiology to diagnosis and treatment insights. Psychiatr Genet. 2020;30(1):1-9.
21. Severance EG, Yolken RH. From Infection to the Microbiome: An Evolving Role of Microbes in Schizophrenia. Curr Top Behav Neurosci. 2020;44:67-84.
22. Brown AS. Exposure to prenatal infection and risk of schizophrenia. Front Psychiatry. 2011;2:63.
23. Tanaka T, Matsuda T, Hayes LN, Yang S, Rodriguez K, Severance EG, et al. Infection and inflammation in schizophrenia and bipolar disorder. Neurosci Res. 2017;115:59-63.
24. Cheslack-Postava K, Brown AS. Prenatal infection and schizophrenia: A decade of further progress. Schizophr Res. 2021.
25. Laupu W. Recommendations to Help Prevent Mental Disorders and Limit Stigma. British Journal of Medical and Health Research. 2018;5(9).
26. Brown AS, Patterson PH. Maternal infection and schizophrenia: implications for prevention. Schizophr Bull. 2011;37(2):284-90.
27. Sørensen HJ, Foldager L, Røge R, Pristed SG, Andreasen JT, Nielsen J. An association between autumn birth and clozapine treatment in patients with schizophrenia: a population-based analysis. Nord J Psychiatry. 2014;68(6):428-32.
28. Kneeland RE, Fatemi SH. Viral infection, inflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:35-48.
29. Demler TL. Challenging the hypothesized link to season of birth in patients with schizophrenia. Innov Clin Neurosci. 2011;8(9):14-9.
30. Coury SM, Lombroso A, Avila-Quintero VJ, Taylor JH, Flores JM, Szejko N, et al. Systematic review and meta-analysis: Season of birth and schizophrenia risk. Schizophr Res. 2023;252:244-52.
31. Karlsson H, Dal H, Gardner RM, Torrey EF, Dalman C. Birth month and later diagnosis of schizophrenia. A population-based cohort study in Sweden. J Psychiatr Res. 2019;116:1-6.
32. Faivre S, Roche N, Lacerre F, Dealberto MJ. Vitamin D deficiency in a psychiatric population and correlation between vitamin D and CRP. Encephale. 2019;45(5):376-83.
33. Cui X, McGrath JJ, Burne THJ, Eyles DW. Vitamin D and schizophrenia: 20 years on. Mol Psychiatry. 2021;26(7):2708-20.
34. Davies C, Segre G, Estradé A, Radua J, De Micheli A, Provenzani U, et al. Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2020;7(5):399-410.
35. King S, St-Hilaire A, Heidkamp D. Prenatal factors in schizophrenia. Curr Dir Psychol Sci. 2010;19(4):209-13.
36. Lipner E, Murphy SK, Ellman LM. Prenatal Maternal Stress and the Cascade of Risk to Schizophrenia Spectrum Disorders in Offspring. Curr Psychiatry Rep. 2019;21(10):99.
37. Miller BJ, Culpepper N, Rapaport MH, Buckley P. Prenatal inflammation and neurodevelopment in schizophrenia: a review of human studies. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:92-100.
38. Yüksel RN, Altunsoy N, Tikir B, Cingi Külük M, Unal K, Goka S, et al. Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation. Ther Adv Psychopharmacol. 2014;4(6):268-75.
39. Schoenrock SA, Tarantino LM. Developmental vitamin D deficiency and schizophrenia: the role of animal models. Genes Brain Behav. 2016;15(1):45-61.
40. Daiva A, Sarjana W, Fitrikasari A, Wijayahadi N, Woroasih S. Correlation of Serum Vitamin D Levels with Cognitive Function in Schizophrenic Patients. Clinical Schizophrenia & Related Psychoses. 2023;17(2).
41. Gaughran F, Stringer D, Wojewodka G, Landau S, Smith S, Gardner-Sood P, et al. Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial. JAMA Netw Open. 2021;4(12):e2140858.
42. Akinlade KS, Olaniyan OA, Lasebikan VO, Rahamon SK. Vitamin D Levels in Different Severity Groups of Schizophrenia. Front Psychiatry. 2017;8:105.
43. Viani-Walsh D, Kennedy-Williams S, Taylor D, Gaughran F, Lally J. Vitamin D deficiency in schizophrenia implications for COVID-19 infection. Ir J Psychol Med. 2021;38(4):278-87.
44. Jaholkowski P, Hindley GFL, Shadrin AA, Tesfaye M, Bahrami S, Nerhus M, et al. Genome-wide Association Analysis of Schizophrenia and Vitamin D Levels Shows Shared Genetic Architecture and Identifies Novel Risk Loci. Schizophr Bull. 2023.
45. Lodge DJ, Grace AA. Developmental pathology, dopamine, stress and schizophrenia. Int J Dev Neurosci. 2011;29(3):207-13.
46. Almuqrin A, Georgiades A, Mouhitzadeh K, Rubinic P, Mechelli A, Tognin S. The association between psychosocial stress, interpersonal sensitivity, social withdrawal and psychosis relapse: a systematic review. Schizophrenia. 2023;9(1):22.
47. Gomes FV, Zhu X, Grace AA. Stress during critical periods of development and risk for schizophrenia. Schizophr Res. 2019;213:107-13.
48. Lange C, Deutschenbaur L, Borgwardt S, Lang UE, Walter M, Huber CG. Experimentally induced psychosocial stress in schizophrenia spectrum disorders: A systematic review. Schizophr Res. 2017;182:4-12.
49. Shoib S, Das S, Gupta AK, Saleem T, Saleem SM. Perceived stress, quality of life, and coping skills among patients with schizophrenia in symptomatic remission. Middle East Current Psychiatry. 2021;28(1):1-8.
50. Tas C, Brown EC, Eskikurt G, Irmak S, Aydın O, Esen-Danaci A, et al. Cortisol response to stress in schizophrenia: Associations with oxytocin, social support and social functioning. Psychiatry Res. 2018;270:1047-52.
51. Streit F, Memic A, Hasandedić L, Rietschel L, Frank J, Lang M, et al. Perceived stress and hair cortisol: Differences in bipolar disorder and schizophrenia. Psychoneuroendocrinology. 2016;69:26-34.
52. Chang X, Lima LA, Liu Y, Li J, Li Q, Sleiman PMA, et al. Common and Rare Genetic Risk Factors Converge in Protein Interaction Networks Underlying Schizophrenia. Front Genet. 2018;9:434.
53. Henriksen MG, Nordgaard J, Jansson LB. Genetics of Schizophrenia: Overview of Methods, Findings and Limitations. Front Hum Neurosci. 2017;11:322.
54. Bishop JR, Zhang L, Lizano P. Inflammation Subtypes and Translating Inflammation-Related Genetic Findings in Schizophrenia and Related Psychoses: A Perspective on Pathways for Treatment Stratification and Novel Therapies. Harv Rev Psychiatry. 2022;30(1):59-70.
55. Degenhardt F. Update on the genetic architecture of schizophrenia. Medizinische Genetik. 2020;32(1):19-24.
56. Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019;381(18):1753-61.
57. Mongan D, Ramesar M, Föcking M, Cannon M, Cotter D. Role of inflammation in the pathogenesis of schizophrenia: A review of the evidence, proposed mechanisms and implications for treatment. Early Interv Psychiatry. 2020;14(4):385-97.
58. Togay A, Togay B, Ozbay Gediz D, Akbaş SH, Köksoy S. Levels of lymphocyte-associated regulators of complement system CD55 and CD59 are changed in schizophrenia patients. Int J Psychiatry Clin Pract. 2021;25(3):277-82.
59. Cleynen I, Engchuan W, Hestand MS, Heung T, Holleman AM, Johnston HR, et al. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Mol Psychiatry. 2021;26(8):4496-510.
60. Matanat Y, Naseer IA, Murtaza A, Tareen NF, Khalid A, Nabeel W, et al. Relation of Schizophrenia to Psychosis with Respect to Immune Dysregulation and Its Impact on Memory and Learning. Arch Microbiol Immunol. 2022;6:123-40.
61. McAllister AK. Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry. 2014;75(4):262-8.
62. Pouget JG. The Emerging Immunogenetic Architecture of Schizophrenia. Schizophr Bull. 2018;44(5):993-1004.
63. Debnath M, Berk M, Leboyer M, Tamouza R. The MHC/HLA gene complex in major psychiatric disorders: emerging roles and implications. Curr Behavioral Neuroscience Reports. 2018;5(2):179-88.
64. Mokhtari R, Lachman HM. The Major Histocompatibility Complex (MHC) in Schizophrenia: A Review. J Clin Cell Immunol. 2016;7(6).
65. Corvin A, Morris DW. Genome-wide association studies: findings at the major histocompatibility complex locus in psychosis. Biol Psychiatry. 2014;75(4):276-83.
66. Kelly DL, Li X, Kilday C, Feldman S, Clark S, Liu F, et al. Increased circulating regulatory T cells in medicated people with schizophrenia. Psychiatry Res. 2018;269:517-23.
67. Woo JJ, Pouget JG, Zai CC, Kennedy JL. The complement system in schizophrenia: where are we now and what's next? Mol Psychiatry. 2020;25(1):114-30.
68. Kanazawa T, Bousman CA, Liu C, Everall IP. Schizophrenia genetics in the genome-wide era: a review of Japanese studies. NPJ Schizophr. 2017;3(1):27.
