{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:12:53Z","timestamp":1792084373399,"version":"4.4.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82001415"],"award-info":[{"award-number":["82001415"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171507"],"award-info":[{"award-number":["82171507"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005189","name":"Estonian Research Competency Council","doi-asserted-by":"publisher","award":["MOBTT77"],"award-info":[{"award-number":["MOBTT77"]}],"id":[{"id":"10.13039\/501100005189","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:p>Innate immune components involved in host defense have been implicated in schizophrenia (SCZ). However, studies exploring their clinical utility in SCZ diagnosis are limited. The main purpose of this study was to evaluate whether circulating endotoxin, high mobility group box 1 protein (HMGB1) and complement component 4 (C4) could act as peripheral biomarkers to distinguish first-episode schizophrenia (FES, <jats:italic>n<\/jats:italic> = 42) patients from healthy controls (HCs, <jats:italic>n<\/jats:italic> = 35) in associations with psychopathological symptoms and cognitive dysfunctions. Also, their changes after 8-week antipsychotic treatment were investigated. The Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scale (PSYRATS), and MATRICS Consensus Cognitive Battery (MCCB) were administered. Receiver operating characteristic (ROC) curves were conducted to evaluate the diagnostic effectiveness of the three biological indicators. Compared to HCs, levels of endotoxin, HMGB1, and C4 were remarkably increased in FES patients after controlling for age, gender, body mass index (BMI) and education years, and the combination of the three biomarkers demonstrated desirable diagnostic performance (AUC = 0.933). Moreover, the endotoxin level was positively correlated with the severity of auditory hallucinations. After 8 weeks of treatment, HMGB1 was decreased significantly in patients but still higher than that in HCs, whereas endotoxin and C4 did not change statistically. The baseline levels of endotoxin, HMGB1, and C4, as well as their changes were not associated with changes in any PANSS subscale score and total score. Our preliminary results suggest that a composite peripheral biomarker of endotoxin, HMGB1, and C4 may have accessory diagnostic value to distinguish SCZ patients from HCs. Additionally, endotoxin might be implicated in the pathogenesis of auditory hallucinations.<\/jats:p>","DOI":"10.3389\/fpsyt.2022.1024299","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T05:36:05Z","timestamp":1665639365000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Alterations in innate immune defense distinguish first-episode schizophrenia patients from healthy controls"],"prefix":"10.3389","volume":"13","author":[{"given":"Song","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengzhuang","family":"Gou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meihong","family":"Xiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongzhen","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1007\/s12035-019-01737-z","article-title":"The role of aberrations in the immune-inflammatory response system (IRS) and the compensatory immune-regulatory reflex system (CIRS) in different phenotypes of schizophrenia: the IRS-CIRS theory of schizophrenia.","volume":"57","author":"Roomruangwong","year":"2020","journal-title":"Mol Neurobiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.schres.2019.05.028","article-title":"The association between schizophrenia and the immune system: review of the evidence from unbiased \u2018Omic-studies\u2019.","volume":"217","author":"van Mierlo","year":"2020","journal-title":"Schizophr Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.molimm.2013.07.008","article-title":"RAGE and TLRs: relatives, friends or neighbours?","volume":"56","author":"Ibrahim","year":"2013","journal-title":"Mol Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/cmi.2016.34","article-title":"HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins.","volume":"14","author":"Bertheloot","year":"2017","journal-title":"Cell Mol Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/nri1594","article-title":"High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal.","volume":"5","author":"Lotze","year":"2005","journal-title":"Nat Rev Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.jss.2013.05.062","article-title":"Endogenous HMGB1 is required in endotoxin tolerance.","volume":"185","author":"Li","year":"2013","journal-title":"J Surg Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"869720","DOI":"10.3389\/fimmu.2022.869720","article-title":"Complement system and alarmin HMGB1 crosstalk: for better or