Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders

Maria Fiorentino, Anna Sapone, Stefania Senger, Stephanie S Camhi, Sarah M Kadzielski, Timothy M Buie, Deanna L Kelly, Nicola Cascella, Alessio Fasano, Maria Fiorentino, Anna Sapone, Stefania Senger, Stephanie S Camhi, Sarah M Kadzielski, Timothy M Buie, Deanna L Kelly, Nicola Cascella, Alessio Fasano

Abstract

Background: Autism spectrum disorders (ASD) are complex conditions whose pathogenesis may be attributed to gene-environment interactions. There are no definitive mechanisms explaining how environmental triggers can lead to ASD although the involvement of inflammation and immunity has been suggested. Inappropriate antigen trafficking through an impaired intestinal barrier, followed by passage of these antigens or immune-activated complexes through a permissive blood-brain barrier (BBB), can be part of the chain of events leading to these disorders. Our goal was to investigate whether an altered BBB and gut permeability is part of the pathophysiology of ASD.

Methods: Postmortem cerebral cortex and cerebellum tissues from ASD, schizophrenia (SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and HC were analyzed for gene and protein expression profiles. Tight junctions and other key molecules associated with the neurovascular unit integrity and function and neuroinflammation were investigated.

Results: Claudin (CLDN)-5 and -12 were increased in the ASD cortex and cerebellum. CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8, tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased in the SCZ cerebellum. Differences between SCZ and ASD were observed for most of the genes analyzed in both brain areas. CLDN-5 protein was increased in ASD cortex and cerebellum, while CLDN-12 appeared reduced in both ASD and SCZ cortexes. In the intestine, 75% of the ASD samples analyzed had reduced expression of barrier-forming TJ components (CLDN-1, OCLN, TRIC), whereas 66% had increased pore-forming CLDNs (CLDN-2, -10, -15) compared to controls.

Conclusions: In the ASD brain, there is an altered expression of genes associated with BBB integrity coupled with increased neuroinflammation and possibly impaired gut barrier integrity. While these findings seem to be specific for ASD, the possibility of more distinct SCZ subgroups should be explored with additional studies.

Keywords: Autism spectrum disorders; Blood–brain barrier; Duodenal biopsies; Gut permeability; Gut–brain axis; Neuroinflammation; Postmortem brain; Schizophrenia.

Figures

Fig. 1
Fig. 1
Altered gene expression level of TJ components in the cortex of ASD subjects. Each dot represents data from a single subject. Gene expression level is reported as 2−ddCT with normalization of mRNA expression to the endogenous control 18S. Mean ± SEM are reported for each group. One-way ANOVA test has been used to evaluate statistical significance. *p < 0.05; **p < 0.01; ***p < 0.001
Fig. 2
Fig. 2
Gene expression profile of BBB function associated components in the cortex of HC, ASD, and SCZ subjects. Each dot represents data from a single subject. Gene expression level is reported as 2−ddCT with normalization of mRNA expression to the endogenous control 18S. Mean ± SEM are reported for each group. One-way ANOVA test has been used to evaluate statistical significance. *p < 0.05; **p < 0.01; ***p < 0.001
Fig. 3
Fig. 3
Gene expression profile of some pro-inflammatory cytokines in the cortex of HC, ASD, and SCZ subjects. Each dot represents data from a single subject. Gene expression level is reported as 2−ddCT with normalization of mRNA expression to the endogenous control 18S. Mean ± SEM are reported for each group. One-way ANOVA test has been used to evaluate statistical significance. **p < 0.01
Fig. 4
Fig. 4
Increased claudins and inflammatory markers gene expression levels in the cerebellum of HC, ASD, and SCZ subjects. Each dot represents data from a single subject. Gene expression level is reported as 2−ddCT with normalization of mRNA expression to the endogenous control 18S. Mean ± SEM are reported for each group. One-way ANOVA test has been used to evaluate statistical significance. *p < 0.05; **p < 0.01
Fig. 5
Fig. 5
Increased CLDN-5 and decreased CLDN-12 expression in the cortex of ASD subjects. a Brain tissues were lysed and immunoblotted with anti-claudin-5, anti-claudin-12, SMA or actin antibody. b Densitometry analysis of the results from the western blots is shown, where the data are normalized against SMA expression and are expressed as the mean ± standard error. Quantitative results represent the average of three independent experiments.*p < 0.05; ****p < 0.0001
