Immunogenetic Factors in the Pathogenesis of Schizophrenia

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Abstract

Human predisposition to neurological diseases such as schizophrenia, Alzheimer’s, Parkinson’s and other neuropathologies is associated with genetic and environmental factors. One of the promising directions in the area of molecular neurosciences is the study of the role of immunogenetic mechanisms in different types of pathological processes in brain. This review explores the role of complex histocompatibility genes in the pathogenesis of schizophrenia, evaluating changes in the immune repertoire of T- and B-cell receptors in neuroinflammation.

About the authors

M. Yu. Plotnikova

Vavilov Institute of General Genetics, Russian Academy of Sciences; Center for Genetics and Life Sciences, “Sirius” University; Lomonosov Moscow State University

Author for correspondence.
Email: plotnikova.m.u.1996@gmail.com
Russia, 119991, Moscow; Russia, 354340, Krasnodarskyi krai, пгт. Sirius; Russia, 119991, Moscow

S. S. Kunizheva

Vavilov Institute of General Genetics, Russian Academy of Sciences; Center for Genetics and Life Sciences, “Sirius” University; Lomonosov Moscow State University

Email: plotnikova.m.u.1996@gmail.com
Russia, 119991, Moscow; Russia, 354340, Krasnodarskyi krai, пгт. Sirius; Russia, 119991, Moscow

E. V. Rozhdestvenskikh

Center for Genetics and Life Sciences, “Sirius” University

Email: plotnikova.m.u.1996@gmail.com
Russia, 354340, Krasnodarskyi krai, пгт. Sirius

T. V. Andreeva

Vavilov Institute of General Genetics, Russian Academy of Sciences; Center for Genetics and Life Sciences, “Sirius” University; Lomonosov Moscow State University

Email: plotnikova.m.u.1996@gmail.com
Russia, 119991, Moscow; Russia, 354340, Krasnodarskyi krai, пгт. Sirius; Russia, 119991, Moscow

