Summary: A new Stanford study reveals a surprising link between schizophrenia and the peripheral immune system. Researchers found that neutrophils—the most numerous white blood cells in circulation—produce the complement protein C4A, previously thought to be produced mainly by the liver. C4A is a well-established genetic risk factor for schizophrenia and is implicated in excessive synaptic pruning, which destroys crucial neural connections in the brain.
The study shows that neutrophils from people with schizophrenia generate high levels of C4A that are rapidly activated or consumed in the bloodstream. This finding raises the possibility of diagnosing and treating some aspects of schizophrenia through blood-based approaches, potentially avoiding the challenges of drug delivery across the blood-brain barrier.
Key Facts
- Neutrophils as unexpected producers: Neutrophils account for over half of circulating white blood cells in a healthy adult. Stanford investigators report that these peripheral immune cells actively express and produce the schizophrenia-associated protein C4A.
- C4A and synaptic pruning: In the brain, C4A participates in synaptic pruning—the developmental process that removes unneeded synapses. In schizophrenia, this pruning is excessive, reducing synapse numbers in the cerebral cortex by roughly 30% and thinning regions tied to higher cognition.
- Gene copy number matters: Variation in the number of C4A gene copies in a person’s genome is the strongest common hereditary risk factor for schizophrenia. The gene copy number correlates with the amount of C4A and its activation fragment (C4-ana) found in blood plasma.
- Clozapine connection: People with schizophrenia often have elevated neutrophil counts. Clozapine—the most effective antipsychotic for treatment-resistant schizophrenia—reduces circulating neutrophils, suggesting that neutrophils may play a central role in disease biology rather than representing a mere side effect.
- Active but depleted: Neutrophils from people with schizophrenia show higher C4A production activity but contain less stored C4A. Plasma levels of C4-ana, the fragment indicating C4A activation, are elevated in schizophrenia, implying rapid consumption or activation of the protein in the body.
- Peripheral intervention potential: If peripheral immune cells are driving part of the disease process, treatments that block neutrophil activation in the bloodstream could slow or prevent progression without needing to cross the blood-brain barrier.
Source: Stanford
Summary of findings
Researchers at Stanford report that neutrophils—short-lived immune cells best known for fighting infections—express and produce the complement protein C4A. The complement system is an ancient part of innate immunity made up of many interacting proteins, and C4A is one of its key components. When C4A is activated, a small peptide fragment called C4-ana is released; this fragment serves as a marker that the complement cascade has been triggered.
C4A is implicated in two very different contexts: in the periphery as part of immune responses and in the brain as a regulator of synaptic pruning. During development, synaptic pruning eliminates redundant or weak synaptic connections to sharpen neural circuits. But overactive pruning can remove essential connections, and multiple lines of evidence link elevated C4A activity to the synapse loss and cortical thinning observed in schizophrenia.
The Stanford team combined analyses of a large gene expression database with laboratory measurements from blood samples. They found that neutrophils and classical monocytes express C4A, and that C4A expression in neutrophils correlates with C4A gene copy number and with clinical measures in people with schizophrenia. Notably, neutrophils from patients showed higher initiation of C4A production but lower intracellular reserves, while plasma levels of C4-ana were elevated—consistent with rapid activation and consumption of the protein outside the cells.
Why this matters
Schizophrenia affects roughly 1% of the global population and produces symptoms that include hallucinations, delusions, disorganized thought, and significant cognitive impairment. Current medications mainly address symptoms without reliably preventing progression or restoring cognitive function. Clozapine remains the most effective option for treatment-resistant cases, but its use is limited by serious side effects, including metabolic and cardiovascular risks, and by its effect on neutrophils.
By identifying neutrophils as a peripheral source of C4A, the study opens new avenues for both diagnostics and therapeutics. Blood-based measures—such as neutrophil counts, neutrophil C4A expression, and plasma C4-ana—could form part of an early diagnostic panel. Therapeutically, targeting neutrophil activation or complement activation in the periphery might reduce the harmful downstream effects on the brain while avoiding the challenge of delivering drugs across the blood-brain barrier.
Research context and implications
Genetic studies have long pointed to C4A as a major common risk factor for schizophrenia, but the mechanism linking peripheral genetics to brain pathology remained unclear. This study helps bridge that gap by showing that neutrophils express C4A in a way that correlates with genetic copy number and patient status. The findings suggest a convergence of innate immune mechanisms with neurodevelopmental processes implicated in schizophrenia.
The authors emphasize that further work is needed to determine where and how C4A is being activated and consumed in people with schizophrenia, and whether intervening in peripheral complement activity can alter clinical outcomes. If validated, such approaches could transform early detection and offer novel, more specific treatments with fewer systemic side effects than current antipsychotics.
Funding: The research was supported by the Stanford Department of Medicine’s Translational Research and Applied Medicine Program and the Stanford Department of Psychiatry and Behavioral Sciences.
Key Questions Answered:
A: The immune system communicates continuously with the brain. Neutrophils can produce C4A, and when C4A activity increases in or near the brain it can drive excessive synaptic pruning—removing critical synapses and impairing cognition. Elevated peripheral production and activation of C4A may therefore influence brain circuits involved in schizophrenia.
A: Clozapine reduces symptoms but has serious side effects and is not suitable for all patients. Proving that neutrophils generate pathogenic C4A suggests we could develop targeted therapies that inhibit specific immune pathways without the broad systemic effects of clozapine.
A: Potentially. Neutrophil activity, C4A gene copy number, and plasma C4-ana produce measurable peripheral signals. Combined with clinical data, these markers could form the basis of predictive or diagnostic tools to identify at-risk individuals earlier.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by editorial staff.
About this genetics and schizophrenia research news
Author: Bruce Goldman
Source: Stanford
Contact: Bruce Goldman – Stanford
Image: The image is credited to Neuroscience News
Original Research: Open access. “Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes” by Agnieszka Kalinowski et al., published in Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2536376123
Abstract
Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes
Because effective disease-modifying treatments for schizophrenia are lacking, novel aspects of its biology warrant study, including innate immune mechanisms outside the brain. C4 protein activation—part of the complement cascade—associates with symptoms and predicts outcomes in schizophrenia. However, complement activation in patients does not align with expected changes in other complement proteins, suggesting an alternative source of C4 activation.
Using fresh whole blood from 10 anonymous donors and extensive public microarray data, the authors found that C4 protein is primarily expressed in neutrophils and monocytes. They measured C4A gene copy number by digital droplet PCR and assessed C4 protein in neutrophils, classical monocytes, and plasma. A strong positive correlation between C4A gene copy number and C4 protein amount was observed specifically in neutrophils from the schizophrenia group. These results support a convergence of innate immune mechanisms with schizophrenia biology and point to further investigation of peripheral immunity as a potential therapeutic target.