69. Hyun JS, Inoue T, Hayashi-Takagi A. Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia. Biomolecules. 2020;10(8).
70. Nimgaonkar VL, Prasad KM, Chowdari KV, Severance EG, Yolken RH. The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis. Mol Psychiatry. 2017;22(11):1554-61.
71. Warwick CA, Keyes AL, Woodruff TM, Usachev YM. The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain. J Biol Chem. 2021;297(3):101085.
72. Kopczynska M, Zelek W, Touchard S, Gaughran F, Di Forti M, Mondelli V, et al. Complement system biomarkers in first episode psychosis. Schizophr Res. 2019;204:16-22.
73. Druart M, Le Magueresse C. Emerging Roles of Complement in Psychiatric Disorders. Front Psychiatry. 2019;10:573.
74. Hogenaar JT, van Bokhoven H. Schizophrenia: Complement Cleaning or Killing. Genes. 2021;12(2):259.
75. Gallego JA, Blanco EA, Morell C, Lencz T, Malhotra AK. Complement component C4 levels in the cerebrospinal fluid and plasma of patients with schizophrenia. Neuropsychopharmacology. 2021;46(6):1140-4.
76. Birnbaum R, Jaffe AE, Chen Q, Shin JH, Kleinman JE, Hyde TM, et al. Investigating the neuroimmunogenic architecture of schizophrenia. Mol Psychiatry. 2018;23(5):1251-60.
77. Johnson EC, Border R, Melroy-Greif WE, de Leeuw CA, Ehringer MA, Keller MC. No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes. Biol Psychiatry. 2017;82(10):702-8.
78. Pollak TA, Drndarski S, Stone JM, David AS, McGuire P, Abbott NJ. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5(1):79-92.
79. Pong S, Karmacharya R, Sofman M, Bishop JR, Lizano P. The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia. Complex Psychiatry. 2020;6(1-2):30-46.
80. Maes M, Sirivichayakul S, Kanchanatawan B, Vodjani A. Breakdown of the Paracellular Tight and Adherens Junctions in the Gut and Blood Brain Barrier and Damage to the Vascular Barrier in Patients with Deficit Schizophrenia. Neurotox Res. 2019;36(2):306-22.
81. Farrell M, Aherne S, O'Riordan S, O'Keeffe E, Greene C, Campbell M. Blood-brain barrier dysfunction in a boxer with chronic traumatic encephalopathy and schizophrenia. Clin Neuropathol. 2019;38(2):51-8.
82. Müller N, Riedel M, Hadjamu M, Schwarz MJ, Ackenheil M, Gruber R. Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia. Am J Psychiatry. 1999;156(4):634-6.
83. Melkersson K, Bensing S. Signs of impaired blood-brain barrier function and lower IgG synthesis within the central nervous system in patients with schizophrenia or related psychosis, compared to that in controls. Neuro Endocrinol Lett. 2018;39(1):33-42.
84. Najjar S, Pahlajani S, De Sanctis V, Stern JNH, Najjar A, Chong D. Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. Front Psychiatry. 2017;8:83.
85. Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44(5):321-30.
86. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, Nordentoft M, Kondziella D, Krogh J, et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry. 2019;24(6):869-87.
87. Masopust J, Malý R, Andrýs C, Vališ M, Bažant J, Hosák L. Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study. BMC Psychiatry. 2011;11:2.
88. de Klerk OL, Willemsen AT, Bosker FJ, Bartels AL, Hendrikse NH, den Boer JA, et al. Regional increase in P-glycoprotein function in the blood-brain barrier of patients with chronic schizophrenia:: A PET study with [11C] verapamil as a probe for P-glycoprotein function. Psychiatry Research: Neuroimaging. 2010;183(2):151-6.
89. Kroken RA, Sommer IE, Steen VM, Dieset I, Johnsen E. Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics. Front Psychiatry. 2018;9:753.
90. Louveau A, Filiano AJ, Kipnis J. Meningeal whole mount preparation and characterization of neural cells by flow cytometry. Curr Protoc Immunol. 2018;121(1):e50.
91. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2(3):258-70.
92. Upthegrove R, Barnes NM. The immune system and schizophrenia: an update for clinicians. Advances in psychiatric treatment. 2014;20(2):83-91.
93. Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry. 2014;75(4):324-31.
94. Fernandez-Egea E, Vértes PE, Flint SM, Turner L, Mustafa S, Hatton A, et al. Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia. PLoS One. 2016;11(5):e0155631.
95. Karpiński P, Frydecka D, Sąsiadek MM, Misiak B. Reduced number of peripheral natural killer cells in schizophrenia but not in bipolar disorder. Brain Behav Immun. 2016;54:194-200.
96. Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2013;73(10):993-9.
97. Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T. Bidirectional Microglia-Neuron Communication in Health and Disease. Front Cell Neurosci. 2018;12:323.
98. Wang C, Aleksic B, Ozaki N. Glia-related genes and their contribution to schizophrenia. Psychiatry Clin Neurosci. 2015;69(8):448-61.
99. Dietz AG, Goldman SA, Nedergaard M. Glial cells in schizophrenia: a unified hypothesis. Lancet Psychiatry. 2020;7(3):272-81.
100. Ormel PR, Böttcher C, Gigase FAJ, Missall RD, van Zuiden W, Fernández Zapata MC, et al. A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells. Brain Behav Immun. 2020;90:196-207.
101. Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P, et al. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med. 2019;49(13):2186-96.
102. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22(3):374-85.
103. Caruso G, Grasso M, Fidilio A, Tascedda F, Drago F, Caraci F. Antioxidant Properties of Second-Generation Antipsychotics: Focus on Microglia. Pharmaceuticals (Basel). 2020;13(12).
104. Ermakov EA, Dmitrieva EM, Parshukova DA, Kazantseva DV, Vasilieva AR, Smirnova LP. Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives. Oxid Med Cell Longev. 2021;2021:8881770.
105. Laskaris LE, Di Biase MA, Everall I, Chana G, Christopoulos A, Skafidas E, et al. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol. 2016;173(4):666-80.
106. Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009;63(3):257-65.
107. Novellino F, Saccà V, Donato A, Zaffino P, Spadea MF, Vismara M, et al. Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases. Int J Mol Sci. 2020;21(3).
108. Wang M, Zhang L, Gage FH. Microglia, complement and schizophrenia. Nat Neurosci. 2019;22(3):333-4.
109. Guo S, Wang H, Yin Y. Microglia Polarization From M1 to M2 in Neurodegenerative Diseases. Front Aging Neurosci. 2022;14:815347.
110. Tahmasebinia F, Pourgholaminejad A. The role of Th17 cells in auto-inflammatory neurological disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt B):408-16.
111. Müller N, Riedel M, Ackenheil M, Schwarz MJ. Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. World J Biol Psychiatry. 2000;1(4):173-9.
112. Asadi-Samani M, Bagheri N, Rafieian-Kopaei M, Shirzad H. Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review. Phytotherapy research : PTR. 2017;31(8):1128-39.
113. Bagheri N, Azadegan-Dehkordi F, Rahimian G, Hashemzadeh-Chaleshtori M, Rafieian-Kopaei M, Kheiri S, et al. Altered Th17 Cytokine Expression in Helicobacter pylori Patients with TLR4 (D299G) Polymorphism. Immunol Invest. 2016;45(2):161-71.
114. Singh RP, Hasan S, Sharma S, Nagra S, Yamaguchi DT, Wong DT, et al. Th17 cells in inflammation and autoimmunity. Autoimmun Rev. 2014;13(12):1174-81.
115. Xin N, Namaka MP, Dou C, Zhang Y. Exploring the role of interleukin-22 in neurological and autoimmune disorders. Int Immunopharmacol. 2015;28(2):1076-83.
116. Ding M, Song X, Zhao J, Gao J, Li X, Yang G, et al. Activation of Th17 cells in drug naïve, first episode schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:78-82.
117. Varun CN, Venkataswamy MM, Ravikumar R, Nagaraju R, Debnath M, Varambally S, et al. Th17 and MAIT cell mediated inflammation in antipsychotic free schizophrenia patients. Schizophr Res. 2019;212:47-53.
118. Debnath M, Berk M. Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull. 2014;40(6):1412-21.
119. Corsi-Zuelli F, Deakin B. Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia. Neurosci Biobehav Rev. 2021;125:637-53.
120. Sahbaz C, Zibandey N, Kurtulmus A, Duran Y, Gokalp M, Kırpınar I, et al. Reduced regulatory T cells with increased proinflammatory response in patients with schizophrenia. Psychopharmacology (Berl). 2020;237(6):1861-71.
121. Sanaei MJ, Nahid-Samiei M, Abadi MSS, Arjmand MH, Ferns GA, Bashash D, et al. New insights into regulatory B cells biology in viral, bacterial, and parasitic infections. Infect Genet Evol. 2021;89:104753.
122. Tanabe S, Yamashita T. B lymphocytes: Crucial contributors to brain development and neurological diseases. Neurosci Res. 2019;139:37-41.
123. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune system abnormalities in schizophrenia: an integrative view and translational perspectives. Frontiers in Psychiatry. 2022;13:880568.