References

  1. Cottler L.B., Zunt J., Weiss B. et al. Building global capacity for brain and nervous system disorders research // Nature. 2015. V. 527. № 7578. P. S207–S213. https://doi.org/10.1038/nature16037
  2. Misra M.K., Damotte V., Hollenbach J.A. The immunogenetics of neurological disease // Immunology. 2018. V. 153. № 4. P. 399–414. https://doi.org/10.1111/imm.12869
  3. International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia // Nature. 2008. V. 455. № 7210. P. 237–241. https://doi.org/10.1038/nature07239
  4. Kato T. A renovation of psychiatry is needed // World Psychiatry. 2011. V. 10. № 3. P. 198–199. https://doi.org/10.1002/j.2051-5545.2011.tb00056.x
  5. Perälä J., Suvisaari J., Saarni S.I. et al. Lifetime prevalence of psychotic and bipolar i disorders in a general population // Arch. Gen. Psychiatry. 2007. V. 64. № 1. P. 19. https://doi.org/10.1001/archpsyc.64.1.19
  6. Trubetskoy V., Pardiñas A.F., Qi T. et al. Mapping genomic loci implicates genes and synaptic biology in schizophrenia // Nature. 2022. V. 604. № 7906. https://doi.org/10.1038/s41586-022-04434-5
  7. Xu B., Roos J.L., Dexheimer P. et al. Exome sequencing supports a de novo mutational paradigm for schizophrenia // Nat. Genet. 2011. V. 43. № 9. P. 864–868. https://doi.org/10.1038/ng.902
  8. Pouget J.G. The emerging immunogenetic architecture of schizophrenia // Schizophr. Bull. 2018. V. 44. № 5. P. 993–1004. https://doi.org/10.1093/schbul/sby038
  9. Anderson G., Maes M. Schizophrenia: Linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression // Prog. Neuropsychopharmacol. Biol. Psychiatry. 2013. V. 42. P. 5–19. https://doi.org/10.1016/j.pnpbp.2012.06.014
  10. Mikocziova I., Greiff V., Sollid L.M. Immunoglobulin germline gene variation and its impact on human disease // Genes Immun. 2021. V. 22. № 4. P. 205–217. https://doi.org/10.1038/s41435-021-00145-5
  11. Malashenkova I.K., Krynskiy S.A., Ogurtsov D.P. et al. A role of the immune system in the pathogenesis of schizophrenia // Zhurnal. Nevrolog. Psikhiatr. im. S.S. Korsakova. 2018. V. 118. № 12. https://doi.org/10.17116/jnevro201811812172
  12. International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder // Nature. 2009. V. 460. № 7256. P. 748–752. https://doi.org/10.1038/nature08185
  13. Bishop J.R., 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. V. 30. № 1. P. 59–70. https://doi.org/10.1097/HRP.0000000000000321
  14. Upthegrove R., Manzanares-Teson N., Barnes N.M. Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis // Schizophr. Res. 2014. V. 155. № 1–3. P. 101–108. https://doi.org/10.1016/j.schres.2014.03.005
  15. Rodrigues-Amorim D., Rivera-Baltanás T., Spuch C. et al. Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship // Schizophr. Res. 2018. V. 197. P. 19–33. https://doi.org/10.1016/j.schres.2017.11.023
  16. Fernandes B.S., Steiner J., Bernstein H.-G. et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: Meta-analysis and implications // Mol. Psychiatry. 2016. V. 21. № 4. P. 554–564. https://doi.org/10.1038/mp.2015.87
  17. Ermakov E.A., Melamud M.M., Buneva V.N., Ivanova S.A. Immune system abnormalities in schizophrenia: an integrative view and translational perspectives // Front. Psychiatry. 2022. V. 13. https://doi.org/10.3389/fpsyt.2022.880568
  18. Trépanier M.O., Hopperton K.E., Mizrahi R. et al. Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review // Mol. Psychiatry. 2016. V. 21. № 8. P. 1009–1026. https://doi.org/10.1038/mp.2016.90
  19. Gelderblom M., Arunachalam P., Magnus T. Î3δ T cells as early sensors of tissue damage and mediators of secondary neurodegeneration // Front. Cell. Neurosci. 2014. V. 8. https://doi.org/10.3389/fncel.2014.00368
  20. Debnath M. Adaptive immunity in schizophrenia: Functional implications of T cells in the etiology, course and treatment // J. of Neuroimmune Pharmacology. 2015. V. 10. № 4. P. 610–619. https://doi.org/10.1007/s11481-015-9626-9
  21. Miller B.J., Buckley P., Seabolt W. et al. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects // Biol. Psychiatry. 2011. V. 70. № 7. P. 663–671. https://doi.org/10.1016/j.biopsych.2011.04.013
  22. Potvin S., Stip E., Sepehry A.A. et al. Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review // Biol. Psychiatry. 2008. V. 63. № 8. P. 801–808. https://doi.org/10.1016/j.biopsych.2007.09.024
