The complement system in schizophrenia: where are we now and what’s next?

Woo, Julia; Pouget, J; Zai, Clement C.; Kennedy, James L.

doi:10.1038/s41380-019-0479-0

Cited by 110 publications

(113 citation statements)

References 92 publications

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“…Consistent with this, Fromer et al found a strong correlation between the risk alleles for schizophrenia and upregulation of expression of C4A in post-mortem schizophrenia patients brains [38]. Indeed, 23 new studies on involvement of complement system in development of schizophrenia have been published in the time period 2008-2019, indicating that overall complement pathway activity appears to be elevated in schizophrenia [39]. Further, Reginia et al demonstrated increased concentrations of C3a and C5a in the peripheral blood of patients suffering from bipolar disorder as compared to healthy individuals [15].…”

Section: Discussionmentioning

confidence: 79%

Complement Activation in 22q11.2 Deletion Syndrome

et al. 2020

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The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.Journal of Clinical Immunology (2020) 40:515-523Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionmentioning

confidence: 79%

Complement Activation in 22q11.2 Deletion Syndrome

et al. 2020

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“…Although there were no significant relationships between ADE levels of GFAP, C3b, and C5b-9, at least one of these levels was out of the control range for every FP patient. It was previously found that some alleles of C4 are associated with schizophrenia and with proportionate elevations of C4A in distinct regions of the brain 27 , 28 . Any relationship between our current findings and the apparent increase in susceptibility to schizophrenia attributable to C4 expression remain to be elucidated.…”

Section: Discussionmentioning

confidence: 98%

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

et al. 2020

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Potentially neurotoxic systems involved in traumatic and degenerative diseases of the brain were assessed in acute psychosis. Astrocyte-derived exosomes (ADEs) and neuron-derived exosomes (NDEs) were immunoprecipitated from plasma of ten untreated first-episode psychotics (FPs) and ten matched normal controls (Cs). Neural mitochondrial electron transport and complement proteins were extracted, quantified by ELISAs and normalized with levels of CD81 exosome marker. Levels of subunits 1 and 6 of NADH-ubiquinone oxidoreductase (complex I) and subunit 10 of cytochrome b-c1 oxidase (complex III), but not of subunit 1 of cytochrome C oxidase (complex IV) or superoxide dismutase 1 (SOD1) were significantly lower in ADEs and NDEs of FPs than Cs. This dysregulated pattern of electron transport proteins is associated with increased generation of reactive oxygen species. ADE glial fibrillary acidic protein levels were significantly higher in FPs than Cs, indicating a higher percentage of inflammatory astrocytes in FPs. ADE levels of C3b opsonin were significantly higher and those of C5b-9 attack complex was marginally higher in FPs than Cs. A significantly lower ADE level of the C3 convertase inhibitor CD55 may explain the higher levels of C3 convertase-generated C3b. ADE levels of the neuroprotective protein leukemia inhibitory factor (LIF) were significantly lower in FPs than Cs, whereas levels of IL-6 were no different. Plasma neural exosome levels of electron transport and complement proteins may be useful in predicting FP and guiding therapy. SOD mimetics, C3 convertase inhibitors and LIF receptor agonists also may have therapeutic benefits in FP.

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“…There have been mixed findings regarding complement polymorphisms in candidate gene studies as reviewed previously by Mayilyan et al (2008b) and more recently by Woo et al (2019) , although genome-wide association studies in schizophrenia provide strong evidence for implication of the major histocompatibility complex ( Consortium, S. W. G. o. t. P. G, 2014 ; Purcell et al, 2009 ; Ripke et al, 2013 ). This association was later partly explained by allelic variation of C4 ( Sekar et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies

Mongan

Sabherwal

Susai

et al. 2020

Schizophrenia Research

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Background There is renewed focus on the complement system in the pathogenesis of schizophrenia. In addition to providing aetiological insights, consistently dysregulated complement proteins in serum or plasma may have clinical utility as biomarkers. Methods We performed a systematic literature review searching PubMed, Embase and PsycINFO for studies measuring complement system activity or complement protein concentrations in serum or plasma from patients with schizophrenia compared to controls. Random-effects meta-analyses were performed to calculate pooled effect estimates (Hedges' g standardised mean difference [SMD]) for complement proteins whose concentrations were measured in three or more studies. The review was pre-registered on the PROSPERO database (CRD42018109012). Results Database searching identified 1146 records. Fifty-eight full-text articles were assessed for eligibility and 24 studies included. Seven studies measured complement system activity. Activity of the classical pathway did not differ between cases and controls in four of six studies, and conflicting results were noted in two studies of alternative pathway activity. Twenty studies quantified complement protein concentrations of which complement components 3 (C3) and 4 (C4) were measured in more than three studies. Meta-analyses showed no evidence of significant differences between cases and controls for 11 studies of C3 (SMD 0.04, 95% confidence interval [CI] -0.29–0.36) and 10 studies of C4 (SMD 0.10, 95% CI -0.21–0.41). Conclusions Serological studies provide mixed evidence regarding dysregulation of the complement system in schizophrenia. Larger studies of a longitudinal nature, focusing on early phenotypes, could provide further insights regarding the potential role of the complement system in psychotic disorders.

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The complement system in schizophrenia: where are we now and what’s next?

Cited by 110 publications

References 92 publications

Complement Activation in 22q11.2 Deletion Syndrome

Complement Activation in 22q11.2 Deletion Syndrome

Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

Peripheral complement proteins in schizophrenia: A systematic review and meta-analysis of serological studies

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