124. Schlaaff K, Dobrowolny H, Frodl T, Mawrin C, Gos T, Steiner J, et al. Increased densities of T and B lymphocytes indicate neuroinflammation in subgroups of schizophrenia and mood disorder patients. Brain Behav Immun. 2020;88:497-506.
125. Colijn MA, Ismail Z. Clinically Relevant Anti-Neuronal Cell Surface Antibodies in Schizophrenia Spectrum Disorders. Neuropsychobiology. 2019;78(2):70-8.
126. Adell A. Brain NMDA Receptors in Schizophrenia and Depression. Biomolecules. 2020;10(6).
127. Kao YC, Lin MI, Weng WC, Lee WT. Neuropsychiatric Disorders Due to Limbic Encephalitis: Immunologic Aspect. Int J Mol Sci. 2020;22(1).
128. Khandaker GM MU, Jones PB. . Neuroin ammation and Schizophrenia: Springer; 1st ed. 2020 edition (January 23, 2020); 2020. Available from: http://www.springer.com/series/7854.; 2020.
129. Hara M, Ariño H, Petit-Pedrol M, Sabater L, Titulaer MJ, Martinez-Hernandez E, et al. DPPX antibody-associated encephalitis: Main syndrome and antibody effects. Neurology. 2017;88(14):1340-8.
130. Coutinho E, Vincent A. Central nervous system neuronal surface antibodies. In: Shoenfeld Y MP, Gershwin ME, editors. , editor. Autoantibodies. (Third Edition). San Diego: ed: Elsevier 2014; 2014. p. 595-603
131. Giannoccaro MP, Crisp SJ, Vincent A. Antibody-mediated central nervous system diseases. Brain Neurosci Adv. 2018;2:2398212818817497.
132. Mader S, Brimberg L. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019;8(2).
133. Vandebroek A, Yasui M. Regulation of AQP4 in the Central Nervous System. Int J Mol Sci. 2020;21(5).
134. Verkman AS, Smith AJ, Phuan PW, Tradtrantip L, Anderson MO. The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets. 2017;21(12):1161-70.
135. Zeppenfeld DM, Simon M, Haswell JD, D'Abreo D, Murchison C, Quinn JF, et al. Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains. JAMA Neurol. 2017;74(1):91-9.
136. Xue X, Zhang W, Zhu J, Chen X, Zhou S, Xu Z, et al. Aquaporin-4 deficiency reduces TGF-β1 in mouse midbrains and exacerbates pathology in experimental Parkinson's disease. J Cell Mol Med. 2019;23(4):2568-82.
137. Stadelmann C, Timmler S, Barrantes-Freer A, Simons M. Myelin in the Central Nervous System: Structure, Function, and Pathology. Physiol Rev. 2019;99(3):1381-431.
138. Pronker MF, Lemstra S, Snijder J, Heck AJ, Thies-Weesie DM, Pasterkamp RJ, et al. Structural basis of myelin-associated glycoprotein adhesion and signalling. Nat Commun. 2016;7:13584.
139. Ambrosius W, Michalak S, Kozubski W, Kalinowska A. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Current Insights into the Disease Pathophysiology, Diagnosis and Management. Int J Mol Sci. 2020;22(1).
140. Peschl P, Bradl M, Höftberger R, Berger T, Reindl M. Myelin Oligodendrocyte Glycoprotein: Deciphering a Target in Inflammatory Demyelinating Diseases. Front Immunol. 2017;8:529.
141. Papasergi-Scott MM, Robertson MJ, Seven AB, Panova O, Mathiesen JM, Skiniotis G. Structures of metabotropic GABA(B) receptor. Nature. 2020;584(7820):310-4.
142. Fatemi SH, Folsom TD, Thuras PD. GABA(A) and GABA(B) receptor dysregulation in superior frontal cortex of subjects with schizophrenia and bipolar disorder. Synapse. 2017;71(7).
143. de Bartolomeis A, Manchia M, Marmo F, Vellucci L, Iasevoli F, Barone A. Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia. Front Psychiatry. 2020;11:369.
144. Karis K, Eskla KL, Kaare M, Täht K, Tuusov J, Visnapuu T, et al. Altered Expression Profile of IgLON Family of Neural Cell Adhesion Molecules in the Dorsolateral Prefrontal Cortex of Schizophrenic Patients. Front Mol Neurosci. 2018;11:8.
145. Venkannagari H, Kasper JM, Misra A, Rush SA, Fan S, Lee H, et al. Highly Conserved Molecular Features in IgLONs Contrast Their Distinct Structural and Biological Outcomes. J Mol Biol. 2020;432(19):5287-303.
146. Gibbons A, Dean B. The Cholinergic System: An Emerging Drug Target for Schizophrenia. Curr Pharm Des. 2016;22(14):2124-33.
147. Ma KG, Qian YH. Alpha 7 nicotinic acetylcholine receptor and its effects on Alzheimer's disease. Neuropeptides. 2019;73:96-106.
148. Debnath M, Berk M. Functional Implications of the IL-23/IL-17 Immune Axis in Schizophrenia. Mol Neurobiol. 2017;54(10):8170-8.
149. Dinarello CA. Proinflammatory cytokines. Chest. 2000;118(2):503-8.
150. Libíkowa H, Stancek D, Wiedermann V, Hasto J, Breier S. Psychopharmaca and electroconvulsive therapy in relation to viral antibodies and interferon. Experimental and clinical study. Arch Immunol Ther Exp (Warsz). 1977;25(5):641-9.
151. Smith RS. A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses. 1992;39(3):248-57.
152. Keshavarz F, Soltani M, Mokhtarian K, Beshkar P, Majidi J, Azadegan-Dehkordi F, et al. Autoantibodies against Central Nervous System Antigens and the Serum Levels of IL-32 in Patients with Schizophrenia. Neuroimmunomodulation. 2022;29(4):493-9.
153. Reale M, Costantini E, Greig NH. Cytokine imbalance in schizophrenia. From research to clinic: potential implications for treatment. Front psychiatry. 2021:82.
154. Brambilla P, Bellani M, Isola M, Bergami A, Marinelli V, Dusi N, et al. Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia. Translational psychiatry. 2014;4(7):e406-e.
155. Akdis M, Aab A, Altunbulakli C, Azkur K, Costa RA, Crameri R, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. Journal of Allergy and Clinical Immunology. 2016;138(4):984-1010.
156. Goldsmith D, Rapaport M, Miller B. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Molecular psychiatry. 2016;21(12):1696-709.
157. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological psychiatry. 2011;70(7):663-71.
158. Dahan S, Bragazzi NL, Yogev A, Bar-Gad M, Barak V, Amital H, et al. The relationship between serum cytokine levels and degree of psychosis in patients with schizophrenia. Psychiatry research. 2018;268:467-72.
159. Romeo B, Brunet-Lecomte M, Martelli C, Benyamina A. Kinetics of cytokine levels during antipsychotic treatment in schizophrenia: a meta-analysis. International Journal of Neuropsychopharmacology. 2018;21(9):828-36.
160. Tourjman V, Kouassi E, Koue M-E, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, et al. Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophrenia research. 2013;151(1-3):43-7.
161. Azizi E, Hosseini AZ, Soudi S, Noorbala AA. Alteration of serum levels of cytokines in schizophrenic patients before and after treatment with risperidone. Iranian Journal of Allergy, Asthma and Immunology. 2019:262-8.
162. Zhang L, Zheng H, Wu R, Kosten TR, Zhang X-Y, Zhao J. The effect of minocycline on amelioration of cognitive deficits and pro-inflammatory cytokines levels in patients with schizophrenia. Schizophrenia research. 2019;212:92-8.
163. Capuzzi E, Bartoli F, Crocamo C, Clerici M, Carrà G. Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: a meta-analysis. Neuroscience & Biobehavioral Reviews. 2017;77:122-8.
164. Song X, Fan X, Li X, Zhang W, Gao J, Zhao J, et al. Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naive, first-episode schizophrenia. Psychopharmacology. 2014;231(2):319-25.
165. Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. Changes in serum interleukin-2,-6, and-8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry. 2004;65(7):940-7.
166. Dikeç G, Arabaci LB, Uzunoglu GB, Mizrak SD. Metabolic side effects in patients using atypical antipsychotic medications during hospitalization. J Psychosoc Nurs Ment Health Serv. 2018;56(4):28-37.
167. Ouyang W, O’Garra A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity. 2019;50(4):871-91.
168. Álvarez-Satta M, Berna-Erro A, Carrasco-Garcia E, Alberro A, Saenz-Antoñanzas A, Vergara I, et al. Relevance of oxidative stress and inflammation in frailty based on human studies and mouse models. Aging (Albany NY). 2020;12(10):9982.
169. Pillinger T, Osimo EF, Brugger S, Mondelli V, McCutcheon RA, Howes OD. A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophrenia bulletin. 2019;45(5):1120-33.
170. Marcinowicz P, Więdłocha M, Zborowska N, Dębowska W, Podwalski P, Misiak B, et al. A meta-analysis of the influence of antipsychotics on cytokines levels in first episode psychosis. J Clin Med. 2021;10(11):2488.
171. Huang A, Cheng L, He M, Nie J, Wang J, Jiang K. Interleukin-35 on B cell and T cell induction and regulation. J Inflamm (Lond). 2017;14:16.