Fig. 6
Fig. 6
Increased CLDN-5 expression in the cerebellum of ASD subjects. a Western blots of brain lysates immunoblotted with anti-claudin-5, anti-claudin-12, SMA or actin antibody. b Densitometry analysis of the results from the western blots is shown, where the data are normalized against SMA expression and are expressed as the mean ± standard error. Quantitative results represent the average of three independent experiments. ***p < 0.001
Fig. 7
Fig. 7
Increased pore-forming claudins and decreased barrier-forming TJ components expression in the small intestine of HC and ASD subjects. Gene expression levels of TJ components in duodenal biopsies from HC (n = 9) and ASD patients (n = 12). CLDN-2, -10 and/or -15 levels are higher in eight out of 12 ASD samples, compared in controls. CLDN-1, OCLN, and/or TRIC levels are decreased in nine out of 12 ASD samples over controls. Each graph represents single patient results. Data are expressed as fold change over the averaged controls
Fig. 8
Fig. 8
Gene expression in the cortex and cerebellum (CBL) of HC, ASD, and SCZ subjects clustered by functional category. Results are represented as scatter plots where each dot represents data obtained from one subject sample. a Cortex BBB sealing properties group includes CLDN-3, -5, and -12, TRIC, and OCLN. b CBL “BBB sealing properties” group includes CLDN-3, -5, and -12, TRIC, and OCLN. c Cortex BBB function associated markers group includes tPA, MMP2/9, and MSFD2A. d CBL BBB function associated markers group includes tPA and MMP-2/9. e Cortex Inflammation group includes IL-1b, IL-6, and IL-8; TSPO; and IBA-1. f CBL Inflammation group includes IL-1b, IL-6, and IL-8; TSPO; IBA-1. Gene expression level is reported as 2−ddCT with normalization of mRNA expression to the endogenous control 18S. Mean ± SEM are reported for each group. One-way ANOVA test has been used to evaluate statistical significance. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001

References

    1. Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, Hansen RL, Phillips TM. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol. 2001;49(5):597–606. doi: 10.1002/ana.1024.
    1. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81. doi: 10.1002/ana.20315.
    1. Zimmerman AW, Connors SL, Matteson KJ, Lee LC, Singer HS, Castaneda JA, Pearce DA. Maternal antibrain antibodies in autism. Brain Behav Immun. 2007;21(3):351–357. doi: 10.1016/j.bbi.2006.08.005.
    1. Zimmerman AW, Jyonouchi H, Comi AM, Connors SL, Milstien S, Varsou A, Heyes MP. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol. 2005;33(3):195–201. doi: 10.1016/j.pediatrneurol.2005.03.014.
    1. Chez MG, Dowling T, Patel PB, Khanna P, Kominsky M. Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr Neurol. 2007;36(6):361–365. doi: 10.1016/j.pediatrneurol.2007.01.012.
    1. Pardo CA, Vargas DL, Zimmerman AW. Immunity, neuroglia and neuroinflammation in autism. Int Rev Psychiatry. 2005;17(6):485–495. doi: 10.1080/02646830500381930.
    1. Kinney DK, Hintz K, Shearer EM, Barch DH, Riffin C, Whitley K, Butler R. A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction. Med Hypotheses. 2010;74(3):555–563. doi: 10.1016/j.mehy.2009.09.040.
    1. Carter CJ. Schizophrenia: a pathogenetic autoimmune disease caused by viruses and pathogens and dependent on genes. J Pathog. 2011;2011:128318. doi: 10.4061/2011/128318.
    1. Barch DM, Carter CS. Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res. 2005;77(1):43–58. doi: 10.1016/j.schres.2004.12.019.
    1. Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, Mortensen PB. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry. 2006;163(3):521–528. doi: 10.1176/appi.ajp.163.3.521.
    1. Avramopoulos D, Pearce BD, McGrath J, Wolyniec P, Wang R, Eckart N, Hatzimanolis A, Goes FS, Nestadt G, Mulle J, et al. Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation. PLoS One. 2015;10(3):e0116696. doi: 10.1371/journal.pone.0116696.
    1. Gantert M, Kreczmanski P, Kuypers E, Jellema R, Strackx E, Bastian N, Gavilanes AW, Zimmermann LJ, Garnier Y, Schmitz C, et al. Effects of in utero endotoxemia on the ovine fetal brain: a model for schizophrenia? Front Biosci (Elite Ed) 2012;4:2845–2853.
