Evidence of neuroinflammation in subgroups of schizophrenia and mood disorder patients: A semiquantitative postmortem study of CD3 and CD20 immunoreactive lymphocytes in several brain regions

Bogerts, Bernhard; Winopal, D.; Schwarz, S.; Schlaaff, Konstantin; Dobrowolny, Henrik; Mawrin, Christian; Frodl, Thomas; Steiner, Johann

doi:10.1016/j.npbr.2016.11.001

Cited by 33 publications

(21 citation statements)

References 39 publications

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“…As such, sICAM1 may contribute to the increased circulation of activated monocytes reported in schizophrenia [54,55] and promote release of pro-inflammatory cytokines from immune cells, further contributing to the inflammatory state. CD3+ T lymphocytes and CD20+ B lymphocytes have been observed in the hippocampus in a small number of schizophrenia brains [33] and in a broader investigation in the hippocampus, frontal cortex, thalamus, medial temporal lobe and cingulate gyrus in schizophrenia [34]. Inflammation related genes including S100A8, S100A9 and CHI3L1 are elevated in the hippocampus in schizophrenia and perivascular macrophages (CD163+) have been identified in the lumen of blood vessels and surrounding the endothelial cells in at least one schizophrenia hippocampus [21].…”

Section: Discussionmentioning

confidence: 96%

“…Peripheral measures of soluble ICAM1 (sICAM1) and VCAM1 have been reported to be both decreased [28,29] and increased [30][31][32] in schizophrenia dependent on the stage of illness and medication status. To our knowledge, there have been no measurements of adhesion molecule expression in brains from people with schizophrenia and limited exploration of evidence to support the hypothesis that there may be peripheral immune cell infiltration [33,34].…”

Section: Introductionmentioning

confidence: 99%

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Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation

et al. 2018

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Elevated pro-inflammatory cytokines exist in both blood and brain of people with schizophrenia but how this affects molecular indices of the blood-brain barrier (BBB) is unclear. Eight mRNAs relating to BBB function, a microglia and three immune cell markers were measured by qPCR in the prefrontal cortex from 37 people with schizophrenia/schizoaffective disorder and 37 matched controls. This cohort was previously grouped into "high inflammation" and "low inflammation" subgroups based on cortical inflammatory-related transcripts. Soluble intercellular adhesion molecule-1 (sICAM1) was measured in the plasma of 78 patients with schizophrenia/schizoaffective disorder and 73 healthy controls. We found that sICAM1 was significantly elevated in schizophrenia. An efflux transporter, ABCG2, was lower, while mRNAs encoding VE-cadherin and ICAM1 were higher in schizophrenia brain. The "high inflammation" schizophrenia subgroup had lower ABCG2 and higher ICAM1, VE-cadherin, occludin and interferon-induced transmembrane protein mRNAs compared to both "low inflammation" schizophrenia and "low inflammation" control subgroups. ICAM1 immunohistochemistry showed enrichment in brain endothelium regardless of diagnosis and was localised to astrocytes in some brains. Microglia mRNA was not altered in schizophrenia nor did it correlate with ICAM1 expression. Immune cell mRNAs were elevated in "high inflammation" schizophrenia compared to both "low inflammation" schizophrenia and controls. CD163+ perivascular macrophages were identified by immunohistochemistry in brain parenchyma in over 40% of "high inflammation" schizophrenia brains. People with high levels of cytokine expression and schizophrenia display changes consistent with greater immune cell transmigration into brain via increased ICAM1, which could contribute to other neuropathological changes found in this subgroup of people.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation

et al. 2018

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“…Subsequently, using semi‐quantitative methods, Bogerts et al . have added further evidence from CD3 and CD20 staining in brain sections from patients with schizophrenia and mood disorders compared with matched controls . Significant differences versus controls were found for both groups for medial temporal lobe CD20 + lymphocyte infiltration and for CD3 + lymphocytes in additional regions such as cortex and thalamus, however, suicide method and rate of death are potential confounders that could explain these observations rather than being due to an aspect of the illness itself.…”

Section: Evidence Of Disease‐specific Adaptive Immune Response In Thementioning

confidence: 95%

Psychosis: an autoimmune disease?

et al. 2017

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Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19 and reduced CD3 lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3 and CD20 lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated (NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.

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“…Because the BBB may be disrupted and allow peripheral blood cells to enter the brain, as has been observed in schizophrenia [29] [30,31], but merely Busse et al [32] distinguished between residual (prevailing negative symptoms) and paranoid schizophrenia (prominent positive symptoms), and reported that in the posterior hippocampus, higher densities of CD3 + T-lymphocytes and CD20 + B-lymphocytes were observed in residual versus healthy controls (CD3: left: p = 0.057, right: p = 0.069; CD20: left: p = 0.008, right: p = 0.006). It was indicated that blood-brain barrier (BBB) impairment and infiltration of T cells and B cells may contribute to the pathophysiology of residual schizophrenia (prevailing negative symptoms).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-to-lymphocyte ratio exhibits the different correlation with psychiatric symptoms in the different status of antipsychotic therapy in schizophrenia: a large-scale retrospective cross-sectional study.

Shen¹,

Zhou²,

Wang³

et al. 2020

Preprint

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Background There are some conflicting results regarding the neutrophil-to-lymphocyte ratio (NLR) and the severity of disease in patients with schizophrenia. Inconsistent findings among the studies might be caused by several limitations, such as, heterogeneous patient populations lacking stratification by antipsychotic therapy, small sample sizes lacking statistical power, ignoring multicollinearity between NLR and other related factors, and lack of controlling for potential confounding factors. In this study, we evaluated the possible correlation between NLR and disease severity as manifested in clinical scores in patients with schizophrenia. In particular, NLR is correlated with discrepant psychiatric symptoms in the different status of antipsychotic medication administration. Methods This was a cross-sectional study conducted in our hospital. We identified inpatients with schizophrenia between July 12, 2018 and March 27, 2019 and who had NLR, Clinical Global Impression Severity scale (CGIS) and Brief Psychiatric Rating Scale (BPRS) scores. Results The records of 1144 identified patients (32.4% male, 76.6% with NLR ≤ 1.98, and 10.8% drug-free patients) were analyzed. Multivariate logistic regression showed that NLR was positively associated with worse psychiatric symptoms, both the CGIS score (moderately ill: OR: 63.578, p = 0.011; severely ill: OR: 53.617, p = 0.015) and the BPRS total score (moderately ill: OR: 4.049, p = 0.055; severely ill: OR: 4.312, p = 0.045). In the drug-therapy subgroup, there was a negative correlation between NLR and severe negative symptoms (severely ill: OR: 0.850, p = 0.018) after controlling for potential confounding factors. Conclusions The study is the first to confirm the hypothesis that NLR is independently associated with severe psychopathology in schizophrenia. There is the different correlation between NLR and psychiatric symptoms in the different status of antipsychotic therapy. Therefore, NLR is not appropriate to be an inflammatory biomarker for assessment of disease severity, but provide potential mechanistic insights on specific pathological cellular processes, as well be a potential target to improve the course of the psychotic disorder.

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Evidence of neuroinflammation in subgroups of schizophrenia and mood disorder patients: A semiquantitative postmortem study of CD3 and CD20 immunoreactive lymphocytes in several brain regions

Cited by 33 publications

References 39 publications

Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation

Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation

Psychosis: an autoimmune disease?

Neutrophil-to-lymphocyte ratio exhibits the different correlation with psychiatric symptoms in the different status of antipsychotic therapy in schizophrenia: a large-scale retrospective cross-sectional study.

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