172. Zhang J, Zhang Y, Wang Q, Li C, Deng H, Si C, et al. Interleukin-35 in immune-related diseases: protection or destruction. Immunology. 2019;157(1):13-20.
173. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566-9.
174. Kochetkova I, Golden S, Holderness K, Callis G, Pascual DW. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol. 2010;184(12):7144-53.
175. Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, et al. 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(11):3021-9.
176. Tirotta E, Duncker P, Oak J, Klaus S, Tsukamoto MR, Gov L, et al. Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis. J Neuroimmunol. 2013;254(1-2):110-6.
177. Huang CH, Loo EX, Kuo IC, Soh GH, Goh DL, Lee BW, et al. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35. J Immunol. 2011;187(1):462-71.
178. Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20(6):633-41.
179. Hu Y, Dong C, Yue Y, Xiong S. In vivo delivery of interleukin-35 relieves coxsackievirus-B3-induced viral myocarditis by inhibiting Th17 cells. Arch Virol. 2014;159(9):2411-9.
180. Huang Y, Lin YZ, Shi Y, Ji QW. IL-35: a potential target for the treatment of atherosclerosis. Pharmazie. 2013;68(10):793-5.
181. Liu Y, Wu Y, Wang Y, Cai Y, Hu B, Bao G, et al. IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects. Leukemia. 2015;29(4):939-46.
182. Soltani M, Beshkar P, Mokhtarian K, Anjomshoa M, Mohammad-Rezaei M, Azadegan-Dehkordi F, et al. A Study of Autoantibodies against Some Central Nervous System Antigens and the IL-35 Serum Level in Schizophrenia. Iranian J Allergy, Asthma, Immunol. 2022;21(4):441-8.
183. Rider P, Carmi Y, Cohen I. Biologics for targeting inflammatory cytokines, clinical uses, and limitations. International journal of cell biology. 2016;2016.
184. Kane JM, Correll CU. Pharmacologic treatment of schizophrenia. Dialogues Clin Neurosci. 2010;12(3):345-57.
185. Yang AC, Tsai SJ. New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. Int J Mol Sci. 2017;18(8).
186. Catts SV, O'Toole BI. The treatment of schizophrenia: Can we raise the standard of care? Aust N Z J Psychiatry. 2016;50(12):1128-38.
187. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P t. 2014;39(9):638-45.
188. Pandurangi AK, Buckley PF. Inflammation, Antipsychotic Drugs, and Evidence for Effectiveness of Anti-inflammatory Agents in Schizophrenia. Curr Top Behav Neurosci. 2020;44:227-44.
189. Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia. J Clin Psychiatry. 2010;71(9):1115-24.
190. Miller BJ, Buckley PF. The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia. Psychiatr Clin North Am. 2016;39(2):187-98.
191. Miller BJ, Goldsmith DR. Towards an Immunophenotype of Schizophrenia: Progress, Potential Mechanisms, and Future Directions. Neuropsychopharmacology. 2017;42(1):299-317.
192. Dimitrov DH, Lee S, Yantis J, Honaker C, Braida N. Cytokine serum levels as potential biological markers for the Psychopathology in Schizophrenia. Advances in Psychiatry. 2014;2014.
193. Ellul P, Groc L, Tamouza R, Leboyer M. The Clinical Challenge of Autoimmune Psychosis: Learning from Anti-NMDA Receptor Autoantibodies. Front Psychiatry. 2017;8:54.
194. Miller BJ, Goldsmith DR. Evaluating the Hypothesis That Schizophrenia Is an Inflammatory Disorder. Focus (Am Psychiatr Publ). 2020;18(4):391-401.
195. Melbourne JK, Feiner B, Rosen C, Sharma RP. Targeting the Immune System with Pharmacotherapy in Schizophrenia. Curr Treat Options Psychiatry. 2017;4(2):139-51.
196. Lennox B, Yeeles K, Jones PB, Zandi M, Joyce E, Yu LM, et al. Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2). Trials. 2019;20(1):331.
197. Căpățînă OO, Micluția IV, Fadgyas-Stănculete M. Current perspectives in treating negative symptoms of schizophrenia: A narrative review (Review). Exp Ther Med. 2021;21(3):276.
198. Umbricht D, Alberati D, Martin-Facklam M, Borroni E, Youssef EA, Ostland M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry. 2014;71(6):637-46.
199. Mazinani R, Nejati S, Khodaei M. Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial. Psychiatry Res. 2017;247:291-5.
200. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):520-7.
201. Sepehrmanesh Z, Heidary M, Akasheh N, Akbari H, Heidary M. Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: A double-blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2018;82:289-96.
202. Zhang L, Zheng H, Wu R, Zhu F, Kosten TR, Zhang XY, et al. Minocycline adjunctive treatment to risperidone for negative symptoms in schizophrenia: Association with pro-inflammatory cytokine levels. Prog Neuropsychopharmacol Biol Psychiatry. 2018;85:69-76.
203. Samadi R, Soluti S, Daneshmand R, Assari S, Manteghi AA. Efficacy of Risperidone Augmentation with Ondansetron in the Treatment of Negative and Depressive Symptoms in Schizophrenia: A Randomized Clinical Trial. Iran J Med Sci. 2017;42(1):14-23.
204. Davidson M, Saoud J, Staner C, Noel N, Luthringer E, Werner S, et al. Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia. Am J Psychiatry. 2017;174(12):1195-202.
205. Conley RR, Boggs DL, Kelly DL, McMahon RP, Dickinson D, Feldman S, et al. The effects of galantamine on psychopathology in chronic stable schizophrenia. Clin Neuropharmacol. 2009;32(2):69-74.
206. Modabbernia A, Rezaei F, Salehi B, Jafarinia M, Ashrafi M, Tabrizi M, et al. Intranasal oxytocin as an adjunct to risperidone in patients with schizophrenia : an 8-week, randomized, double-blind, placebo-controlled study. CNS Drugs. 2013;27(1):57-65.
207. Prvulovic D, Hampel H, Pantel J. Galantamine for Alzheimer's disease. Expert Opin Drug Metab Toxicol. 2010;6(3):345-54.
208. Langevitz P, Livneh A, Bank I, Pras M. Benefits and risks of minocycline in rheumatoid arthritis. Drug Saf. 2000;22(5):405-14.
209. Kavirajan H. Memantine: a comprehensive review of safety and efficacy. Expert Opin Drug Saf. 2009;8(1):89-109.
2. Nakazawa K, Sapkota K. The origin of NMDA receptor hypofunction in schizophrenia. Pharmacol Ther. 2020;205:107426.
3. Severance EG, Dickerson FB, Yolken RH. Autoimmune phenotypes in schizophrenia reveal novel treatment targets. Pharmacol Ther. 2018;189:184-98.
4. Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, et al. Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr Bull. 2018;44(6):1195-203.
5. Zhang W, Amos TB, Gutkin SW, Lodowski N, Giegerich E, Joshi K. A systematic literature review of the clinical and health economic burden of schizophrenia in privately insured patients in the United States. Clinicoecon Outcomes Res. 2018;10:309-20.
6. Marcellusi A, Fabiano G, Viti R, Francesa Morel PC, Nicolò G, Siracusano A, et al. Economic burden of schizophrenia in Italy: a probabilistic cost of illness analysis. BMJ Open. 2018;8(2):e018359.
7. Fond G, Lançon C, Korchia T, Auquier P, Boyer L. The Role of Inflammation in the Treatment of Schizophrenia. Front Psychiatry. 2020;11:160.
8. Mohebbi A, Yasaghi M, Mamizadeh Z, Salehnia A, Lorestani N, Tabarraei A. Risk of Borna Disease Virus among Asian Psychiatric Patients: A Systematic Review and Meta-Analysis. Iran J Virol. 2018;12(1):6-19.
9. van Mierlo HC, Broen JCA, Kahn RS, de Witte LD. B-cells and schizophrenia: A promising link or a finding lost in translation? Brain Behav Immun. 2019;81:52-62.
10. Whelan R, St Clair D, Mustard CJ, Hallford P, Wei J. Study of Novel Autoantibodies in Schizophrenia. Schizophr Bull. 2018;44(6):1341-9.
11. Momtazmanesh S, Zare-Shahabadi A, Rezaei N. Cytokine Alterations in Schizophrenia: An Updated Review. Front Psychiatry. 2019;10:892.
12. Comer AL, Carrier M, Tremblay M, Cruz-Martín A. The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation. Front Cell Neurosci. 2020;14:274.
13. Shalev H, Serlin Y, Friedman A. Breaching the blood-brain barrier as a gate to psychiatric disorder. Cardiovasc Psychiatry Neurol. 2009;2009:278531.
14. Sæther SG, Rø ADB, Larsen JB, Vaaler A, Kondziella D, Reitan SK. Biomarkers of Autoimmunity in Acute Psychiatric Disorders. J Neuropsychiatry Clin Neurosci. 2019;31(3):246-53.
15. Fatani BZ, Aldawod R, Alhawaj A, Alsadah S, Slais FR, Alyaseen EN, et al. Schizophrenia: etiology, pathophysiology and management-a review. The Egyptian Journal of Hospital Medicine. 2017;69(6):2640-6.