    1. Hope S, Dieset I, Agartz I, Steen NE, Ueland T, Melle I, Aukrust P, Andreassen OA. Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia. J Psychiatr Res. 2011;45(12):1608–1616. doi: 10.1016/j.jpsychires.2011.08.003.
    1. Yang Y, Wan C, Li H, Zhu H, La Y, Xi Z, Chen Y, Jiang L, Feng G, He L. Altered levels of acute phase proteins in the plasma of patients with schizophrenia. Anal Chem. 2006;78(11):3571–3576. doi: 10.1021/ac051916x.
    1. Wan C, La Y, Zhu H, Yang Y, Jiang L, Chen Y, Feng G, Li H, Sang H, Hao X, et al. Abnormal changes of plasma acute phase proteins in schizophrenia and the relation between schizophrenia and haptoglobin (Hp) gene. Amino Acids. 2007;32(1):101–108. doi: 10.1007/s00726-005-0292-8.
    1. Ashwood P, Wakefield AJ. Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms. J Neuroimmunol. 2006;173(1–2):126–134. doi: 10.1016/j.jneuroim.2005.12.007.
    1. Cascella NG, Santora D, Gregory P, Kelly DL, Fasano A, Eaton WW. Increased prevalence of transglutaminase 6 antibodies in sera from schizophrenia patients. Schizophr Bull. 2013;39(4):867–871. doi: 10.1093/schbul/sbs064.
    1. Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol. 2005;71:317–341. doi: 10.1016/S0074-7742(05)71013-8.
    1. Singh VK. Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism. Ann Clin Psychiatry. 2009;21(3):148–161.
    1. Kliushnik TP, Androsova LV, Simashkova NV, Zozulia SA, Otman IN, Koval'-Zaitsev AA. [Innate and adaptive immunity in children with psychotic forms of autism-spectrum disorders] Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111(8 Pt 1):41–45.
    1. Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16(8):469–486. doi: 10.1038/nrn3978.
    1. Chen SJ, Chao YL, Chen CY, Chang CM, Wu EC, Wu CS, Yeh HH, Chen CH, Tsai HJ. Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study. Br J Psychiatry. 2012;200(5):374–380. doi: 10.1192/bjp.bp.111.092098.
    1. Kalaydjian AE, Eaton W, Cascella N, Fasano A. The gluten connection: the association between schizophrenia and celiac disease. Acta Psychiatr Scand. 2006;113(2):82–90. doi: 10.1111/j.1600-0447.2005.00687.x.
    1. Wu S, Ding Y, Wu F, Li R, Xie G, Hou J, Mao P. Family history of autoimmune diseases is associated with an increased risk of autism in children: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2015;55:322–332. doi: 10.1016/j.neubiorev.2015.05.004.
    1. Billeci L, Tonacci A, Tartarisco G, Ruta L, Pioggia G, Gangemi S. Association between atopic dermatitis and autism spectrum disorders: a systematic review. Am J Clin Dermatol. 2015;16:371–88. doi: 10.1007/s40257-015-0145-5.
    1. Kohane IS, McMurry A, Weber G, MacFadden D, Rappaport L, Kunkel L, Bickel J, Wattanasin N, Spence S, Murphy S, et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7(4):e33224. doi: 10.1371/journal.pone.0033224.
    1. Zerbo O, Leong A, Barcellos L, Bernal P, Fireman B, Croen LA. Immune mediated conditions in autism spectrum disorders. Brain Behav Immun. 2015;46:232–236. doi: 10.1016/j.bbi.2015.02.001.
    1. Magalhaes ES, Pinto-Mariz F, Bastos-Pinto S, Pontes AT, Prado AE, deAzevedo LC. Immune allergic response in Asperger syndrome. J Neuroimmunol. 2009;216(1–2):108–112. doi: 10.1016/j.jneuroim.2009.09.015.
    1. Gorrindo P, Williams KC, Lee EB, Walker LS, McGrew SG, Levitt P. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012;5(2):101–108. doi: 10.1002/aur.237.
    1. Valicenti-McDermott MD, McVicar K, Cohen HJ, Wershil BK, Shinnar S. Gastrointestinal symptoms in children with an autism spectrum disorder and language regression. Pediatr Neurol. 2008;39(6):392–398. doi: 10.1016/j.pediatrneurol.2008.07.019.
    1. Buie T, Campbell DB, Fuchs GJ, 3rd, Furuta GT, Levy J, Vandewater J, Whitaker AH, Atkins D, Bauman ML, Beaudet AL, et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010;125(Suppl 1):S1–18. doi: 10.1542/peds.2009-1878C.
