Kalinowski A et al., PNAS - This study reports that C4 protein is enriched in human neutrophils and monocytes and that neutrophil C4 protein levels correlate with C4A gene copy number specifically in people with schizophrenia, linking peripheral innate immunity to disease-related biology. Key terms: schizophrenia, complement C4, neutrophils, monocytes, innate immunity.

Study Highlights:
Using public gene-expression data and fresh whole blood, the authors show C4 protein is primarily localized to neutrophils and monocytes. In a clinical cohort, neutrophil C4 protein positively correlated with C4A gene copy number in schizophrenia (Spearman rho = 0.63). Neutrophil and classical monocyte C4 protein were reduced in schizophrenia versus controls, and neutrophil C4 associated with perceived stress and symptom measures. Findings support a peripheral, cell-associated source of complement activation in schizophrenia.

Conclusion:
Neutrophils are a peripheral cellular reservoir of C4 that links C4A gene copy number to complement protein levels in schizophrenia, implicating innate immune cell mechanisms as potential contributors and targets for disease modification.

Music:
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Article title:
Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes

First author:
Kalinowski A

Journal:
PNAS

DOI:
10.1073/pnas.2536376123

Reference:
Kalinowski A., Macaubas C., Guo H., et al. Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes. PNAS. 2026;123(20):e2536376123. doi:10.1073/pnas.2536376123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-11.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of the transcript’s core scientific narrative: peripheral C4 biology in SZ (cellular localization, genetic associations, plasma vs cellular activation), links to symptoms/stress, and translational implications, with attention to study limitations.
- transcript topics: Innate immunity and C4 in schizophrenia; C4 protein expression in neutrophils and monocytes; C4A gene copy number correlates with neutrophil C4 protein in SZ; Plasma C4 vs cell-associated C4 activation; Clinical associations: perceived stress and PANSS; Limitations and confounds (medication, BMI, sample size)

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- C4 protein is expressed and localized in neutrophils and monocytes (cellular localization, not plasma only)
- C4A gene copy number correlates with neutrophil C4 protein in schizophrenia (Spearman rho ≈ 0.63; P ≈ 0.012)
- In schizophrenia, neutrophil C4 protein is lower than controls after adjustment (BMI or related covariates; notable P-values in exploratory analyses)
- Plasma C4 did not show the same correlations with C4A gene copies, suggesting a non-plasma cellular source
- Neutrophil C4 protein depletion correlates with higher perceived stress (PSS) and PANSS general psychopathology in SZ
- Study limitations include all SZ participants being medicated; replication in medication-naive/first-episode samples is needed

QC result: Pass.