16. Tamminga CA, Medoff DR. The biology of schizophrenia. Dialogues in clinical neuroscience. 2022.
17. Arab A, Mohebbi A, Afshar H, Moradi A. Multi-factorial Etiology of Bipolar Disorder and Schizophrenia in Iran: No Evidence of Borna Disease Virus Genome. Med Laboratory J. 2018;12(5):42-9.
18. McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry. 2020;19(1):15-33.
19. Sonnenschein SF, Gomes FV, Grace AA. Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia. Front Psychiatry. 2020;11:613.
20. Zamanpoor M. Schizophrenia in a genomic era: a review from the pathogenesis, genetic and environmental etiology to diagnosis and treatment insights. Psychiatr Genet. 2020;30(1):1-9.
21. Severance EG, Yolken RH. From Infection to the Microbiome: An Evolving Role of Microbes in Schizophrenia. Curr Top Behav Neurosci. 2020;44:67-84.
22. Brown AS. Exposure to prenatal infection and risk of schizophrenia. Front Psychiatry. 2011;2:63.
23. Tanaka T, Matsuda T, Hayes LN, Yang S, Rodriguez K, Severance EG, et al. Infection and inflammation in schizophrenia and bipolar disorder. Neurosci Res. 2017;115:59-63.
24. Cheslack-Postava K, Brown AS. Prenatal infection and schizophrenia: A decade of further progress. Schizophr Res. 2021.
25. Laupu W. Recommendations to Help Prevent Mental Disorders and Limit Stigma. British Journal of Medical and Health Research. 2018;5(9).
26. Brown AS, Patterson PH. Maternal infection and schizophrenia: implications for prevention. Schizophr Bull. 2011;37(2):284-90.
27. Sørensen HJ, Foldager L, Røge R, Pristed SG, Andreasen JT, Nielsen J. An association between autumn birth and clozapine treatment in patients with schizophrenia: a population-based analysis. Nord J Psychiatry. 2014;68(6):428-32.
28. Kneeland RE, Fatemi SH. Viral infection, inflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:35-48.
29. Demler TL. Challenging the hypothesized link to season of birth in patients with schizophrenia. Innov Clin Neurosci. 2011;8(9):14-9.
30. Coury SM, Lombroso A, Avila-Quintero VJ, Taylor JH, Flores JM, Szejko N, et al. Systematic review and meta-analysis: Season of birth and schizophrenia risk. Schizophr Res. 2023;252:244-52.
31. Karlsson H, Dal H, Gardner RM, Torrey EF, Dalman C. Birth month and later diagnosis of schizophrenia. A population-based cohort study in Sweden. J Psychiatr Res. 2019;116:1-6.
32. Faivre S, Roche N, Lacerre F, Dealberto MJ. Vitamin D deficiency in a psychiatric population and correlation between vitamin D and CRP. Encephale. 2019;45(5):376-83.
33. Cui X, McGrath JJ, Burne THJ, Eyles DW. Vitamin D and schizophrenia: 20 years on. Mol Psychiatry. 2021;26(7):2708-20.
34. Davies C, Segre G, Estradé A, Radua J, De Micheli A, Provenzani U, et al. Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2020;7(5):399-410.
35. King S, St-Hilaire A, Heidkamp D. Prenatal factors in schizophrenia. Curr Dir Psychol Sci. 2010;19(4):209-13.
36. Lipner E, Murphy SK, Ellman LM. Prenatal Maternal Stress and the Cascade of Risk to Schizophrenia Spectrum Disorders in Offspring. Curr Psychiatry Rep. 2019;21(10):99.
37. Miller BJ, Culpepper N, Rapaport MH, Buckley P. Prenatal inflammation and neurodevelopment in schizophrenia: a review of human studies. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:92-100.
38. Yüksel RN, Altunsoy N, Tikir B, Cingi Külük M, Unal K, Goka S, et al. Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation. Ther Adv Psychopharmacol. 2014;4(6):268-75.
39. Schoenrock SA, Tarantino LM. Developmental vitamin D deficiency and schizophrenia: the role of animal models. Genes Brain Behav. 2016;15(1):45-61.
40. Daiva A, Sarjana W, Fitrikasari A, Wijayahadi N, Woroasih S. Correlation of Serum Vitamin D Levels with Cognitive Function in Schizophrenic Patients. Clinical Schizophrenia & Related Psychoses. 2023;17(2).
41. Gaughran F, Stringer D, Wojewodka G, Landau S, Smith S, Gardner-Sood P, et al. Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial. JAMA Netw Open. 2021;4(12):e2140858.
42. Akinlade KS, Olaniyan OA, Lasebikan VO, Rahamon SK. Vitamin D Levels in Different Severity Groups of Schizophrenia. Front Psychiatry. 2017;8:105.
43. Viani-Walsh D, Kennedy-Williams S, Taylor D, Gaughran F, Lally J. Vitamin D deficiency in schizophrenia implications for COVID-19 infection. Ir J Psychol Med. 2021;38(4):278-87.
44. Jaholkowski P, Hindley GFL, Shadrin AA, Tesfaye M, Bahrami S, Nerhus M, et al. Genome-wide Association Analysis of Schizophrenia and Vitamin D Levels Shows Shared Genetic Architecture and Identifies Novel Risk Loci. Schizophr Bull. 2023.
45. Lodge DJ, Grace AA. Developmental pathology, dopamine, stress and schizophrenia. Int J Dev Neurosci. 2011;29(3):207-13.
46. Almuqrin A, Georgiades A, Mouhitzadeh K, Rubinic P, Mechelli A, Tognin S. The association between psychosocial stress, interpersonal sensitivity, social withdrawal and psychosis relapse: a systematic review. Schizophrenia. 2023;9(1):22.
47. Gomes FV, Zhu X, Grace AA. Stress during critical periods of development and risk for schizophrenia. Schizophr Res. 2019;213:107-13.
48. Lange C, Deutschenbaur L, Borgwardt S, Lang UE, Walter M, Huber CG. Experimentally induced psychosocial stress in schizophrenia spectrum disorders: A systematic review. Schizophr Res. 2017;182:4-12.
49. Shoib S, Das S, Gupta AK, Saleem T, Saleem SM. Perceived stress, quality of life, and coping skills among patients with schizophrenia in symptomatic remission. Middle East Current Psychiatry. 2021;28(1):1-8.
50. Tas C, Brown EC, Eskikurt G, Irmak S, Aydın O, Esen-Danaci A, et al. Cortisol response to stress in schizophrenia: Associations with oxytocin, social support and social functioning. Psychiatry Res. 2018;270:1047-52.
51. Streit F, Memic A, Hasandedić L, Rietschel L, Frank J, Lang M, et al. Perceived stress and hair cortisol: Differences in bipolar disorder and schizophrenia. Psychoneuroendocrinology. 2016;69:26-34.
52. Chang X, Lima LA, Liu Y, Li J, Li Q, Sleiman PMA, et al. Common and Rare Genetic Risk Factors Converge in Protein Interaction Networks Underlying Schizophrenia. Front Genet. 2018;9:434.
53. Henriksen MG, Nordgaard J, Jansson LB. Genetics of Schizophrenia: Overview of Methods, Findings and Limitations. Front Hum Neurosci. 2017;11:322.
54. Bishop JR, Zhang L, Lizano P. Inflammation Subtypes and Translating Inflammation-Related Genetic Findings in Schizophrenia and Related Psychoses: A Perspective on Pathways for Treatment Stratification and Novel Therapies. Harv Rev Psychiatry. 2022;30(1):59-70.
55. Degenhardt F. Update on the genetic architecture of schizophrenia. Medizinische Genetik. 2020;32(1):19-24.
56. Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019;381(18):1753-61.
57. Mongan D, Ramesar M, Föcking M, Cannon M, Cotter D. Role of inflammation in the pathogenesis of schizophrenia: A review of the evidence, proposed mechanisms and implications for treatment. Early Interv Psychiatry. 2020;14(4):385-97.
58. Togay A, Togay B, Ozbay Gediz D, Akbaş SH, Köksoy S. Levels of lymphocyte-associated regulators of complement system CD55 and CD59 are changed in schizophrenia patients. Int J Psychiatry Clin Pract. 2021;25(3):277-82.
59. Cleynen I, Engchuan W, Hestand MS, Heung T, Holleman AM, Johnston HR, et al. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Mol Psychiatry. 2021;26(8):4496-510.
60. Matanat Y, Naseer IA, Murtaza A, Tareen NF, Khalid A, Nabeel W, et al. Relation of Schizophrenia to Psychosis with Respect to Immune Dysregulation and Its Impact on Memory and Learning. Arch Microbiol Immunol. 2022;6:123-40.
61. McAllister AK. Major histocompatibility complex I in brain development and schizophrenia. Biol Psychiatry. 2014;75(4):262-8.
62. Pouget JG. The Emerging Immunogenetic Architecture of Schizophrenia. Schizophr Bull. 2018;44(5):993-1004.
63. Debnath M, Berk M, Leboyer M, Tamouza R. The MHC/HLA gene complex in major psychiatric disorders: emerging roles and implications. Curr Behavioral Neuroscience Reports. 2018;5(2):179-88.
64. Mokhtari R, Lachman HM. The Major Histocompatibility Complex (MHC) in Schizophrenia: A Review. J Clin Cell Immunol. 2016;7(6).
65. Corvin A, Morris DW. Genome-wide association studies: findings at the major histocompatibility complex locus in psychosis. Biol Psychiatry. 2014;75(4):276-83.