    1. Lightdale JR, Hayer C, Duer A, Lind-White C, Jenkins S, Siegel B, Elliott GR, Heyman MB. Effects of intravenous secretin on language and behavior of children with autism and gastrointestinal symptoms: a single-blinded, open-label pilot study. Pediatrics. 2001;108(5) doi: 10.1542/peds.108.5.e90.
    1. Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999;135(5):559–563. doi: 10.1016/S0022-3476(99)70052-1.
    1. Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep. 2002;4(3):251–258. doi: 10.1007/s11894-002-0071-6.
    1. Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002;14(5):583–587. doi: 10.1097/00008480-200210000-00004.
    1. Kang V, Wagner GC, Ming X. Gastrointestinal dysfunction in children with autism spectrum disorders. Autism Res. 2014;7(4):501–506. doi: 10.1002/aur.1386.
    1. Torrente F, Anthony A, Heuschkel RB, Thomson MA, Ashwood P, Murch SH. Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis. Am J Gastroenterol. 2004;99(4):598–605. doi: 10.1111/j.1572-0241.2004.04142.x.
    1. Torrente F, Ashwood P, Day R, Machado N, Furlano RI, Anthony A, Davies SE, Wakefield AJ, Thomson MA, Walker-Smith JA, et al. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry. 2002;7(4):375–382. doi: 10.1038/sj.mp.4001077.
    1. D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996;85(9):1076–1079. doi: 10.1111/j.1651-2227.1996.tb14220.x.
    1. de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010;51(4):418–424. doi: 10.1097/MPG.0b013e3181dcc4a5.
    1. de Magistris L, Picardi A, Siniscalco D, Riccio MP, Sapone A, Cariello R, Abbadessa S, Medici N, Lammers KM, Schiraldi C, et al. Antibodies against food antigens in patients with autistic spectrum disorders. Biomed Res Int. 2013;2013:729349. doi: 10.1155/2013/729349.
    1. Dalton N, Chandler S, Turner C, Charman T, Pickles A, Loucas T, Simonoff E, Sullivan P, Baird G. Gut permeability in autism spectrum disorders. Autism Res. 2014;7(3):305–313. doi: 10.1002/aur.1350.
    1. Niebuhr DW, Li Y, Cowan DN, Weber NS, Fisher JA, Ford GM, Yolken R. Association between bovine casein antibody and new onset schizophrenia among US military personnel. Schizophr Res. 2011;128(1–3):51–55. doi: 10.1016/j.schres.2011.02.005.
    1. Jackson J, Eaton W, Cascella N, Fasano A, Warfel D, Feldman S, Richardson C, Vyas G, Linthicum J, Santora D, et al. A gluten-free diet in people with schizophrenia and anti-tissue transglutaminase or anti-gliadin antibodies. Schizophr Res. 2012;140(1–3):262–263. doi: 10.1016/j.schres.2012.06.011.
    1. Severance EG, Dickerson FB, Halling M, Krivogorsky B, Haile L, Yang S, Stallings CR, Origoni AE, Bossis I, Xiao J, et al. Subunit and whole molecule specificity of the anti-bovine casein immune response in recent onset psychosis and schizophrenia. Schizophr Res. 2010;118(1–3):240–247. doi: 10.1016/j.schres.2009.12.030.
    1. Jackson J, Eaton W, Cascella N, Fasano A, Santora D, Sullivan K, Feldman S, Raley H, McMahon RP, Carpenter WT, Jr, et al. Gluten sensitivity and relationship to psychiatric symptoms in people with schizophrenia. Schizophr Res. 2014;159(2–3):539–542. doi: 10.1016/j.schres.2014.09.023.
    1. Moor AC, de Vries HE, de Boer AG, Breimer DD. The blood–brain barrier and multiple sclerosis. Biochem Pharmacol. 1994;47(10):1717–1724. doi: 10.1016/0006-2952(94)90297-6.
    1. Hemmer B, Cepok S, Zhou D, Sommer N. Multiple sclerosis—a coordinated immune attack across the blood brain barrier. Curr Neurovasc Res. 2004;1(2):141–150. doi: 10.2174/1567202043480152.
    1. Yang Y, Rosenberg GA. Blood–brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke. 2011;42(11):3323–3328. doi: 10.1161/STROKEAHA.110.608257.
