title: Immune system disturbances in schizophrenia.
abstract: Epidemiological, genetic, transcriptome, postmortem, peripheral biomarker, and therapeutic studies of schizophrenia all point to a dysregulation of both innate and adaptive immune systems in the disease, and it is likely that these immune changes actively contribute to disease symptoms. Gene expression disturbances in the brain of subjects with schizophrenia show complex, region-specific changes with consistently replicated and potentially interdependent induction of serpin peptidase inhibitor, clade A member 3 (SERPINA3) and interferon inducible transmembrane protein (IFITM) family transcripts in the prefrontal cortex. Recent data suggest that IFITM3 expression is a critical mediator of maternal immune activation. Because the IFITM gene family is primarily expressed in the endothelial cells and meninges, and because the meninges play a critical role in interneuron development, we suggest that these two non-neuronal cell populations might play an important role in the disease pathophysiology. Finally, we propose that IFITM3 in particular might be a novel, appealing, knowledge-based drug target for treatment of schizophrenia.
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee; Department of Psychiatry, University of Szeged, 6725 Szeged, Hungary.
authors.forename: Szatmár
authors.initials: S
authors.lastname: Horváth
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee; Department of Psychiatry, University of Szeged, 6725 Szeged, Hungary. Electronic address: karoly.mirnics@vanderbilt.edu.
authors.forename: Károly
authors.initials: K
authors.lastname: Mirnics
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018811:Maternal Exposure; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000893:Anti-Inflammatory Agents; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C516148:SERPINA3 protein, human; D015843:Serpins
keywords: Blood-brain barrier; CD14; CHI3L1; IFITM; IFITM3; SERPINA3; blood vessels; immune; meninges; pia mater; postmortem; schizophrenia
references.citation: Neuropsychopharmacology. 2011 Sep;36(10):2103-10
references.pmid: 21677653
references.citation: Biol Psychiatry. 2010 Dec 15;68(12):1172-81
references.pmid: 21130225
references.citation: Curr Protein Pept Sci. 2013 Feb;14(1):21-32
references.pmid: 23441898
references.citation: J Biol Chem. 2006 May 12;281(19):13126-13133
references.pmid: 16565071
references.citation: Hum Mol Genet. 2012 May 1;21(9):1968-78
references.pmid: 22246292
references.citation: Science. 2013 Mar 1;339(6123):1095-9
references.pmid: 23449593
references.citation: PLoS One. 2012;7(4):e36351
references.pmid: 22558445
references.citation: Curr Pharm Biotechnol. 2012 Jun;13(8):1606-13
references.pmid: 22283758
references.citation: Nature. 2009 Aug 6;460(7256):744-7
references.pmid: 19571808
references.citation: Cancer Sci. 2005 Mar;96(3):183-90
references.pmid: 15771622
references.citation: Biol Psychiatry. 2011 Oct 1;70(7):696-8
references.pmid: 21514568
references.citation: Am J Psychiatry. 2008 Apr;165(4):479-89
references.pmid: 18281411
references.citation: Arch Gen Psychiatry. 2012 Dec;69(12):1205-13
references.pmid: 22868662
references.citation: Dev Neurobiol. 2012 Oct;72(10):1317-26
references.pmid: 22753006
references.citation: J Neuroimmunol. 2011 Oct 28;239(1-2):37-43
references.pmid: 21911260
references.citation: BMC Med Genomics. 2010 May 13;3:18
references.pmid: 20465783
references.citation: J Mol Histol. 2007 Mar;38(1):33-43
references.pmid: 17242979
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15718-23
references.pmid: 9861036
references.citation: Biol Psychiatry. 2007 Oct 1;62(7):711-21
references.pmid: 17568569
references.citation: J Neurosci. 2013 May 1;33(18):7654-66
references.pmid: 23637159
references.citation: Cell Signal. 2012 Jun;24(6):1185-94
references.pmid: 22330073
references.citation: Synapse. 2006 Dec 15;60(8):585-98
references.pmid: 16983646
references.citation: Biol Psychiatry. 2011 Jan 15;69(2):157-62
references.pmid: 20801428
references.citation: Mol Psychiatry. 2008 Feb;13(2):147-61
references.pmid: 17471287
references.citation: Mol Psychiatry. 1999 Mar;4(2):145-54
references.pmid: 10208446
references.citation: Psychiatry Clin Neurosci. 2010 Jun;64(3):217-30
references.pmid: 20602722
references.citation: Biol Psychiatry. 2011 Oct 1;70(7):663-71
references.pmid: 21641581
references.citation: Schizophr Res. 2010 Aug;121(1-3):118-24
references.pmid: 20570110
references.citation: Transl Psychiatry. 2012 Apr 03;2:e98
references.pmid: 22832908
references.citation: PLoS Pathog. 2011 Oct;7(10):e1002337
references.pmid: 22046135
references.citation: Nat Genet. 2011 Sep 18;43(10):969-76
references.pmid: 21926974
references.citation: J Neurosci. 2007 Oct 3;27(40):10695-702
references.pmid: 17913903
references.citation: Biol Psychiatry. 2009 Mar 15;65(6):481-8
references.pmid: 19058794
references.citation: Front Biosci. 2007 May 01;12:2821-35
references.pmid: 17485262
references.citation: Nat Neurosci. 2006 Oct;9(10):1284-93