66. Kelly DL, Li X, Kilday C, Feldman S, Clark S, Liu F, et al. Increased circulating regulatory T cells in medicated people with schizophrenia. Psychiatry Res. 2018;269:517-23.
67. Woo JJ, Pouget JG, Zai CC, Kennedy JL. The complement system in schizophrenia: where are we now and what's next? Mol Psychiatry. 2020;25(1):114-30.
68. Kanazawa T, Bousman CA, Liu C, Everall IP. Schizophrenia genetics in the genome-wide era: a review of Japanese studies. NPJ Schizophr. 2017;3(1):27.
69. Hyun JS, Inoue T, Hayashi-Takagi A. Multi-Scale Understanding of NMDA Receptor Function in Schizophrenia. Biomolecules. 2020;10(8).
70. Nimgaonkar VL, Prasad KM, Chowdari KV, Severance EG, Yolken RH. The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis. Mol Psychiatry. 2017;22(11):1554-61.
71. Warwick CA, Keyes AL, Woodruff TM, Usachev YM. The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain. J Biol Chem. 2021;297(3):101085.
72. Kopczynska M, Zelek W, Touchard S, Gaughran F, Di Forti M, Mondelli V, et al. Complement system biomarkers in first episode psychosis. Schizophr Res. 2019;204:16-22.
73. Druart M, Le Magueresse C. Emerging Roles of Complement in Psychiatric Disorders. Front Psychiatry. 2019;10:573.
74. Hogenaar JT, van Bokhoven H. Schizophrenia: Complement Cleaning or Killing. Genes. 2021;12(2):259.
75. Gallego JA, Blanco EA, Morell C, Lencz T, Malhotra AK. Complement component C4 levels in the cerebrospinal fluid and plasma of patients with schizophrenia. Neuropsychopharmacology. 2021;46(6):1140-4.
76. Birnbaum R, Jaffe AE, Chen Q, Shin JH, Kleinman JE, Hyde TM, et al. Investigating the neuroimmunogenic architecture of schizophrenia. Mol Psychiatry. 2018;23(5):1251-60.
77. Johnson EC, Border R, Melroy-Greif WE, de Leeuw CA, Ehringer MA, Keller MC. No Evidence That Schizophrenia Candidate Genes Are More Associated With Schizophrenia Than Noncandidate Genes. Biol Psychiatry. 2017;82(10):702-8.
78. Pollak TA, Drndarski S, Stone JM, David AS, McGuire P, Abbott NJ. The blood-brain barrier in psychosis. Lancet Psychiatry. 2018;5(1):79-92.
79. Pong S, Karmacharya R, Sofman M, Bishop JR, Lizano P. The Role of Brain Microvascular Endothelial Cell and Blood-Brain Barrier Dysfunction in Schizophrenia. Complex Psychiatry. 2020;6(1-2):30-46.
80. Maes M, Sirivichayakul S, Kanchanatawan B, Vodjani A. Breakdown of the Paracellular Tight and Adherens Junctions in the Gut and Blood Brain Barrier and Damage to the Vascular Barrier in Patients with Deficit Schizophrenia. Neurotox Res. 2019;36(2):306-22.
81. Farrell M, Aherne S, O'Riordan S, O'Keeffe E, Greene C, Campbell M. Blood-brain barrier dysfunction in a boxer with chronic traumatic encephalopathy and schizophrenia. Clin Neuropathol. 2019;38(2):51-8.
82. Müller N, Riedel M, Hadjamu M, Schwarz MJ, Ackenheil M, Gruber R. Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia. Am J Psychiatry. 1999;156(4):634-6.
83. Melkersson K, Bensing S. Signs of impaired blood-brain barrier function and lower IgG synthesis within the central nervous system in patients with schizophrenia or related psychosis, compared to that in controls. Neuro Endocrinol Lett. 2018;39(1):33-42.
84. Najjar S, Pahlajani S, De Sanctis V, Stern JNH, Najjar A, Chong D. Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. Front Psychiatry. 2017;8:83.
85. Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res. 2010;44(5):321-30.
86. Orlovska-Waast S, Köhler-Forsberg O, Brix SW, Nordentoft M, Kondziella D, Krogh J, et al. Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis. Mol Psychiatry. 2019;24(6):869-87.
87. Masopust J, Malý R, Andrýs C, Vališ M, Bažant J, Hosák L. Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study. BMC Psychiatry. 2011;11:2.
88. de Klerk OL, Willemsen AT, Bosker FJ, Bartels AL, Hendrikse NH, den Boer JA, et al. Regional increase in P-glycoprotein function in the blood-brain barrier of patients with chronic schizophrenia:: A PET study with [11C] verapamil as a probe for P-glycoprotein function. Psychiatry Research: Neuroimaging. 2010;183(2):151-6.
89. Kroken RA, Sommer IE, Steen VM, Dieset I, Johnsen E. Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics. Front Psychiatry. 2018;9:753.
90. Louveau A, Filiano AJ, Kipnis J. Meningeal whole mount preparation and characterization of neural cells by flow cytometry. Curr Protoc Immunol. 2018;121(1):e50.
91. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2(3):258-70.
92. Upthegrove R, Barnes NM. The immune system and schizophrenia: an update for clinicians. Advances in psychiatric treatment. 2014;20(2):83-91.
93. Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry. 2014;75(4):324-31.
94. Fernandez-Egea E, Vértes PE, Flint SM, Turner L, Mustafa S, Hatton A, et al. Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia. PLoS One. 2016;11(5):e0155631.
95. Karpiński P, Frydecka D, Sąsiadek MM, Misiak B. Reduced number of peripheral natural killer cells in schizophrenia but not in bipolar disorder. Brain Behav Immun. 2016;54:194-200.
96. Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2013;73(10):993-9.
97. Szepesi Z, Manouchehrian O, Bachiller S, Deierborg T. Bidirectional Microglia-Neuron Communication in Health and Disease. Front Cell Neurosci. 2018;12:323.
98. Wang C, Aleksic B, Ozaki N. Glia-related genes and their contribution to schizophrenia. Psychiatry Clin Neurosci. 2015;69(8):448-61.
99. Dietz AG, Goldman SA, Nedergaard M. Glial cells in schizophrenia: a unified hypothesis. Lancet Psychiatry. 2020;7(3):272-81.
100. Ormel PR, Böttcher C, Gigase FAJ, Missall RD, van Zuiden W, Fernández Zapata MC, et al. A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells. Brain Behav Immun. 2020;90:196-207.
101. Marques TR, Ashok AH, Pillinger T, Veronese M, Turkheimer FE, Dazzan P, et al. Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies. Psychol Med. 2019;49(13):2186-96.
102. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB, et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22(3):374-85.
103. Caruso G, Grasso M, Fidilio A, Tascedda F, Drago F, Caraci F. Antioxidant Properties of Second-Generation Antipsychotics: Focus on Microglia. Pharmaceuticals (Basel). 2020;13(12).
104. Ermakov EA, Dmitrieva EM, Parshukova DA, Kazantseva DV, Vasilieva AR, Smirnova LP. Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives. Oxid Med Cell Longev. 2021;2021:8881770.
105. Laskaris LE, Di Biase MA, Everall I, Chana G, Christopoulos A, Skafidas E, et al. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol. 2016;173(4):666-80.
106. Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009;63(3):257-65.
107. Novellino F, Saccà V, Donato A, Zaffino P, Spadea MF, Vismara M, et al. Innate Immunity: A Common Denominator between Neurodegenerative and Neuropsychiatric Diseases. Int J Mol Sci. 2020;21(3).
108. Wang M, Zhang L, Gage FH. Microglia, complement and schizophrenia. Nat Neurosci. 2019;22(3):333-4.
109. Guo S, Wang H, Yin Y. Microglia Polarization From M1 to M2 in Neurodegenerative Diseases. Front Aging Neurosci. 2022;14:815347.
110. Tahmasebinia F, Pourgholaminejad A. The role of Th17 cells in auto-inflammatory neurological disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2017;79(Pt B):408-16.
111. Müller N, Riedel M, Ackenheil M, Schwarz MJ. Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. World J Biol Psychiatry. 2000;1(4):173-9.
112. Asadi-Samani M, Bagheri N, Rafieian-Kopaei M, Shirzad H. Inhibition of Th1 and Th17 Cells by Medicinal Plants and Their Derivatives: A Systematic Review. Phytotherapy research : PTR. 2017;31(8):1128-39.
113. Bagheri N, Azadegan-Dehkordi F, Rahimian G, Hashemzadeh-Chaleshtori M, Rafieian-Kopaei M, Kheiri S, et al. Altered Th17 Cytokine Expression in Helicobacter pylori Patients with TLR4 (D299G) Polymorphism. Immunol Invest. 2016;45(2):161-71.
114. Singh RP, Hasan S, Sharma S, Nagra S, Yamaguchi DT, Wong DT, et al. Th17 cells in inflammation and autoimmunity. Autoimmun Rev. 2014;13(12):1174-81.
115. Xin N, Namaka MP, Dou C, Zhang Y. Exploring the role of interleukin-22 in neurological and autoimmune disorders. Int Immunopharmacol. 2015;28(2):1076-83.
116. Ding M, Song X, Zhao J, Gao J, Li X, Yang G, et al. Activation of Th17 cells in drug naïve, first episode schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:78-82.