    1. Weissberg I, Reichert A, Heinemann U, Friedman A. Blood–brain barrier dysfunction in epileptogenesis of the temporal lobe. Epilepsy Res Treat. 2011;2011:143908.
    1. de Vries HE, Kuiper J, de Boer AG, Van Berkel TJ, Breimer DD. The blood–brain barrier in neuroinflammatory diseases. Pharmacol Rev. 1997;49(2):143–155.
    1. Heinemann U, Kaufer D, Friedman A. Blood–brain barrier dysfunction, TGFbeta signaling, and astrocyte dysfunction in epilepsy. Glia. 2012;60(8):1251–1257. doi: 10.1002/glia.22311.
    1. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, Friedman A. Lasting blood–brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci. 2004;24(36):7829–7836. doi: 10.1523/JNEUROSCI.1751-04.2004.
    1. Gray MT, Woulfe JM. Striatal blood–brain barrier permeability in Parkinson's disease. J Cereb Blood Flow Metab. 2015;35(5):747–750. doi: 10.1038/jcbfm.2015.32.
    1. Bell RD, Zlokovic BV. Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer's disease. Acta Neuropathol. 2009;118(1):103–113. doi: 10.1007/s00401-009-0522-3.
    1. Lee H, Pienaar IS. Disruption of the blood–brain barrier in Parkinson's disease: curse or route to a cure? Front Biosci (Landmark Ed) 2014;19:272–280. doi: 10.2741/4206.
    1. Eaton W, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac disease and schizophrenia: population based case control study with linkage of Danish national registers. BMJ. 2004;328(7437):438–439. doi: 10.1136/bmj.328.7437.438.
    1. Hanson DR, Gottesman II. Theories of schizophrenia: a genetic-inflammatory-vascular synthesi. BMC Med Genet. 2005;6:7. doi: 10.1186/1471-2350-6-7.
    1. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–1108. doi: 10.1038/nprot.2008.73.
    1. Al Ahmad A, Gassmann M, Ogunshola OO. Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown. Microvasc Res. 2012;84(2):222–225. doi: 10.1016/j.mvr.2012.05.008.
    1. Engelhardt S, Al-Ahmad AJ, Gassmann M, Ogunshola OO. Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism. J Cell Physiol. 2014;229(8):1096–1105. doi: 10.1002/jcp.24544.
    1. Amasheh S, Meiri N, Gitter AH, Schoneberg T, Mankertz J, Schulzke JD, Fromm M. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci. 2002;115(Pt 24):4969–4976. doi: 10.1242/jcs.00165.
    1. Gunzel D, Stuiver M, Kausalya PJ, Haisch L, Krug SM, Rosenthal R, Meij IC, Hunziker W, Fromm M, Muller D. Claudin-10 exists in six alternatively spliced isoforms that exhibit distinct localization and function. J Cell Sci. 2009;122(Pt 10):1507–1517. doi: 10.1242/jcs.040113.
    1. Inai T, Kamimura T, Hirose E, Iida H, Shibata Y. The protoplasmic or exoplasmic face association of tight junction particles cannot predict paracellular permeability or heterotypic claudin compatibility. Eur J Cell Biol. 2010;89(7):547–556. doi: 10.1016/j.ejcb.2010.01.003.
    1. Tamura A, Hayashi H, Imasato M, Yamazaki Y, Hagiwara A, Wada M, Noda T, Watanabe M, Suzuki Y, Tsukita S. Loss of claudin-15, but not claudin-2, causes Na + deficiency and glucose malabsorption in mouse small intestine. Gastroenterology. 2011;140(3):913–923. doi: 10.1053/j.gastro.2010.08.006.
    1. Leppert D, Ford J, Stabler G, Grygar C, Lienert C, Huber S, Miller KM, Hauser SL, Kappos L. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain. 1998;121(Pt 12):2327–2334. doi: 10.1093/brain/121.12.2327.
    1. Kandagaddala LD, Kang MJ, Chung BC, Patterson TA, Kwon OS. Expression and activation of matrix metalloproteinase-9 and NADPH oxidase in tissues and plasma of experimental autoimmune encephalomyelitis in mice. Exp Toxicol Pathol. 2012;64(1–2):109–114. doi: 10.1016/j.etp.2010.07.002.
    1. Minagar A, Alexander JS. Blood–brain barrier disruption in multiple sclerosis. Mult Scler. 2003;9(6):540–549. doi: 10.1191/1352458503ms965oa.