  23. Bernstein H.-G., Steiner J., Bogerts B. Glial cells in schizophrenia: Pathophysiological significance and possible consequences for therapy // Expert Rev. Neurother. 2009. V. 9. № 7. P. 1059–1071. https://doi.org/10.1586/ern.09.59
  24. Van Berckel B.N., Bossong M.G., Boellaard R. et al. Microglia activation in recent-onset schizophrenia: A quantitative (R)-[11C]PK11195 positron emission tomography study // Biol. Psychiatry. 2008. V. 64. № 9. P. 820–822. https://doi.org/10.1016/j.biopsych.2008.04.025
  25. Ermakov E.A., Mednova I.A., Boiko A.S. et al. Chemokine dysregulation and neuroinflammation in schizophrenia: A systematic review // Int. J. Mol. Sci. 2023. V. 24. № 3. P. 2215. https://doi.org/10.3390/ijms24032215
  26. Murphy C.E., Walker A.K., Weickert C.S. Neuroinflammation in schizophrenia: The role of nuclear factor kappa B // Transl. Psychiatry. 2021. V. 11. № 1. P. 528. https://doi.org/10.1038/s41398-021-01607-0
  27. Cho M., Lee T.Y., Kwak Y.B. et al. Adjunctive use of anti-inflammatory drugs for schizophrenia: A meta-analytic investigation of randomized controlled trials // Australian & New Zeal. J. of Psychiatry. 2019. V. 53. № 8. P. 742–759. https://doi.org/10.1177/0004867419835028
  28. Warren R.L., Freeman J.D., Zeng T. et al. Exhaustive T‑cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes // Genome Res. 2011. V. 21. № 5. P. 790–797. https://doi.org/10.1101/gr.115428.110
  29. Rosati E., Dowds C.M., Liaskou E. et al. Overview of methodologies for T-cell receptor repertoire analysis // BMC Biotechnol. 2017. V. 17. № 1. P. 61. https://doi.org/10.1186/s12896-017-0379-9
  30. Aliseychik M., Patrikeev A., Gusev F. et al. Dissection of the human T-cell receptor γ gene repertoire in the brain and peripheral blood identifies age- and Alzheimer’s disease-associated clonotype profiles // Front. Immunol. 2020. V. 11. https://doi.org/10.3389/fimmu.2020.00012
  31. Robinson J., Barker D.J., Georgiou X. et al. IPD-IMGT/HLA Database // Nucl. Ac. Res. 2019. https://doi.org/10.1093/nar/gkz950
  32. Bagaev D.V., Vroomans R.M.A., Samir J. et al. VDJdb in 2019: Database extension, new analysis infrastructure and a T-cell receptor motif compendium // Nuc. Ac. Res. 2020. V. 48. № D1. P. D1057–D1062. https://doi.org/10.1093/nar/gkz874
  33. Fan X., Pristach C., Liu E.Y. et al. Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia // Psychiatry Res. 2007. V. 149. № 1–3. P. 267–271. https://doi.org/10.1016/j.psychres.2006.07.011
  34. Dickerson F., Stallings C., Origoni A. et al. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia // Schizophr. Res. Elsevier. 2007. V. 93. № 1–3. P. 261–265.
  35. Jacomb I., Stanton C., Vasudevan R. et al. C-reactive protein: Higher during acute psychotic episodes and related to cortical thickness in schizophrenia and healthy controls // Front. Immunol. 2018. V. 9. https://doi.org/10.3389/fimmu.2018.02230
  36. Fillman S.G., Weickert T.W., Lenroot R.K. et al. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area Vume // Mol. Psychiatry. 2016. V. 21. № 8. P. 1090–1098. https://doi.org/10.1038/mp.2015.90
  37. Debnath M., Berk M., Leboyer M., Tamouza R. The MHC/HLA gene complex in major psychiatric disorders: Emerging roles and implications // Curr. Behav. Neurosci. Rep. Springer. 2018. V. 5. № 2. P. 179–188.
  38. Eberhard G., Franzén G., Löw B. Schizophrenia susceptibility and HL-A antigen // Neuropsychobiology. 1975. V. 1. № 4. P. 211–217. https://doi.org/10.1159/000117496
  39. Cazzullo C.L., Smeraldi E. HLA system, psychiatry and psychopharmacology // Prog. Neuropsychopharmacol. 1979. V. 3. № 1–3. P. 137–146. https://doi.org/10.1016/0364-7722(79)90079-1
  40. Morozova A.Yu., Zubkov E.A., Zorkina Ya.A. et al. Genetic aspects of schizophrenia // Zhurnal. Nevrol. Psikhiatr. im. S.S. Korsakova. 2017. V. 117. № 6. P. 126. https://doi.org/10.17116/jnevro201711761126-132
  41. Druart M., le Magueresse C. Emerging roles of complement in psychiatric disorders // Front. Psychiatry. 2019. V. 10. https://doi.org/10.3389/fpsyt.2019.00573
  42. Trowsdale J., Knight J.C. Major histocompatibility complex genomics and human disease // Annu. Rev. Genomics Hum. Genet. 2013. V. 14. № 1. P. 301–323. https://doi.org/10.1146/annurev-genom-091212-153455
  43. IMGT/HLA Database [Electronic resource]. 2020. URL: https://www.ebi.ac.uk/ipd/imgt/hla/
