Rola układu immunologicznego w rozwoju schizofrenii – droga zrozumienia choroby i jej terapii?

Autorzy

Rafał Górka - Studenckie Koło Naukowe przy Katedrze i Zakładzie Biofizyki im.prof. Zbigniewa Religii. Wydział Nauk Medycznych w Zabrzu, Śląski Uniwersytet Medyczny; Anna Gajak; Julia Parkolap; Joanna Owsiak; Martyna Leśniak; Patryk Adamczyk

Słowa kluczowe:

schizofrenia, zapalenie, psychoneuroimmunologia, mikroglej, terapia

Streszczenie

Schizofrenia jest chorobą psychiczną stanowiącą poważny problem społeczny, a także znacząco wpływająca na jakość życia dotkniętych nią osób. Występują w niej objawy pozytywne, negatywne i dotyczące sfery kognitywnej. Obecnie dostępne leczenie przeciwpsychotyczne pozwala na redukcję objawów pozytywnych (wytwórczych), jednak ma tylko niewielki wpływ na objawy negatywne i funkcje poznawcze pacjenta, będące kluczowe dla codziennego funkcjonowania. Pojawiające się dowody na korelację między stanem zapalnym, a rozwojem schizofrenii mogą otworzyć drogę do zrozumienia wciąż niejasnej patogenezy tej choroby oraz pozwolić na rozwój nowych terapii. Prawdopodobnie kluczową rolę odgrywają komórki mikrogleju, będące rezydualnymi makrofagami w ośrodkowym układzie nerowym. Ich zaburzenie może prowadzić do uszkodzenia tkanki nerwowej, nieprawidłowego trzebienia synaps oraz aberracji w funkcjonowaniu obwodów neuronalnych. Zjawiska te mogą prowadzić do zaburzeń pozytywnych jak i negatywnych, a zastosowanie leczenia przeciwzapalnego lub wpływającego na komórki mikrogleju wykazuje skuteczność w leczeniu schizofrenii

Bibliografia

Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. PLoS Med. 2005;2(5):e141. doi:10.1371/journal.pmed.0020141

Laursen TM, Nordentoft M, Mortensen PB. Excess early mortality in schizophrenia. Annu Rev Clin Psychol. 2014;10:425-448. doi:10.1146/annurev-clinpsy-032813-153657

Hor K, Taylor M. Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol. 2010;24(4 Suppl):81-90. doi:10.1177/1359786810385490

Marwaha S, Johnson S. Schizophrenia and employment - a review. Soc Psychiatry Psychiatr Epidemiol. 2004;39(5):337-349. doi:10.1007/s00127-004-0762-4

L. MCJ. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Geneva: World Health Organization; 1996.

Gałecki P, Szulc A. Psychiatria. Wrocław: Edra Urban & Partner; 2020.

Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019;381(18):1753-1761. doi:10.1056/NEJMra1808803

Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet. 2016;388(10039):86-97. doi:10.1016/S0140-6736(15)01121-6

McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia-An Overview. JAMA Psychiatry. 2020;77(2):201-210. doi:10.1001/jamapsychiatry.2019.3360

Hilker R, Helenius D, Fagerlund B, et al. Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register. Biol Psychiatry. 2018;83(6):492-498. doi:10.1016/j.biopsych.2017.08.017

D'Souza DC, Sewell RA, Ranganathan M. Cannabis and psychosis/schizophrenia: human studies. Eur Arch Psychiatry Clin Neurosci. 2009;259(7):413-431. doi:10.1007/s00406-009-0024-2

Angrist B, Sathananthan G, Wilk S, Gershon S. Amphetamine psychosis: behavioral and biochemical aspects. J Psychiatr Res. 1974;11:13-23. doi:10.1016/0022-3956(74)90064-8

Sun Y, Farzan F, Barr MS, et al. γ oscillations in schizophrenia: mechanisms and clinical significance. Brain Res. 2011;1413:98-114. doi:10.1016/j.brainres.2011.06.065

Dameshek, W. White blood cells in dementia praecox and dementia paralytica. Arch Neurol Psychiatry, 1930;24, 855.