    1. Nygardas PT, Hinkkanen AE. Up-regulation of MMP-8 and MMP-9 activity in the BALB/c mouse spinal cord correlates with the severity of experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2002;128(2):245–254. doi: 10.1046/j.1365-2249.2002.01855.x.
    1. Yong VW, Zabad RK, Agrawal S, Goncalves Dasilva A, Metz LM. Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. J Neurol Sci. 2007;259(1–2):79–84. doi: 10.1016/j.jns.2006.11.021.
    1. Chiu PS, Lai SC. Matrix metalloproteinase-9 leads to blood–brain barrier leakage in mice with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis. Acta Trop. 2014;140:141–150. doi: 10.1016/j.actatropica.2014.08.015.
    1. Dal-Pizzol F, Rojas HA, dos Santos EM, Vuolo F, Constantino L, Feier G, Pasquali M, Comim CM, Petronilho F, Gelain DP, et al. Matrix metalloproteinase-2 and metalloproteinase-9 activities are associated with blood–brain barrier dysfunction in an animal model of severe sepsis. Mol Neurobiol. 2013;48(1):62–70. doi: 10.1007/s12035-013-8433-7.
    1. Lee MA, Palace J, Stabler G, Ford J, Gearing A, Miller K. Serum gelatinase B, TIMP-1 and TIMP-2 levels in multiple sclerosis. A longitudinal clinical and MRI study. Brain. 1999;122(Pt 2):191–197. doi: 10.1093/brain/122.2.191.
    1. Waubant E. Biomarkers indicative of blood–brain barrier disruption in multiple sclerosis. Dis Markers. 2006;22(4):235–244. doi: 10.1155/2006/709869.
    1. Lavisse S, Guillermier M, Herard AS, Petit F, Delahaye M, Van Camp N, Ben Haim L, Lebon V, Remy P, Dolle F, et al. Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. J Neurosci. 2012;32(32):10809–10818. doi: 10.1523/JNEUROSCI.1487-12.2012.
    1. Wang M, Wang X, Zhao L, Ma W, Rodriguez IR, Fariss RN, Wong WT. Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina. J Neurosci. 2014;34(10):3793–3806. doi: 10.1523/JNEUROSCI.3153-13.2014.
    1. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010;9(12):971–988. doi: 10.1038/nrd3295.
    1. Karlstetter M, Nothdurfter C, Aslanidis A, Moeller K, Horn F, Scholz R, Neumann H, Weber BH, Rupprecht R, Langmann T. Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation. 2014;11:3. doi: 10.1186/1742-2094-11-3.
    1. Chen MK, Guilarte TR. Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol Ther. 2008;118(1):1–17. doi: 10.1016/j.pharmthera.2007.12.004.
    1. Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, Lee SC. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol. 2009;35(3):306–328. doi: 10.1111/j.1365-2990.2008.01006.x.
    1. Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, Antel JP. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res. 1997;50(2):345–353. doi: 10.1002/(SICI)1097-4547(19971015)50:2<345::AID-JNR22>;2-5.
    1. Morita K, Sasaki H, Furuse M, Tsukita S. Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol. 1999;147(1):185–194. doi: 10.1083/jcb.147.1.185.
    1. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S. Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. J Cell Biol. 2003;161(3):653–660. doi: 10.1083/jcb.200302070.
    1. Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H. Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol. 2000;100(3):323–331. doi: 10.1007/s004010000180.
    1. Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, Risau W, Engelhardt B. Localization of claudin-3 in tight junctions of the blood–brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol. 2003;105(6):586–592.
    1. Krug SM, Amasheh S, Richter JF, Milatz S, Gunzel D, Westphal JK, Huber O, Schulzke JD, Fromm M. Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell. 2009;20(16):3713–3724. doi: 10.1091/mbc.E09-01-0080.
    1. Ohtsuki S, Yamaguchi H, Katsukura Y, Asashima T, Terasaki T. mRNA expression levels of tight junction protein genes in mouse brain capillary endothelial cells highly purified by magnetic cell sorting. J Neurochem. 2008;104(1):147–154.
    1. Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A, Wolburg H, Fruttiger M, et al. Wnt/beta-catenin signaling controls development of the blood–brain barrier. J Cell Biol. 2008;183(3):409–417. doi: 10.1083/jcb.200806024.
    1. Schrade A, Sade H, Couraud PO, Romero IA, Weksler BB, Niewoehner J. Expression and localization of claudins-3 and -12 in transformed human brain endothelium. Fluids Barriers CNS. 2012;9:6. doi: 10.1186/2045-8118-9-6.