  44. Khandaker G.M., Dantzer R., Jones P.B. Immunopsychiatry: Important facts // Psychol. Med. 2017. V. 47. № 13. P. 2229–2237. https://doi.org/10.1017/S0033291717000745
  45. Tamouza R., Krishnamoorthy R., Leboyer M. Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context // Brain Behav. Immun. 2021. V. 91. P. 731–739. https://doi.org/10.1016/j.bbi.2020.09.033
  46. International Schizophrenia Consortium, Purcell S.M., Wray N.R., Stone J.L. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder // Nature. 2009. V. 460. № 7256. P. 748–752. https://doi.org/10.1038/nature08185
  47. Shi J., Levinson D.F., Duan J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia // Nature. 2009. V. 460. № 7256. P. 753–757. https://doi.org/10.1038/nature08192
  48. Stefansson H., Ophoff R.A., Steinberg S. et al. Common variants conferring risk of schizophrenia // Nature. 2009. V. 460. № 7256. P. 744–747. https://doi.org/10.1038/nature08186
  49. Irish Schizophrenia Genomics Consortium and the Wellcome Trust Case Control Consortium 2. Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia // Biol. Psychiatry. 2012. V. 72. № 8. P. 620–628. https://doi.org/10.1016/j.biopsych.2012.05.035
  50. Tamouza R., Krishnamoorthy R., Giegling I. et al. The HLA 8.1 ancestral haplotype in schizophrenia: Dual implication in neuro – synaptic pruning and autoimmunity? // Acta Psychiatr. Scand. 2020. V. 141. № 2. P. 169–171. https://doi.org/10.1111/acps.13125
  51. Sekar A., Bialas A.R., de Rivera H. et al. Schizophrenia risk from complex variation of complement component 4 // Nature. 2016. V. 530. № 7589. P. 177–183. https://doi.org/10.1038/nature16549
  52. Bian B., Couvy-Duchesne B., Wray N.R., McRae A.F. The role of critical immune genes in brain disorders: Insights from neuroimaging immunogenetics // Brain Commun. 2022. V. 4. № 2. https://doi.org/10.1093/braincomms/fcac078
  53. Eaton W.W., Rodriguez K.M., Thomas M.A. et al. Immunologic profiling in schizophrenia and rheumatoid arthritis // Psychiatry Res. 2022. V. 317. https://doi.org/10.1016/j.psychres.2022.114812
  54. Shivakumar V., Debnath M., Venugopal D. et al. Influence of correlation between HLA-G polymorphism and Interleukin-6 (IL6) gene expression on the risk of schizophrenia // Cytokine. 2018. V. 107. P. 59–64. https://doi.org/10.1016/j.cyto.2017.11.016
  55. Li J., Yoshikawa A., Alliey-Rodriguez N., Meltzer H.Y. Schizophrenia risk loci from xMHC region were associated with antipsychotic response in chronic schizophrenic patients with persistent positive symptom // Transl. Psychiatry. 2022. V. 12. № 1. P. 92. https://doi.org/10.1038/s41398-022-01854-9
  56. Tamouza R., Fernell E., Eriksson M.A. et al. HLA polymorphism in regressive and non-regressive autism: A preliminary study // Autism Research. 2020. V. 13. № 2. P. 182–186. https://doi.org/10.1002/aur.2217
  57. Druart M., Le Magueresse C. Emerging roles of complement in psychiatric disorders // Front. Psychiatry. 2019. V. 10. https://doi.org/10.3389/fpsyt.2019.00573
  58. Wissemann W.T., Hill-Burns E.M., Zabetian C.P. et al. Association of Parkinson disease with structural and regulatory variants in the HLA region // Am. J. Hum. Genet. 2013. V. 93. № 5. P. 984–993. https://doi.org/10.1016/j.ajhg.2013.10.009
  59. Hollenbach J.A., Norman P.J., Creary L.E. et al. A specific amino acid motif of HLA-DRB1 mediates risk and interacts with smoking history in Parkinson’s disease // PNAS. 2019. V. 116. № 15. P. 7419–7424. https://doi.org/10.1073/pnas.1821778116
  60. Kunkle B.W., Grenier-Boley B., Sims R. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing // Nat. Genet. 2019. V. 51. № 3. P. 414–430. https://doi.org/10.1038/s41588-019-0358-2
  61. Jansen I.E., Savage J.E., Watanabe K. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk // Nat. Genet. 2019. V. 51. № 3. P. 404–413. https://doi.org/10.1038/s41588-018-0311-9
  62. Lincoln M.R., Montpetit A., Cader M.Z. et al. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis // Nat. Genet. 2005. V. 37. № 10. P. 1108–1112. https://doi.org/10.1038/ng1647
  63. Patsopoulos N.A., Baranzini S.E., Santaniello A. et al. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility // Science. 2019. V. 365. № 6460. https://doi.org/10.1126/science.aav7188