Gołąb J, Jakóbisiak M, Lasek W, Stokłosa T. Immunologia. Warszawa: Wydawnictwo Naukowe PWN SA; 2022.

Müller N. Inflammation in Schizophrenia: Pathogenetic Aspects and Therapeutic Considerations. Schizophr Bull. 2018;44(5):973-982. doi:10.1093/schbul/sby024

Upthegrove R, Khandaker GM. Cytokines, Oxidative Stress and Cellular Markers of Inflammation in Schizophrenia. Curr Top Behav Neurosci. 2020;44:49-66. doi:10.1007/7854_2018_88

Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21(12):1696-1709. doi:10.1038/mp.2016.3

Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663-671. doi:10.1016/j.biopsych.2011.04.013

Dickerson F, Stallings C, Origoni A, et al. C-reactive protein is elevated in schizophrenia. Schizophr Res. 2013;143(1):198-202. doi:10.1016/j.schres.2012.10.041

Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 2014 Oct;71(10):1121-8. doi: 10.1001/jamapsychiatry.2014.1332. PMID: 25133871; PMCID: PMC4561502.

Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry. 2011;168(12):1303-1310. doi:10.1176/appi.ajp.2011.11030516

Allswede DM, Cannon TD. Prenatal inflammation and risk for schizophrenia: A role for immune proteins in neurodevelopment. Dev Psychopathol. 2018;30(3):1157-1178. doi:10.1017/S0954579418000317

Rodrigues-Neves AC, Ambrósio AF, Gomes CA. Microglia sequelae: brain signature of innate immunity in schizophrenia. Transl Psychiatry. 2022;12(1):493. Published 2022 Nov 28. doi:10.1038/s41398-022-02197-1

Smith SE, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27(40):10695-10702. doi:10.1523/JNEUROSCI.2178-07.2007

Severance EG, Yolken RH. Deciphering microbiome and neuroactive immune gene interactions in schizophrenia. Neurobiol Dis. 2020;135:104331. doi:10.1016/j.nbd.2018.11.016

Khandaker GM, Zammit S, Burgess S, Lewis G, Jones PB. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain Behav Immun. 2018;69:264-272. doi:10.1016/j.bbi.2017.11.020

Wang AK, Miller BJ. Meta-analysis of Cerebrospinal Fluid Cytokine and Tryptophan Catabolite Alterations in Psychiatric Patients: Comparisons Between Schizophrenia, Bipolar Disorder, and Depression. Schizophr Bull. 2018;44(1):75-83. doi:10.1093/schbul/sbx035

Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011;130(2):226-238. doi:10.1016/j.pharmthera.2011.01.014

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. doi:10.1016/S2215-0366(17)30293-6

Monji A, Kato TA, Mizoguchi Y, et al. Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry. 2013;42:115-121. doi:10.1016/j.pnpbp.2011.12.002

Cowan M, Petri WA Jr. Microglia: Immune Regulators of Neurodevelopment. Front Immunol. 2018;9:2576. Published 2018 Nov 7. doi:10.3389/fimmu.2018.02576

Gober R, Ardalan M, Shiadeh SMJ, et al. Microglia activation in postmortem brains with schizophrenia demonstrates distinct morphological changes between brain regions. Brain Pathol. 2022;32(1):e13003. doi:10.1111/bpa.13003

Uranova NA, Vikhreva OV, Rakhmanova VI. Abnormal microglial reactivity in gray matter of the prefrontal cortex in schizophrenia. Asian J Psychiatr. 2021;63:102752. doi:10.1016/j.ajp.2021.102752

Wierzba-Bobrowicz T, Lewandowska E, Lechowicz W, Stepień T, Pasennik E. Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics. Folia Neuropathol. 2005;43(2):81-89.