worse.","volume":"13","author":"Gaboriaud","year":"2022","journal-title":"Front Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"543","DOI":"10.3389\/fimmu.2019.00543","article-title":"Targeting complement pathways in polytrauma- and sepsis-induced multiple-organ dysfunction.","volume":"10","author":"Karasu","year":"2019","journal-title":"Front Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2018.12.002","article-title":"Brain changes in a maternal immune activation model of neurodevelopmental brain disorders.","volume":"175","author":"Bergdolt","year":"2019","journal-title":"Prog Neurobiol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.bbi.2010.03.005","article-title":"Effects of prenatal infection on brain development and behavior: a review of findings from animal models.","volume":"24","author":"Boksa","year":"2010","journal-title":"Brain Behav Immun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4345","DOI":"10.1007\/s12035-020-02028-8","article-title":"Maternal immune activation causes schizophrenia-like behaviors in the offspring through activation of immune-inflammatory, oxidative and apoptotic pathways, and lowered antioxidant defenses and neuroprotection.","volume":"57","author":"Talukdar","year":"2020","journal-title":"Mol Neurobiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1093\/schbul\/sbt200","article-title":"Hospital contacts with infection and risk of schizophrenia: a population-based cohort study with linkage of Danish national registers.","volume":"40","author":"Nielsen","year":"2014","journal-title":"Schizophr Bull."},{"key":"B13","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1186\/s12974-016-0670-z","article-title":"HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer\u2019s disease.","volume":"13","author":"Festoff","year":"2016","journal-title":"J Neuroinflammation."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1523\/JNEUROSCI.3732-10.2011","article-title":"HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration.","volume":"31","author":"Gao","year":"2011","journal-title":"J Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s43440-020-00163-6","article-title":"Molecular insights into the therapeutic promise of targeting HMGB1 in depression.","volume":"73","author":"Rana","year":"2021","journal-title":"Pharmacol Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"849","DOI":"10.3390\/cells11050849","article-title":"High mobility group box 1: biological functions and relevance in oxidative stress related chronic diseases.","volume":"11","author":"Taverna","year":"2022","journal-title":"Cells."},{"key":"B17","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1093\/schbul\/sbaa136","article-title":"High mobility group protein 1 and dickkopf-related protein 1 in schizophrenia and treatment-resistant schizophrenia: associations with interleukin-6, symptom domains, and neurocognitive impairments.","volume":"47","author":"Al-Dujaili","year":"2021","journal-title":"Schizophr Bull."},{"key":"B18","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.schres.2018.10.017","article-title":"Inflammatory biomarkers in psychosis and clinical high risk populations.","volume":"206","author":"Delaney","year":"2019","journal-title":"Schizophr Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.psychres.2017.05.005","article-title":"The association between immune markers and recent suicide attempts in patients with serious mental illness: a pilot study.","volume":"255","author":"Dickerson","year":"2017","journal-title":"Psychiatry Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"704069","DOI":"10.3389\/fnsys.2021.704069","article-title":"Bacterial translocation associates with aggression in schizophrenia inpatients.","volume":"15","author":"Wang","year":"2021","journal-title":"Front Syst Neurosci."},{"key":"B21","first-page":"3818","article-title":"[Analysis of the changes of serum high mobility group protein B1 and cytokines in first-episode schizophrenia patients].","volume":"95","author":"Zhu","year":"2015","journal-title":"Zhonghua Yi Xue Za Zhi."},{"key":"B22","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/s41380-019-0479-0","article-title":"The complement system in schizophrenia: where are we now and what\u2019s next?","volume":"25","author":"Woo","year":"2020","journal-title":"Mol Psychiatry."},{"key":"B23","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/nature16549","article-title":"Schizophrenia risk from complex variation of complement component 4.","volume":"530","author":"Sekar","year":"2016","journal-title":"Nature."