  64. Kordi-Tamandani D.M., Vaziri S., Dahmardeh N., Torkamanzehi A. Evaluation of polymorphism, hypermethylation and expression pattern of CTLA4 gene in a sample of Iranian patients with schizophrenia // Mol. Biol. Rep. 2013. V. 40. № 8. P. 5123–5128. https://doi.org/10.1007/s11033-013-2614-3
  65. Lu Y., Ruan Y., Hong P. et al. T cell senescence: A crucial player in autoimmune diseases // Clin. Immunology. 2022. https://doi.org/10.1016/j.clim.2022.109202
  66. Langerak A.W., Groenen P.J.T.A., Brüggemann M. et al. EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations // Leukemia. 2012. V. 26. № 10. P. 2159–2171. https://doi.org/10.1038/leu.2012.246
  67. Израельсон М., Касацкая С., Погорелый М. и др. Анализ индивидуальных репертуаров Т-клеточных рецепторов // Иммунология. ООО Изд. гр. “ГЭОТАР-Медиа”. 2016. V. 37. № 6. P. 347–352.
  68. Calsolaro V., Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions // Alzheimer’s & Dementia. 2016. V. 12. № 6. P. 719–732. https://doi.org/10.1016/j.jalz.2016.02.010
  69. De Chirico F., Poeta E., Babini G. et al. New models of Parkinson’s like neuroinflammation in human microglia clone 3: Activation profiles induced by INF-γ plus high glucose and mitochondrial inhibitors // Front. Cell.Neurosci. 2022. V. 16. https://doi.org/10.3389/fncel.2022.1038721
  70. Pandey J.P., Namboodiri A.M., Elston R.C. Immunoglobulin G genotypes and the risk of schizophrenia // Hum. Genet. 2016. V. 135. № 10. P. 1175–1179. https://doi.org/10.1007/s00439-016-1706-2
  71. Shirts B., Prasad K., Poguegeile M. et al. Antibodies to cytomegalovirus and Herpes Simplex Virus 1 associated with cognitive function in schizophrenia // Schizophr. Res. 2008. V. 106. № 2–3. P. 268–274. https://doi.org/10.1016/j.schres.2008.07.017
  72. Atherton A., Armour K.L., Bell S. et al. The herpes simplex virus type 1 Fc receptor discriminates between IgG1 allotypes // Eur. J. Immunol. 2000. V. 30. № 9. P. 2540–2547. https://doi.org/10.1002/1521-4141(200009)30:9<25-40::AID-IMMU2540>3.0.CO;2-S
  73. Pandey J.P., Namboodiri A.M., Radwan F.F., Nietert P.J. The decoy Fcγ receptor encoded by the cytomegalovirus UL119-UL118 gene has differential affinity to IgG proteins expressing different GM allotypes // Hum. Immunol. 2015. V. 76. № 8. P. 591–594. https://doi.org/10.1016/j.humimm.2015.09.005
  74. Pandey J.P., Namboodiri A.M., Mohan S. et al. Genetic markers of immunoglobulin G and immunity to cytomegalovirus in patients with breast cancer // Cell. Immunol. 2017. V. 312. P. 67–70. https://doi.org/10.1016/j.cellimm.2016.11.003
  75. Pandey J.P., Namboodiri A.M., Nietert P.J. et al. Immunoglobulin genotypes and cognitive functions in schizophrenia // Immunogenetics. 2018. V. 70. № 1. P. 67–72. https://doi.org/10.1007/s00251-017-1030-6
  76. Kezai A.M., Lecoeur C., Hot D. et al. Association between schizophrenia and Toxoplasma gondii infection in Algeria // Psychiatry Res. 2020. V. 291. https://doi.org/10.1016/j.psychres.2020.113293
  77. Wang A.W., Avramopoulos D., Lori A. et al. Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk // Prog. Neuropsychopharmacol. Biol. Psychiatry. 2019. V. 92. P. 133–147. https://doi.org/10.1016/j.pnpbp.2018.12.019
  78. Whelan R., St Clair D., Mustard C.J. et al. Study of novel autoantibodies in schizophrenia // Schizophr. Bull. 2018. V. 44. № 6. P. 1341–1349. https://doi.org/10.1093/schbul/sbx175
  79. Mehr R. Immune system modeling and analysis // Front. Immunol. 2014. V. 5. https://doi.org/10.3389/fimmu.2014.00644
  80. Agorastos A., Bozikas V.P. Gut microbiome and adaptive immunity in schizophrenia // Psychiatriki. 2019. V. 30. № 3. P. 189–192. https://doi.org/10.22365/jpsych.2019.303.189
  81. Li Q., Zhou J., Cao X. et al. Clonal characteristics of T‑cell receptor repertoires in violent and non-violent patients with schizophrenia // Front. Psychiatry. 2018. V. 9. https://doi.org/10.3389/fpsyt.2018.00403
  82. Luo C., Pi X., Hu N. et al. Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function // Mol. Psychiatry. 2021. V. 26. № 11. P. 6926–6936. https://doi.org/10.1038/s41380-021-01308-6
  83. Gao Y., Fan Y., Yang Z. et al. Systems biological assessment of altered cytokine responses to bacteria and fungi reveals impaired immune functionality in schizophrenia // Mol. Psychiatry. 2022. V. 27. № 2. P. 1205–1216. https://doi.org/10.1038/s41380-021-01362-0

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