    1. Milatz S, Krug SM, Rosenthal R, Gunzel D, Muller D, Schulzke JD, Amasheh S, Fromm M. Claudin-3 acts as a sealing component of the tight junction for ions of either charge and uncharged solutes. Biochim Biophys Acta. 2010;1798(11):2048–2057. doi: 10.1016/j.bbamem.2010.07.014.
    1. Piontek J, Fritzsche S, Cording J, Richter S, Hartwig J, Walter M, Yu D, Turner JR, Gehring C, Rahn HP, et al. Elucidating the principles of the molecular organization of heteropolymeric tight junction strands. Cell Mol Life Sci. 2011;68(23):3903–3918. doi: 10.1007/s00018-011-0680-z.
    1. Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP, Stefanis CN. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res. 2001;47(1):13–25. doi: 10.1016/S0920-9964(00)00007-4.
    1. Song XQ, Lv LX, Li WQ, Hao YH, Zhao JP. The interaction of nuclear factor-kappa B and cytokines is associated with schizophrenia. Biol Psychiatry. 2009;65(6):481–488. doi: 10.1016/j.biopsych.2008.10.018.
    1. Erbagci AB, Herken H, Koyluoglu O, Yilmaz N, Tarakcioglu M. Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediators Inflamm. 2001;10(3):109–115. doi: 10.1080/09629350123895.
    1. Coelho FM, Reis HJ, Nicolato R, Romano-Silva MA, Teixeira MM, Bauer ME, Teixeira AL. Increased serum levels of inflammatory markers in chronic institutionalized patients with schizophrenia. Neuroimmunomodulation. 2008;15(2):140–144.
    1. Zakharyan R, Boyajyan A. Inflammatory cytokine network in schizophrenia. World J Biol Psychiatry. 2014;15(3):174–187. doi: 10.3109/15622975.2013.830774.
    1. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry. 2008;63(8):801–808. doi: 10.1016/j.biopsych.2007.09.024.
    1. 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.
    1. 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):1696–709.
    1. Al-Asmari AK, Khan MW. Inflammation and schizophrenia: alterations in cytokine levels and perturbation in antioxidative defense systems. Hum Exp Toxicol. 2014;33(2):115–122. doi: 10.1177/0960327113493305.
    1. Hoirisch-Clapauch S, Nardi AE. Low activity of plasminogen activator: a common feature of non-iatrogenic comorbidities of schizophrenia. CNS Neurol Disord Drug Targets. 2015;14(3):325–330. doi: 10.2174/1871527314666150225142705.
    1. Hoirisch-Clapauch S, Nardi AE. Markers of low activity of tissue plasminogen activator/plasmin are prevalent in schizophrenia patients. Schizophr Res. 2014;159(1):118–123. doi: 10.1016/j.schres.2014.08.011.
    1. Kirch DG, Alexander RC, Suddath RL, Papadopoulos NM, Kaufmann CA, Daniel DG, Wyatt RJ. Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia. J Neural Transm Gen Sect. 1992;89(3):219–232. doi: 10.1007/BF01250674.
    1. Uranova NA, Zimina IS, Vikhreva OV, Krukov NO, Rachmanova VI, Orlovskaya DD. Ultrastructural damage of capillaries in the neocortex in schizophrenia. World J Biol Psychiatry. 2010;11(3):567–578. doi: 10.3109/15622970903414188.
    1. Bechter K, Benveniste H. Quinckes’ pioneering 19th centuries CSF studies may inform 21th centuries research. Neurol Psychiatry Brain Res. 2015;21(2):79–81. doi: 10.1016/j.npbr.2015.02.001.
    1. Muller 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):634–636.
    1. Elmorsy E, Smith PA. Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics. Biochem Biophys Res Commun. 2015;460(3):857–862. doi: 10.1016/j.bbrc.2015.03.122.
    1. Zetterberg H, Jakobsson J, Redsater M, Andreasson U, Palsson E, Ekman CJ, Sellgren C, Johansson AG, Blennow K, Landen M. Blood-cerebrospinal fluid barrier dysfunction in patients with bipolar disorder in relation to antipsychotic treatment. Psychiatry Res. 2014;217(3):143–146. doi: 10.1016/j.psychres.2014.03.045.
    1. Al-Amin MM, Nasir Uddin MM, Mahmud Reza H. Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. Clin Psychopharmacol Neurosci. 2013;11(3):144–151. doi: 10.9758/cpn.2013.11.3.144.