},{"key":"B24","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/s41593-018-0334-7","article-title":"Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.","volume":"22","author":"Sellgren","year":"2019","journal-title":"Nat Neurosci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e3000604","DOI":"10.1371\/journal.pbio.3000604","article-title":"Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction.","volume":"18","author":"Comer","year":"2020","journal-title":"PLoS Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.schres.2018.03.035","article-title":"Increased complement component 4 (C4) gene expression in the cingulate cortex of rats exposed to late gestation immune activation.","volume":"199","author":"Duchatel","year":"2018","journal-title":"Schizophr Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"647246","DOI":"10.3389\/fgene.2021.647246","article-title":"Associations between genotype and peripheral complement proteins in first-episode psychosis: evidences from C3 and C4.","volume":"12","author":"Chen","year":"2021","journal-title":"Front Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.schres.2017.12.012","article-title":"Complement system biomarkers in first episode psychosis.","volume":"204","author":"Kopczynska","year":"2019","journal-title":"Schizophr Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.schres.2018.11.035","article-title":"Investigation of peripheral complement factors across stages of psychosis.","volume":"204","author":"Laskaris","year":"2019","journal-title":"Schizophr Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3081","DOI":"10.3760\/cma.j.cn112137-20200425-01316","article-title":"[Correlation of the peripheral serum complement protein levels and cognitive function in first-episode drug-naive patients with schizophrenia].","volume":"100","author":"Xia","year":"2020","journal-title":"Zhonghua Yi Xue Za Zhi."},{"key":"B31","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.schres.2018.11.001","article-title":"More dampened monocytic Toll-like receptor 4 response to lipopolysaccharide and its association with cognitive function in Chinese Han first-episode patients with schizophrenia.","volume":"206","author":"Chen","year":"2019","journal-title":"Schizophr Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1017\/s0033291799008661","article-title":"Scales to measure dimensions of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS).","volume":"29","author":"Haddock","year":"1999","journal-title":"Psychol Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"812293","DOI":"10.3389\/fimmu.2022.812293","article-title":"Multi-omics analysis reveals aberrant gut-metabolome-immune network in schizophrenia.","volume":"13","author":"Fan","year":"2022","journal-title":"Front Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"205","DOI":"10.3389\/fpsyt.2018.00205","article-title":"\u201cImmune gate\u201d of psychopathology-the role of gut derived immune activation in major psychiatric disorders.","volume":"9","author":"Rudzki","year":"2018","journal-title":"Front Psychiatry."},{"key":"B35","doi-asserted-by":"publisher","first-page":"156","DOI":"10.3389\/fpsyt.2020.00156","article-title":"The gut microbiome and schizophrenia: the current state of the field and clinical applications.","volume":"11","author":"Szeligowski","year":"2020","journal-title":"Front Psychiatry."},{"key":"B36","doi-asserted-by":"publisher","first-page":"768108","DOI":"10.3389\/fcimb.2021.768108","article-title":"Blood-brain barrier disruption by lipopolysaccharide and sepsis-associated encephalopathy.","volume":"11","author":"Peng","year":"2021","journal-title":"Front Cell Infect Microbiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1152\/physrev.00050.2017","article-title":"Blood-brain barrier: from physiology to disease and back.","volume":"99","author":"Sweeney","year":"2019","journal-title":"Physiol Rev."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3622","DOI":"10.1021\/acschemneuro.9b00225","article-title":"Methamphetamine Activates toll-like receptor 4 to induce central immune signaling within the ventral tegmental area and contributes to extracellular dopamine increase in the nucleus accumbens shell.","volume":"10","author":"Wang","year":"2019","journal-title":"ACS Chem Neurosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"10054","DOI":"10.1523\/JNEUROSCI.1502-21.2021","article-title":"A proinflammatory stimulus disrupts hippocampal plasticity and learning via microglial activation and 25-hydroxycholesterol.","volume":"41","author":"Izumi","year":"2021","journal-title":"J Neurosci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"E371","DOI":"10.1503\/jpn.200131","article-title":"Cortico-cortical connectivity behind acoustic information transfer to mouse orbitofrontal cortex is sensitive to neuromodulation and displays local sensory gating: relevance in disorders with auditory hallucinations?","volume":"46","author":"Tripathi","year":"2021","journal-title":"J Psychiatry Neurosci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.3389\/fimmu.2020.01823","article-title":"Psychological stress, intestinal barrier dysfunctions, and autoimmune disorders: an