Relationship of selective complement markers with schizophrenia

Jalil, Mohd Asyraf Abdull; Rahim, Nour El Huda Abd.; Noor, Hanisah Mohd; Zaifah, Norsidah Ku; Talib, Norlelawati A.

doi:10.1016/j.jneuroim.2021.577793

Cited by 14 publications

(7 citation statements)

References 26 publications

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“…found that complement C1q and C3c levels were significantly reduced in newly diagnosed patients with schizophrenia compared to controls. Several previous studies [ 28 , 40 – 42 ] have measured peripheral inflammatory cytokines and complement proteins in psychosis, producing mixed results. Our finding of decreased TNF-α and some complement factors in CHR populations is in contrast to studies reporting increased immuno-inflammatory levels in patients with established psychosis [ 3 , 4 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Serum complement proteins rather than inflammatory factors is effective in predicting psychosis in individuals at clinical high risk

Zhang

Zeng

et al. 2023

Transl Psychiatry

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Immunological/inflammatory factors are implicated in the development of psychosis. Complement is a key driver of inflammation; however, it remains unknown which factor is better at predicting the onset of psychosis. This study aimed to compare the alteration and predictive performance of inflammation and complement in individuals at clinical high risk (CHR). We enrolled 49 individuals at CHR and 26 healthy controls (HCs). Twenty-five patients at CHR had converted to psychosis (converter) by the 3-year follow-up. Inflammatory cytokines, including interleukin (IL)-1β, 6, 8, 10, tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor levels, and complement proteins (C1q, C2, C3, C3b, C4, C4b, C5, C5a, factor B, D, I, H) were measured by enzyme-linked immunosorbent assay at baseline. Except for TNF- alpha, none of the inflammatory cytokines reached a significant level in either the comparison of CHR individuals and HC or between CHR-converters and non-converters. The C5, C3, D, I, and H levels were significantly lower (C5, p = 0.006; C3, p = 0.009; D, p = 0.026; I, p = 0.016; H, p = 0.019) in the CHR group than in the HC group. Compared to non-converters, converters had significantly lower levels of C5 (p = 0.012) and C5a (p = 0.007). None of the inflammatory factors, but many complement factors, showed significant correlations with changes in general function and symptoms. None of the inflammatory markers, except for C5a and C5, were significant in the discrimination of conversion outcomes in CHR individuals. Our results suggest that altered complement levels in the CHR population are more associated with conversion to psychosis than inflammatory factors. Therefore, an activated complement system may precede the first-episode of psychosis and contribute to neurological pathogenesis at the CHR stage.

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Section: Discussionmentioning

confidence: 99%

Serum complement proteins rather than inflammatory factors is effective in predicting psychosis in individuals at clinical high risk

Zhang

Zeng

et al. 2023

Transl Psychiatry

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“…In addition to CX3CR1, mouse studies also highlight the critical role the classical complement cascade plays in regulating microglial elimination of synapses during CNS development [ 44 , 167 ], as abnormal synaptic pruning due to the dysregulation of specific complement system components can perturb neurodevelopment [ 98 , 124 ]. The complement system is a complex network of soluble plasma components that play critical roles in innate immunity, the host’s defence, and developmental synaptic pruning [ 167 , 183 ].…”

Section: Introductionmentioning

confidence: 99%

Microglial contribution to the pathology of neurodevelopmental disorders in humans

Matuleviciute,

Akinluyi,

Muntslag

et al. 2023

Acta Neuropathol

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Microglia are the brain’s resident macrophages, which guide various developmental processes crucial for brain maturation, activity, and plasticity. Microglial progenitors enter the telencephalic wall by the 4th postconceptional week and colonise the fetal brain in a manner that spatiotemporally tracks key neurodevelopmental processes in humans. However, much of what we know about how microglia shape neurodevelopment comes from rodent studies. Multiple differences exist between human and rodent microglia warranting further focus on the human condition, particularly as microglia are emerging as critically involved in the pathological signature of various cognitive and neurodevelopmental disorders. In this article, we review the evidence supporting microglial involvement in basic neurodevelopmental processes by focusing on the human species. We next concur on the neuropathological evidence demonstrating whether and how microglia contribute to the aetiology of two neurodevelopmental disorders: autism spectrum conditions and schizophrenia. Next, we highlight how recent technologies have revolutionised our understanding of microglial biology with a focus on how these tools can help us elucidate at unprecedented resolution the links between microglia and neurodevelopmental disorders. We conclude by reviewing which current treatment approaches have shown most promise towards targeting microglia in neurodevelopmental disorders and suggest novel avenues for future consideration.

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“…Future potential biomarker goals might include detection of neuroinflammation, more rapid identification of early psychoses, identification of cognitive deficits and other symptomatology, choice of treatment, and monitoring of treatment efficacies [38][39][40][41][42][43]. Interrogations of peripheral C4, however, have produced remarkably mixed results, with peripheral C4 sometimes elevated, sometimes reduced and sometimes unchanged in schizophrenia versus comparison groups [33,36,38,40,[44][45][46][47][48][49][50].…”

Section: Introductionmentioning

confidence: 99%

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Severance,

Prandovszky,

Yang

et al. 2023

Dev Neurosci

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Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system (CNS)-derived neuroinflammation, synapse pruning and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal (GI), inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n=335) and/or in non-psychiatric comparison subjects (NCs; n=233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-Reactive Protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F=20.74, p<0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants (CNVs), plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff=0.39, CI=0.01-0.77, R2=0.18, p<0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA (dsDNA) IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus (CMV) IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index (BMI), race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide (LPS)-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F=5.16, p<0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 require replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

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Relationship of selective complement markers with schizophrenia

Cited by 14 publications

References 26 publications

Serum complement proteins rather than inflammatory factors is effective in predicting psychosis in individuals at clinical high risk

Serum complement proteins rather than inflammatory factors is effective in predicting psychosis in individuals at clinical high risk

Microglial contribution to the pathology of neurodevelopmental disorders in humans

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

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