    1. Borovcanin M, Jovanovic I, Radosavljevic G, Djukic Dejanovic S, Stefanovic V, Arsenijevic N, Lukic ML. Antipsychotics can modulate the cytokine profile in schizophrenia: attenuation of the type-2 inflammatory response. Schizophr Res. 2013;147(1):103–109. doi: 10.1016/j.schres.2013.03.027.
    1. Tourjman V, Kouassi E, Koue ME, Rocchetti M, Fortin-Fournier S, Fusar-Poli P, Potvin S. Antipsychotics’ effects on blood levels of cytokines in schizophrenia: a meta-analysis. Schizophr Res. 2013;151(1–3):43–47. doi: 10.1016/j.schres.2013.10.011.
    1. Song C, Lin A, Kenis G, Bosmans E, Maes M. Immunosuppressive effects of clozapine and haloperidol: enhanced production of the interleukin-1 receptor antagonist. Schizophr Res. 2000;42(2):157–164. doi: 10.1016/S0920-9964(99)00116-4.
    1. Ajami A, Abedian F, Hamzeh Hosseini S, Akbarian E, Alizadeh-Navaei R, Taghipour M. Serum TNF-alpha, IL-10 and IL-2 in schizophrenic patients before and after treatment with risperidone and clozapine. Iran J Immunol. 2014;11(3):200–209.
    1. Cazzullo CL, Sacchetti E, Galluzzo A, Panariello A, Adorni A, Pegoraro M, Bosis S, Colombo F, Trabattoni D, Zagliani A, et al. Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(1):33–39. doi: 10.1016/S0278-5846(01)00221-4.
    1. Noto C, Ota VK, Gouvea ES, Rizzo LB, Spindola LM, Honda PH, Cordeiro Q, Belangero SI, Bressan RA, Gadelha A et al. Effects of risperidone on cytokine profile in drug-naive first-episode psychosis. Int J Neuropsychopharmacol. 2015;18(4).
    1. MacDowell KS, Garcia-Bueno B, Madrigal JL, Parellada M, Arango C, Mico JA, Leza JC. Risperidone normalizes increased inflammatory parameters and restores anti-inflammatory pathways in a model of neuroinflammation. Int J Neuropsychopharmacol. 2013;16(1):121–135. doi: 10.1017/S1461145711001775.
    1. Tobiasova Z, van der Lingen KH, Scahill L, Leckman JF, Zhang Y, Chae W, McCracken JT, McDougle CJ, Vitiello B, Tierney E, et al. Risperidone-related improvement of irritability in children with autism is not associated with changes in serum of epidermal growth factor and interleukin-13. J Child Adolesc Psychopharmacol. 2011;21(6):555–564. doi: 10.1089/cap.2010.0134.
    1. Choi JE, Widjaja F, Careaga M, Bent S, Ashwood P, Hendren RL. Change in plasma cytokine levels during risperidone treatment in children with autism. J Child Adolesc Psychopharmacol. 2014;24(10):586–589. doi: 10.1089/cap.2013.0108.
    1. Kato T, Monji A, Hashioka S, Kanba S. Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro. Schizophr Res. 2007;92(1–3):108–115. doi: 10.1016/j.schres.2007.01.019.
    1. Zhu F, Zheng Y, Ding YQ, Liu Y, Zhang X, Wu R, Guo X, Zhao J. Minocycline and risperidone prevent microglia activation and rescue behavioral deficits induced by neonatal intrahippocampal injection of lipopolysaccharide in rats. PLoS One. 2014;9(4):e93966. doi: 10.1371/journal.pone.0093966.
    1. Edmonson C, Ziats MN, Rennert OM. Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol Autism. 2014;5(1):3. doi: 10.1186/2040-2392-5-3.
    1. de Theije CG, Koelink PJ, Korte-Bouws GA, Lopes da Silva S, Korte SM, Olivier B, Garssen J, Kraneveld AD. Intestinal inflammation in a murine model of autism spectrum disorders. Brain Behav Immun. 2014;37:240–247. doi: 10.1016/j.bbi.2013.12.004.
    1. Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, Codelli JA, Chow J, Reisman SE, Petrosino JF, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7):1451–1463. doi: 10.1016/j.cell.2013.11.024.
    1. Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, Korecka A, Bakocevic N, Ng LG, Kundu P, et al. The gut microbiota influences blood–brain barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158. doi: 10.1126/scitranslmed.3009759.

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