What is it about?
Scientists have found that people with schizophrenia have unusual immune system activity, specifically in something called the 'complement system.' This immune activity tracks with how severe their symptoms are, shows up in brain scans, and predicts how well they'll do over time. But here's the puzzle: the immune abnormalities we see don't match what textbooks say should happen. Trying to solve this mystery, we discovered something completely unexpected: certain white blood cells called neutrophils actually make a protein called C4A—something no one knew they could do. And in people with schizophrenia, these neutrophils are working overtime, constantly producing and breaking down this protein.
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Why is it important?
This is especially exciting because it brings together previously disparate pieces of the schizophrenia pathophysiology puzzle: i. Genetic disease risk: association of C4A gene copy number with schizophrenia; ii. Evidence of active innate immune system in schizophrenia, reflected in elevated neutrophil counts; iii. Complement activation in people with schizophrenia with patterns that do not follow traditional complement cascade pathways; and iv. The most effective medication for schizophrenia inhibits neutrophils, which could be the efficacy mechanism of clozapine.
Perspectives
We discovered that neutrophils produce C4 protein—never known before. In people with schizophrenia, we see evidence that neutrophils are actively making and consuming C4 in what appears to be an activation process. Because C4 genetics determine disease risk AND neutrophil counts follow disease symptoms, this neutrophil C4 activity may be central to schizophrenia's underlying biology. This offers a provocative twist: what if clozapine's dangerous side effect on immune cells is actually the reason it works so well?
Agnes Kalinowski
Stanford University
Read the Original
This page is a summary of: Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes, Proceedings of the National Academy of Sciences, May 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2536376123.
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