Bloomfield PS, Selvaraj S, Veronese M, et al. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study [published correction appears in Am J Psychiatry. 2017 Apr 1;174(4):402]. Am J Psychiatry. 2016;173(1):44-52. doi:10.1176/appi.ajp.2015.14101358

Di Biase MA, Zalesky A, O'keefe G, et al. PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia. Transl Psychiatry. 2017;7(8):e1225. Published 2017 Aug 29. doi:10.1038/tp.2017.193

Collste K, Plavén-Sigray P, Fatouros-Bergman H, et al. Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28. Mol Psychiatry. 2017;22(6):850-856. doi:10.1038/mp.2016.247

Esshili A, Manitz MP, Freund N, Juckel G. Induction of inducible nitric oxide synthase expression in activated microglia and astrocytes following pre- and postnatal immune challenge in an animal model of schizophrenia. Eur Neuropsychopharmacol. 2020;35:100-110. doi:10.1016/j.euroneuro.2020.04.002

Mattei D, Ivanov A, Ferrai C, et al. Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment. Transl Psychiatry. 2017;7(5):e1120. Published 2017 May 9. doi:10.1038/tp.2017.80

Van den Eynde K, Missault S, Fransen E, et al. Hypolocomotive behaviour associated with increased microglia in a prenatal immune activation model with relevance to schizophrenia. Behav Brain Res. 2014;258:179-186. doi:10.1016/j.bbr.2013.10.005

Pregi N, Wenker S, Vittori D, Leirós CP, Nesse A. TNF-alpha-induced apoptosis is prevented by erythropoietin treatment on SH-SY5Y cells. Exp Cell Res. 2009;315(3):419-431. doi:10.1016/j.yexcr.2008.11.005

Buntinx M, Moreels M, Vandenabeele F, et al. Cytokine-induced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-gamma and TNF-alpha on apoptosis. J Neurosci Res. 2004;76(6):834-845. doi:10.1002/jnr.20118

Parellada E, Gassó P. Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia. Transl Psychiatry. 2021;11(1):271. Published 2021 May 6. doi:10.1038/s41398-021-01385-9

Paolicelli RC, Bolasco G, Pagani F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456-1458. doi:10.1126/science.1202529

Schafer DP, Lehrman EK, Kautzman AG, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691-705. doi:10.1016/j.neuron.2012.03.026

Sominsky L, De Luca S, Spencer SJ. Microglia: Key players in neurodevelopment and neuronal plasticity. Int J Biochem Cell Biol. 2018;94:56-60. doi:10.1016/j.biocel.2017.11.012

Uhlhaas PJ, Singer W. Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci. 2010;11(2):100-113. doi:10.1038/nrn2774

Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol. 2009;19(2):220-230. doi:10.1016/j.conb.2009.05.001

Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med. 2000;6(1):67-70. doi:10.1038/71555

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):520-527. doi:10.4088/JCP.09m05117yel

Chen AT, Chibnall JT, Nasrallah HA. Placebo-controlled augmentation trials of the antioxidant NAC in schizophrenia: A review. Ann Clin Psychiatry. 2016;28(3):190-196.

Shen H, Li R, Yan R, et al. Adjunctive therapy with statins in schizophrenia patients: A meta-analysis and implications. Psychiatry Res. 2018;262:84-93. doi:10.1016/j.psychres.2018.02.018

Cho M, Lee TY, Kwak YB, Yoon YB, Kim M, Kwon JS. Adjunctive use of anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials. Aust N Z J Psychiatry. 2019;53(8):742-759. doi:10.1177/0004867419835028

Inta D, Lang UE, Borgwardt S, Meyer-Lindenberg A, Gass P. Microglia Activation and Schizophrenia: Lessons From the Effects of Minocycline on Postnatal Neurogenesis, Neuronal Survival and Synaptic Pruning. Schizophr Bull. 2017;43(3):493-496. doi:10.1093/schbul/sbw088

Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J. Possible antipsychotic effects of minocycline in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(1):304-307. doi:10.1016/j.pnpbp.2006.08.013

Solmi M, Veronese N, Thapa N, et al. Systematic review and meta-analysis of the efficacy and safety of minocycline in schizophrenia. CNS Spectrums. 2017;22(5):415-426. doi:10.1017/S1092852916000638

Røge R, Møller BK, Andersen CR, Correll CU, Nielsen J. Immunomodulatory effects of clozapine and their clinical implications: what have we learned so far?. Schizophr Res. 2012;140(1-3):204-213. doi:10.1016/j.schres.2012.06.020

Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154. doi:10.1001/archgenpsychiatry.2009.192

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):385-397. doi:10.1111/eip.12859

Opublikowane

5 marca 2023