117. Varun CN, Venkataswamy MM, Ravikumar R, Nagaraju R, Debnath M, Varambally S, et al. Th17 and MAIT cell mediated inflammation in antipsychotic free schizophrenia patients. Schizophr Res. 2019;212:47-53.
118. Debnath M, Berk M. Th17 pathway-mediated immunopathogenesis of schizophrenia: mechanisms and implications. Schizophr Bull. 2014;40(6):1412-21.
119. Corsi-Zuelli F, Deakin B. Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia. Neurosci Biobehav Rev. 2021;125:637-53.
120. Sahbaz C, Zibandey N, Kurtulmus A, Duran Y, Gokalp M, Kırpınar I, et al. Reduced regulatory T cells with increased proinflammatory response in patients with schizophrenia. Psychopharmacology (Berl). 2020;237(6):1861-71.
121. Sanaei MJ, Nahid-Samiei M, Abadi MSS, Arjmand MH, Ferns GA, Bashash D, et al. New insights into regulatory B cells biology in viral, bacterial, and parasitic infections. Infect Genet Evol. 2021;89:104753.
122. Tanabe S, Yamashita T. B lymphocytes: Crucial contributors to brain development and neurological diseases. Neurosci Res. 2019;139:37-41.
123. Ermakov EA, Melamud MM, Buneva VN, Ivanova SA. Immune system abnormalities in schizophrenia: an integrative view and translational perspectives. Frontiers in Psychiatry. 2022;13:880568.
124. Schlaaff K, Dobrowolny H, Frodl T, Mawrin C, Gos T, Steiner J, et al. Increased densities of T and B lymphocytes indicate neuroinflammation in subgroups of schizophrenia and mood disorder patients. Brain Behav Immun. 2020;88:497-506.
125. Colijn MA, Ismail Z. Clinically Relevant Anti-Neuronal Cell Surface Antibodies in Schizophrenia Spectrum Disorders. Neuropsychobiology. 2019;78(2):70-8.
126. Adell A. Brain NMDA Receptors in Schizophrenia and Depression. Biomolecules. 2020;10(6).
127. Kao YC, Lin MI, Weng WC, Lee WT. Neuropsychiatric Disorders Due to Limbic Encephalitis: Immunologic Aspect. Int J Mol Sci. 2020;22(1).
128. Khandaker GM MU, Jones PB. . Neuroin ammation and Schizophrenia: Springer; 1st ed. 2020 edition (January 23, 2020); 2020. Available from: http://www.springer.com/series/7854.; 2020.
129. Hara M, Ariño H, Petit-Pedrol M, Sabater L, Titulaer MJ, Martinez-Hernandez E, et al. DPPX antibody-associated encephalitis: Main syndrome and antibody effects. Neurology. 2017;88(14):1340-8.
130. Coutinho E, Vincent A. Central nervous system neuronal surface antibodies. In: Shoenfeld Y MP, Gershwin ME, editors. , editor. Autoantibodies. (Third Edition). San Diego: ed: Elsevier 2014; 2014. p. 595-603
131. Giannoccaro MP, Crisp SJ, Vincent A. Antibody-mediated central nervous system diseases. Brain Neurosci Adv. 2018;2:2398212818817497.
132. Mader S, Brimberg L. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019;8(2).
133. Vandebroek A, Yasui M. Regulation of AQP4 in the Central Nervous System. Int J Mol Sci. 2020;21(5).
134. Verkman AS, Smith AJ, Phuan PW, Tradtrantip L, Anderson MO. The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets. 2017;21(12):1161-70.
135. Zeppenfeld DM, Simon M, Haswell JD, D'Abreo D, Murchison C, Quinn JF, et al. Association of Perivascular Localization of Aquaporin-4 With Cognition and Alzheimer Disease in Aging Brains. JAMA Neurol. 2017;74(1):91-9.
136. Xue X, Zhang W, Zhu J, Chen X, Zhou S, Xu Z, et al. Aquaporin-4 deficiency reduces TGF-β1 in mouse midbrains and exacerbates pathology in experimental Parkinson's disease. J Cell Mol Med. 2019;23(4):2568-82.
137. Stadelmann C, Timmler S, Barrantes-Freer A, Simons M. Myelin in the Central Nervous System: Structure, Function, and Pathology. Physiol Rev. 2019;99(3):1381-431.
138. Pronker MF, Lemstra S, Snijder J, Heck AJ, Thies-Weesie DM, Pasterkamp RJ, et al. Structural basis of myelin-associated glycoprotein adhesion and signalling. Nat Commun. 2016;7:13584.
139. Ambrosius W, Michalak S, Kozubski W, Kalinowska A. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Current Insights into the Disease Pathophysiology, Diagnosis and Management. Int J Mol Sci. 2020;22(1).
140. Peschl P, Bradl M, Höftberger R, Berger T, Reindl M. Myelin Oligodendrocyte Glycoprotein: Deciphering a Target in Inflammatory Demyelinating Diseases. Front Immunol. 2017;8:529.
141. Papasergi-Scott MM, Robertson MJ, Seven AB, Panova O, Mathiesen JM, Skiniotis G. Structures of metabotropic GABA(B) receptor. Nature. 2020;584(7820):310-4.
142. Fatemi SH, Folsom TD, Thuras PD. GABA(A) and GABA(B) receptor dysregulation in superior frontal cortex of subjects with schizophrenia and bipolar disorder. Synapse. 2017;71(7).
143. de Bartolomeis A, Manchia M, Marmo F, Vellucci L, Iasevoli F, Barone A. Glycine Signaling in the Framework of Dopamine-Glutamate Interaction and Postsynaptic Density. Implications for Treatment-Resistant Schizophrenia. Front Psychiatry. 2020;11:369.
144. Karis K, Eskla KL, Kaare M, Täht K, Tuusov J, Visnapuu T, et al. Altered Expression Profile of IgLON Family of Neural Cell Adhesion Molecules in the Dorsolateral Prefrontal Cortex of Schizophrenic Patients. Front Mol Neurosci. 2018;11:8.
145. Venkannagari H, Kasper JM, Misra A, Rush SA, Fan S, Lee H, et al. Highly Conserved Molecular Features in IgLONs Contrast Their Distinct Structural and Biological Outcomes. J Mol Biol. 2020;432(19):5287-303.
146. Gibbons A, Dean B. The Cholinergic System: An Emerging Drug Target for Schizophrenia. Curr Pharm Des. 2016;22(14):2124-33.
147. Ma KG, Qian YH. Alpha 7 nicotinic acetylcholine receptor and its effects on Alzheimer's disease. Neuropeptides. 2019;73:96-106.
148. Debnath M, Berk M. Functional Implications of the IL-23/IL-17 Immune Axis in Schizophrenia. Mol Neurobiol. 2017;54(10):8170-8.
149. Dinarello CA. Proinflammatory cytokines. Chest. 2000;118(2):503-8.
150. Libíkowa H, Stancek D, Wiedermann V, Hasto J, Breier S. Psychopharmaca and electroconvulsive therapy in relation to viral antibodies and interferon. Experimental and clinical study. Arch Immunol Ther Exp (Warsz). 1977;25(5):641-9.
151. Smith RS. A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses. 1992;39(3):248-57.
152. Keshavarz F, Soltani M, Mokhtarian K, Beshkar P, Majidi J, Azadegan-Dehkordi F, et al. Autoantibodies against Central Nervous System Antigens and the Serum Levels of IL-32 in Patients with Schizophrenia. Neuroimmunomodulation. 2022;29(4):493-9.
153. Reale M, Costantini E, Greig NH. Cytokine imbalance in schizophrenia. From research to clinic: potential implications for treatment. Front psychiatry. 2021:82.
154. Brambilla P, Bellani M, Isola M, Bergami A, Marinelli V, Dusi N, et al. Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia. Translational psychiatry. 2014;4(7):e406-e.
155. Akdis M, Aab A, Altunbulakli C, Azkur K, Costa RA, Crameri R, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. Journal of Allergy and Clinical Immunology. 2016;138(4):984-1010.
156. Goldsmith D, Rapaport M, Miller B. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Molecular psychiatry. 2016;21(12):1696-709.
157. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological psychiatry. 2011;70(7):663-71.
158. Dahan S, Bragazzi NL, Yogev A, Bar-Gad M, Barak V, Amital H, et al. The relationship between serum cytokine levels and degree of psychosis in patients with schizophrenia. Psychiatry research. 2018;268:467-72.
159. Romeo B, Brunet-Lecomte M, Martelli C, Benyamina A. Kinetics of cytokine levels during antipsychotic treatment in schizophrenia: a meta-analysis. International Journal of Neuropsychopharmacology. 2018;21(9):828-36.
160. Tourjman V, Kouassi E, Koue M-E, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, et al. Antipsychotics' effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophrenia research. 2013;151(1-3):43-7.
161. Azizi E, Hosseini AZ, Soudi S, Noorbala AA. Alteration of serum levels of cytokines in schizophrenic patients before and after treatment with risperidone. Iranian Journal of Allergy, Asthma and Immunology. 2019:262-8.
162. Zhang L, Zheng H, Wu R, Kosten TR, Zhang X-Y, Zhao J. The effect of minocycline on amelioration of cognitive deficits and pro-inflammatory cytokines levels in patients with schizophrenia. Schizophrenia research. 2019;212:92-8.