overview.","volume":"11","author":"Ilchmann-Diounou","year":"2020","journal-title":"Front Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.jpsychires.2021.04.019","article-title":"Alarmins (IL-33, sST2, HMGB1, and S100B) as potential biomarkers for schizophrenia.","volume":"138","author":"Kozlowska","year":"2021","journal-title":"J Psychiatr Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"295","DOI":"10.5937\/jomb0-28108","article-title":"High mobility group box-1 levels in schizophrenia: potential biomarker of remission phase.","volume":"40","author":"Yilmaz","year":"2021","journal-title":"J Med Biochem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1038\/s41380-021-01362-0","article-title":"Systems biological assessment of altered cytokine responses to bacteria and fungi reveals impaired immune functionality in schizophrenia.","volume":"27","author":"Gao","year":"2022","journal-title":"Mol Psychiatry."},{"key":"B45","doi-asserted-by":"publisher","first-page":"4147","DOI":"10.1038\/s41598-017-03736-3","article-title":"Uniting the neurodevelopmental and immunological hypotheses: neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia.","volume":"7","author":"Keri","year":"2017","journal-title":"Sci Rep."},{"key":"B46","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.psychres.2011.12.049","article-title":"Impaired monocyte activation in schizophrenia.","volume":"198","author":"Muller","year":"2012","journal-title":"Psychiatry Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"5297","DOI":"10.1038\/s41380-020-01008-7","article-title":"Natural killer cells in first-episode psychosis: an innate immune signature?","volume":"26","author":"Tarantino","year":"2021","journal-title":"Mol Psychiatry."},{"key":"B48","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1186\/cc13110","article-title":"Pathophysiology of endotoxin tolerance: mechanisms and clinical consequences.","volume":"17","author":"Lopez-Collazo","year":"2013","journal-title":"Crit Care."},{"key":"B49","doi-asserted-by":"publisher","first-page":"564","DOI":"10.3390\/cells10030564","article-title":"The immune tolerance role of the HMGB1-RAGE axis.","volume":"10","author":"Watanabe","year":"2021","journal-title":"Cells."},{"key":"B50","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.schres.2020.05.036","article-title":"Peripheral complement proteins in schizophrenia: a systematic review and meta-analysis of serological studies.","volume":"222","author":"Mongan","year":"2020","journal-title":"Schizophr Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.bbi.2021.11.014","article-title":"Peripheral complement is increased in schizophrenia and inversely related to cortical thickness.","volume":"101","author":"Ji","year":"2022","journal-title":"Brain Behav Immun."},{"key":"B52","doi-asserted-by":"publisher","first-page":"577793","DOI":"10.1016\/j.jneuroim.2021.577793","article-title":"Relationship of selective complement markers with schizophrenia.","volume":"363","author":"Mohd Asyraf","year":"2022","journal-title":"J Neuroimmunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"103110","DOI":"10.1016\/j.ajp.2022.103110","article-title":"Plasma complement component 4 alterations in patients with schizophrenia before and after antipsychotic treatment.","volume":"73","author":"Su","year":"2022","journal-title":"Asian J Psychiatr."},{"key":"B54","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.bbi.2020.01.014","article-title":"Baseline high levels of complement component 4 predict worse clinical outcome at 1-year follow-up in first-episode psychosis.","volume":"88","author":"Mondelli","year":"2020","journal-title":"Brain Behav Immun."},{"key":"B55","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1086\/342777","article-title":"Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex.","volume":"71","author":"Chung","year":"2002","journal-title":"Am J Hum Genet."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1007\/s00406-022-01409-5","article-title":"Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability.","volume":"272","author":"Hatzimanolis","year":"2022","journal-title":"Eur Arch Psychiatry Clin Neurosci."},{"key":"B57","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1038\/s41593-020-00763-8","article-title":"Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.","volume":"24","author":"Yilmaz","year":"2021","journal-title":"Nat Neurosci."}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2022.1024299\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T05:36:12Z","timestamp":1665639372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2022.1024299\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,13]]},"references-count":57,"alternative-id":["10.3389\/fpsyt.2022.1024299"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2022.1024299","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,13]]},"article-number":"1024299"}}