references.pmid: 16964252
references.citation: Ann Neurol. 2012 Nov;72(5):648-72
references.pmid: 23280789
references.citation: BMC Med. 2013 Mar 18;11:74
references.pmid: 23506529
references.citation: Neurosci Lett. 2013 Apr 29;541:263-8
references.pmid: 23454452
references.citation: Mol Psychiatry. 2011 Jan;16(1):37-58
references.pmid: 19935739
references.citation: J Neurosci. 2003 Jan 1;23(1):297-302
references.pmid: 12514227
references.citation: Hum Mol Genet. 2005 Jan 15;14(2):241-53
references.pmid: 15563509
references.citation: Methods Mol Biol. 2012;829:445-51
references.pmid: 22231831
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):129-58
references.pmid: 17266109
references.citation: Behav Brain Res. 2009 Dec 7;204(2):313-21
references.pmid: 19136031
references.citation: Arch Gen Psychiatry. 1998 Mar;55(3):215-24
references.pmid: 9510215
references.citation: J Biol Chem. 2005 Dec 30;280(52):43168-78
references.pmid: 16141197
references.citation: Arch Gen Psychiatry. 1995 Apr;52(4):258-66
references.pmid: 7702443
references.citation: Neuron. 2000 Oct;28(1):53-67
references.pmid: 11086983
references.citation: Hypertension. 2007 Jan;49(1):76-83
references.pmid: 17088445
references.citation: Nat Med. 2009 May;15(5):488-90
references.pmid: 19424205
references.citation: Brain Behav Immun. 2010 Aug;24(6):881-97
references.pmid: 20230889
references.citation: J Neurosci. 2011 Feb 2;31(5):1863-72
references.pmid: 21289196
references.citation: World J Biol Psychiatry. 2012 Oct;13(7):482-92
references.pmid: 21707463
references.citation: J Psychiatr Res. 2010 Oct;44(14):989-91
references.pmid: 20381070
references.citation: Biol Psychiatry. 2002 Oct 1;52(7):708-15
references.pmid: 12372661
references.citation: J Biol Chem. 2006 Jan 27;281(4):1956-63
references.pmid: 16303762
references.citation: J Immunol. 2009 Jul 1;183(1):613-20
references.pmid: 19535637
references.citation: Biol Psychiatry. 2006 Jul 15;60(2):163-76
references.pmid: 16616896
references.citation: Expert Rev Neurother. 2010 Jan;10(1):59-76
references.pmid: 20021321
references.citation: Neurobiol Dis. 2010 Mar;37(3):738-46
references.pmid: 20034564
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4746-51
references.pmid: 11296301
references.citation: Curr Opin Investig Drugs. 2010 Jan;11(1):31-42
references.pmid: 20047157
references.citation: Int J Dev Neurosci. 2011 May;29(3):305-9
references.pmid: 21382468
references.citation: Neural Dev. 2012 Jan 17;7:2
references.pmid: 22248045
references.citation: Biol Psychiatry. 2008 Jul 15;64(2):98-103
references.pmid: 18281018
references.citation: Schizophr Res. 2010 Feb;116(2-3):126-32
references.pmid: 20051317
references.citation: Neurosci Res. 2006 Sep;56(1):2-13
references.pmid: 16837094
references.citation: Schizophr Res. 2001 Apr 15;49(1-2):73-8
references.pmid: 11343866
references.citation: Immunology. 2013 Mar;138(3):190-7
references.pmid: 23173987
references.citation: JAMA Psychiatry. 2013 Mar;70(3):271-8
references.pmid: 23344076
references.citation: J Psychiatr Res. 2010 Dec;44(16):1176-89
references.pmid: 20471030
references.citation: Schizophr Res. 2005 Sep 15;77(2-3):241-52
references.pmid: 15923110
references.citation: Mol Psychiatry. 2007 Apr;12(4):385-97
references.pmid: 17264840
references.citation: Cell. 2009 Dec 24;139(7):1243-54
references.pmid: 20064371
references.citation: Neurosci Lett. 2012 Apr 4;513(2):204-8
references.pmid: 22366530
references.citation: Mol Psychiatry. 2013 Feb;18(2):206-14
references.pmid: 22869038
references.citation: Am J Pathol. 1989 Nov;135(5):827-34
references.pmid: 2817081
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2009 Mar 17;33(2):303-7
references.pmid: 19138716
references.citation: Schizophr Bull. 2012 Nov;38(6):1149-54
references.pmid: 22966150
references.citation: Prog Neurobiol. 2011 Jan;93(1):23-58
references.pmid: 20955757
references.citation: Dev Neurobiol. 2012 Oct;72(10):1277-87
references.pmid: 22753382
references.citation: Am J Psychiatry. 2005 Apr;162(4):767-73
references.pmid: 15800151
references.citation: BMC Psychiatry. 2007 Sep 06;7:46
references.pmid: 17822540
references.citation: Int J Neuropsychopharmacol. 2011 Aug;14(7):997-1012
references.pmid: 21156092
references.citation: J Neurosci. 2002 Apr 1;22(7):2718-29
references.pmid: 11923437
references.citation: Am J Psychiatry. 2010 Mar;167(3):261-80
references.pmid: 20123911
references.citation: J Med Genet. 2012 Feb;49(2):96-103
references.pmid: 22187495
references.citation: Nat Rev Immunol. 2011 May;11(5):318-29
references.pmid: 21508982
references.citation: Ann Med. 2008;40(4):281-95
references.pmid: 18428021
references.citation: Glia. 2013 May;61(5):679-93
references.pmid: 23382131
references.citation: Nat Rev Immunol. 2013 Jan;13(1):46-57
references.pmid: 23237964
references.citation: Trends Neurosci. 2001 Aug;24(8):479-86
references.pmid: 11476888
references.citation: PLoS Pathog. 2012 Sep;8(9):e1002909
references.pmid: 22969429
references.citation: Neurobiol Dis. 2008 Jun;30(3):303-311
references.pmid: 18378158