163. Capuzzi E, Bartoli F, Crocamo C, Clerici M, Carrà G. Acute variations of cytokine levels after antipsychotic treatment in drug-naïve subjects with a first-episode psychosis: a meta-analysis. Neuroscience & Biobehavioral Reviews. 2017;77:122-8.
164. Song X, Fan X, Li X, Zhang W, Gao J, Zhao J, et al. Changes in pro-inflammatory cytokines and body weight during 6-month risperidone treatment in drug naive, first-episode schizophrenia. Psychopharmacology. 2014;231(2):319-25.
165. Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. Changes in serum interleukin-2,-6, and-8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry. 2004;65(7):940-7.
166. Dikeç G, Arabaci LB, Uzunoglu GB, Mizrak SD. Metabolic side effects in patients using atypical antipsychotic medications during hospitalization. J Psychosoc Nurs Ment Health Serv. 2018;56(4):28-37.
167. Ouyang W, O’Garra A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity. 2019;50(4):871-91.
168. Álvarez-Satta M, Berna-Erro A, Carrasco-Garcia E, Alberro A, Saenz-Antoñanzas A, Vergara I, et al. Relevance of oxidative stress and inflammation in frailty based on human studies and mouse models. Aging (Albany NY). 2020;12(10):9982.
169. Pillinger T, Osimo EF, Brugger S, Mondelli V, McCutcheon RA, Howes OD. A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis. Schizophrenia bulletin. 2019;45(5):1120-33.
170. Marcinowicz P, Więdłocha M, Zborowska N, Dębowska W, Podwalski P, Misiak B, et al. A meta-analysis of the influence of antipsychotics on cytokines levels in first episode psychosis. J Clin Med. 2021;10(11):2488.
171. Huang A, Cheng L, He M, Nie J, Wang J, Jiang K. Interleukin-35 on B cell and T cell induction and regulation. J Inflamm (Lond). 2017;14:16.
172. Zhang J, Zhang Y, Wang Q, Li C, Deng H, Si C, et al. Interleukin-35 in immune-related diseases: protection or destruction. Immunology. 2019;157(1):13-20.
173. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007;450(7169):566-9.
174. Kochetkova I, Golden S, Holderness K, Callis G, Pascual DW. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol. 2010;184(12):7144-53.
175. Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, et al. 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(11):3021-9.
176. Tirotta E, Duncker P, Oak J, Klaus S, Tsukamoto MR, Gov L, et al. Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis. J Neuroimmunol. 2013;254(1-2):110-6.
177. Huang CH, Loo EX, Kuo IC, Soh GH, Goh DL, Lee BW, et al. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35. J Immunol. 2011;187(1):462-71.
178. Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20(6):633-41.
179. Hu Y, Dong C, Yue Y, Xiong S. In vivo delivery of interleukin-35 relieves coxsackievirus-B3-induced viral myocarditis by inhibiting Th17 cells. Arch Virol. 2014;159(9):2411-9.
180. Huang Y, Lin YZ, Shi Y, Ji QW. IL-35: a potential target for the treatment of atherosclerosis. Pharmazie. 2013;68(10):793-5.
181. Liu Y, Wu Y, Wang Y, Cai Y, Hu B, Bao G, et al. IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects. Leukemia. 2015;29(4):939-46.
182. Soltani M, Beshkar P, Mokhtarian K, Anjomshoa M, Mohammad-Rezaei M, Azadegan-Dehkordi F, et al. A Study of Autoantibodies against Some Central Nervous System Antigens and the IL-35 Serum Level in Schizophrenia. Iranian J Allergy, Asthma, Immunol. 2022;21(4):441-8.
183. Rider P, Carmi Y, Cohen I. Biologics for targeting inflammatory cytokines, clinical uses, and limitations. International journal of cell biology. 2016;2016.
184. Kane JM, Correll CU. Pharmacologic treatment of schizophrenia. Dialogues Clin Neurosci. 2010;12(3):345-57.
185. Yang AC, Tsai SJ. New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. Int J Mol Sci. 2017;18(8).
186. Catts SV, O'Toole BI. The treatment of schizophrenia: Can we raise the standard of care? Aust N Z J Psychiatry. 2016;50(12):1128-38.
187. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and treatment options. P t. 2014;39(9):638-45.
188. Pandurangi AK, Buckley PF. Inflammation, Antipsychotic Drugs, and Evidence for Effectiveness of Anti-inflammatory Agents in Schizophrenia. Curr Top Behav Neurosci. 2020;44:227-44.
189. Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia. J Clin Psychiatry. 2010;71(9):1115-24.
190. Miller BJ, Buckley PF. The Case for Adjunctive Monoclonal Antibody Immunotherapy in Schizophrenia. Psychiatr Clin North Am. 2016;39(2):187-98.
191. Miller BJ, Goldsmith DR. Towards an Immunophenotype of Schizophrenia: Progress, Potential Mechanisms, and Future Directions. Neuropsychopharmacology. 2017;42(1):299-317.
192. Dimitrov DH, Lee S, Yantis J, Honaker C, Braida N. Cytokine serum levels as potential biological markers for the Psychopathology in Schizophrenia. Advances in Psychiatry. 2014;2014.
193. Ellul P, Groc L, Tamouza R, Leboyer M. The Clinical Challenge of Autoimmune Psychosis: Learning from Anti-NMDA Receptor Autoantibodies. Front Psychiatry. 2017;8:54.
194. Miller BJ, Goldsmith DR. Evaluating the Hypothesis That Schizophrenia Is an Inflammatory Disorder. Focus (Am Psychiatr Publ). 2020;18(4):391-401.
195. Melbourne JK, Feiner B, Rosen C, Sharma RP. Targeting the Immune System with Pharmacotherapy in Schizophrenia. Curr Treat Options Psychiatry. 2017;4(2):139-51.
196. Lennox B, Yeeles K, Jones PB, Zandi M, Joyce E, Yu LM, et al. Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2). Trials. 2019;20(1):331.
197. Căpățînă OO, Micluția IV, Fadgyas-Stănculete M. Current perspectives in treating negative symptoms of schizophrenia: A narrative review (Review). Exp Ther Med. 2021;21(3):276.
198. Umbricht D, Alberati D, Martin-Facklam M, Borroni E, Youssef EA, Ostland M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study. JAMA Psychiatry. 2014;71(6):637-46.
199. Mazinani R, Nejati S, Khodaei M. Effects of memantine added to risperidone on the symptoms of schizophrenia: A randomized double-blind, placebo-controlled clinical trial. Psychiatry Res. 2017;247:291-5.
200. Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):520-7.
201. Sepehrmanesh Z, Heidary M, Akasheh N, Akbari H, Heidary M. Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: A double-blind, randomized clinical trial. Prog Neuropsychopharmacol Biol Psychiatry. 2018;82:289-96.
202. Zhang L, Zheng H, Wu R, Zhu F, Kosten TR, Zhang XY, et al. Minocycline adjunctive treatment to risperidone for negative symptoms in schizophrenia: Association with pro-inflammatory cytokine levels. Prog Neuropsychopharmacol Biol Psychiatry. 2018;85:69-76.
203. Samadi R, Soluti S, Daneshmand R, Assari S, Manteghi AA. Efficacy of Risperidone Augmentation with Ondansetron in the Treatment of Negative and Depressive Symptoms in Schizophrenia: A Randomized Clinical Trial. Iran J Med Sci. 2017;42(1):14-23.
204. Davidson M, Saoud J, Staner C, Noel N, Luthringer E, Werner S, et al. Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia. Am J Psychiatry. 2017;174(12):1195-202.
205. Conley RR, Boggs DL, Kelly DL, McMahon RP, Dickinson D, Feldman S, et al. The effects of galantamine on psychopathology in chronic stable schizophrenia. Clin Neuropharmacol. 2009;32(2):69-74.
206. Modabbernia A, Rezaei F, Salehi B, Jafarinia M, Ashrafi M, Tabrizi M, et al. Intranasal oxytocin as an adjunct to risperidone in patients with schizophrenia : an 8-week, randomized, double-blind, placebo-controlled study. CNS Drugs. 2013;27(1):57-65.
207. Prvulovic D, Hampel H, Pantel J. Galantamine for Alzheimer's disease. Expert Opin Drug Metab Toxicol. 2010;6(3):345-54.
208. Langevitz P, Livneh A, Bank I, Pras M. Benefits and risks of minocycline in rheumatoid arthritis. Drug Saf. 2000;22(5):405-14.
209. Kavirajan H. Memantine: a comprehensive review of safety and efficacy. Expert Opin Drug Saf. 2009;8(1):89-109.
| Files | ||
| Issue | Vol 23 No 1 (2024) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i1.14951 | |
| Keywords | ||
| Blood-brain barrier Immune system Inflammation Cytokines Psychoneuroimmunology Schizophrenia Therapeutics | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Soltani M, Mirzaei Y, Mer AH, Mohammad-Rezaei M, Shafaghat Z, Fattahi S, Azadegan-Dehkordi F, Abdollahpour-Alitappeh M, Bagheri N. The Role of Innate and Adaptive Immune System in the Pathogenesis of Schizophrenia. Iran J Allergy Asthma Immunol. 2024;23(1):1-28.
