Increased activation product of complement 4 protein in plasma of individuals with schizophrenia

Abstract

Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood–brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

Deregulation of complement components C4A and CSMD1 peripheral expression in first-episode psychosis and links to cognitive ability

“…2 ), whereas no association was found with CSMD1 mRNA levels ( β = − 0.03; p = 0.817), as expected. In agreement with recent evidence from an independent FEP study [ 22 ], we observed that the AL-BL haplotype group was the most common among FEP cases (56%), compared to a much lower frequency reported within healthy individuals (41%) in the original study by Sekar et al . (2016).…”

“…Moreover, we acknowledge as an additional limiting factor the slightly smaller number of FEP cases included in the C4A protein assays that might have reduced the statistical power of the analysis. Likewise, C4 haplogroup analysis among FEP cases did not reveal an association between C4A copy number status and C4A protein levels in serum, as opposed to an earlier study which examined a limited number of plasma samples from medicated SZ patients [ 22 ].…”

“…With respect to differences in psychotic symptoms, increased C4A mRNA levels in peripheral blood cells have been shown to correlate with greater severity of psychopathology in SZ patients, specifically delusional symptoms [ 21 ]. Additionally, up-regulation of C4A protein levels has been found in plasma as well as in cerebrospinal fluid from patients with SZ [ 22 – 25 ]. Preliminary findings also suggest that higher total C4 plasma levels may predict unfavorable treatment response among FEP patients followed-up for twelve months [ 26 ].…”

Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia

“…However, it remains to be seen whether the existing references and level of interest are sufficient to generate more evidence and obtain approval of those substances for the treatment of schizophrenia. Furthermore, following the increasing recognition of the significant role of inflammation and immunological dysregulation in the development of schizophrenia, a growing number of compounds are also being explored in this area [306][307][308][309][310][311], although these approaches are currently at early stages of development.…”

“…Moreover, subclinical inflammation seems to correlate with higher levels of cognitive impairment, underlining the possible utility of anti-inflammatory agents [306][307][308]. Additionally, based on genetic, transcriptomic, and functional studies, dysregulation in the complement system, which mediates innate immunity, has been reported in patients with schizophrenia [309].…”