2026-05-19 スタンフォード大学
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＜関連情報＞
- https://news.stanford.edu/stories/2026/05/neutrophils-produce-schizophrenia-linked-c4a-protein
- https://www.pnas.org/doi/10.1073/pnas.2536376123
- https://www.nature.com/articles/s41398-021-01583-5
統合失調症における末梢補体C4タンパク質：遺伝子コピー数および免疫細胞サブタイプとの関連性 Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes
Agnieszka Kalinowski, Claudia Macaubas, Hanmin Guo, +10 , and Alexander E. Urban
Proceedings of the National Academy of Sciences Published:May 11, 2026
DOI:https://doi.org/10.1073/pnas.2536376123
Significance
The number of C4A gene copies is associated with the risk of schizophrenia in genome-wide association studies of individuals with European ancestry. Higher C4A gene expression is associated with higher levels of synaptic pruning in the brain. We found that neutrophils from people with schizophrenia show C4 protein amounts that are positively correlated with the number of C4A gene copies. Neutrophils may gain access to the central nervous system, during some critical periods in the development of schizophrenia. The role of neutrophils both outside the brain in the peripheral circulation and within the brain invites further exploration, potentially leading to new therapeutics.
Abstract
The lack of highly effective disease-modifying treatments for schizophrenia necessitates exploration of novel aspects of its pathophysiology, including attention to innate immune mechanisms outside the brain. C4 protein activation, associated with the complement cascade of innate immunity, associates with symptoms and predicts outcomes in schizophrenia. However, C4 protein activation does not coincide with expected changes to other proteins in the complement cascade, suggesting another source of C4 protein activation. Studying a combination of fresh whole blood from 10 anonymous donors and a large set of publicly available microarray data, we show that C4 protein is found and expressed primarily in neutrophils and monocytes. Then, we compared the correlation between C4 protein in neutrophils, classical monocytes, plasma, and the number of C4A gene copies. We determined the number of C4A genes using digital droplet PCR, C4 protein in neutrophils (15 patients/21 controls) and plasma (30 patients/38 controls) using Western blotting, and classical monocytes (30 patients/38 controls) using flow cytometry. We found a large positive correlation between the number of C4A gene copies and the amount of C4 protein only in neutrophils and only in the schizophrenia group (Spearman’s rho = 0.63, 95% BCa CI: 0.12 to 0.89, P = 0.012). Our results indicate a convergence of innate immunity mechanisms associated with schizophrenia. The involvement of innate immunity deserves further attention to determine whether it could be a target for therapy in schizophrenia.
統合失調症患者の血漿中の補体活性化産物4タンパク質の増加 Increased activation product of complement 4 protein in plasma of individuals with schizophrenia
Agnieszka Kalinowski,Joanna Liliental,Lauren A. Anker,Omer Linkovski,Collin Culbertson,Jacob N. Hall,Reenal Pattni,Chiara Sabatti,Douglas Noordsy,Joachim F. Hallmayer,Elizabeth D. Mellins,Jacob S. Ballon,Ruth O’Hara,Douglas F. Levinson & Alexander E. Urban
Translational Psychiatry Published:22 September 2021
DOI:https://doi.org/10.1038/s41398-021-01583-5
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.
