Summary: A new study reveals an unexpected link between schizophrenia and the peripheral immune system. Researchers found that neutrophils—the most abundant circulating white blood cells—actively produce C4A, a complement protein previously thought to be produced mainly in the liver. C4A is the strongest common genetic risk factor for schizophrenia and promotes excessive synaptic pruning in the brain, removing vital neural connections.
The investigators report that neutrophils from people with schizophrenia ramp up C4A production, and that the protein is rapidly activated or consumed in the bloodstream. This discovery suggests the potential to diagnose or intervene in schizophrenia by targeting peripheral blood chemistry, avoiding the challenge of delivering drugs across the blood-brain barrier.
Key Facts
- The Unexpected Factory: Neutrophils account for more than half of circulating white blood cells in healthy adults. For the first time, Stanford researchers show these peripheral immune cells can produce the schizophrenia-associated complement protein C4A.
- The Over-Pruning Editor: In the brain, C4A helps regulate synaptic pruning—normal removal of unnecessary synapses during development. In schizophrenia, this pruning is excessive, with studies showing roughly 30% fewer synapses in the cerebral cortex and thinning of high-level cortical regions.
- The Genetic Copy Catalyst: Variation in the number of C4A gene copies is the most significant common hereditary risk factor for schizophrenia. Individuals with more C4A gene copies tend to have higher levels of C4A and its activation fragment (C4-ana) detectable in blood plasma.
- The Clozapine Paradox: People with schizophrenia often show elevated neutrophil counts, and the most effective antipsychotic, clozapine, reduces circulating neutrophils—suggesting these cells may drive disease biology rather than being a mere side effect.
- The Activation Mystery: Although neutrophils from patients produce abundant C4A, they retain less of the intact protein. Elevated plasma C4-ana indicates that much of the C4A is being activated or consumed in the body.
- Bypassing the Blood-Brain Barrier: If peripheral immune cells contribute directly to schizophrenia pathology, therapies that act in the bloodstream could modulate disease processes without needing to penetrate the central nervous system.
Source: Stanford
The most common white blood cells in the body—neutrophils—can produce a complement protein linked to schizophrenia, Stanford Medicine investigators report. This finding strengthens growing evidence that schizophrenia, traditionally viewed as a brain disorder, has meaningful connections to immune activity elsewhere in the body.
The study is reported in a paper published online May 11 in Proceedings of the National Academy of Sciences.
This neutrophil connection helps unify several puzzling observations. Large genetic studies have identified C4A as a major risk factor for schizophrenia, and clinical data show elevated neutrophil counts in many affected individuals. Additionally, clozapine, the most effective antipsychotic for treatment-resistant cases, decreases circulating neutrophils.
“Connecting these disparate findings may deepen our understanding of schizophrenia and point toward better diagnostics and treatments,” said Agnes Kalinowski, MD, PhD, clinical assistant professor of psychiatry and behavioral sciences and lead author of the study.
Kalinowski, who treats patients with schizophrenia and conducts research in the field, co-led the study with senior author Alexander Urban, PhD, associate professor of psychiatry and behavioral sciences and of genetics.
Schizophrenia affects about one percent of people worldwide and typically presents with hallucinations, delusions, disorganized thinking, and significant cognitive impairment. Current medications reduce symptoms but do not reliably stop disease progression or restore cognitive function.
“Clozapine can be life-changing for some patients,” Kalinowski said, “but it carries serious side effects from weight gain to cardiovascular risks. Notably, clozapine also lowers neutrophil counts, which prompted us to investigate whether neutrophils play a more direct role in disease biology.”
C4A: a neutrophil–brain connection?
Neutrophils are short-lived frontline immune cells that respond rapidly to infection. They engulf microbes, release bactericidal substances, and form extracellular traps. Despite their short lifespan, neutrophils are highly active in circulation and tissues.
C4A is part of the complement system, a group of roughly 50 proteins that coordinate innate immune responses. Activation of complement proceeds through sequential protein cleavages; when C4A is activated a small fragment called C4-ana is released. Activated complement can attack microbes, and markers of complement activation are consistently observed in blood samples from people with schizophrenia.
In the brain, C4A has a different role: it tags synapses for elimination during synaptic pruning, a normal developmental process. While pruning refines neural circuits and supports cognitive development, excessive pruning can remove needed connections. Studies have shown reduced cortical synapse density and cortical thinning in schizophrenia, and some reports associate cortical thickness with circulating neutrophil measures.
Genetic risk and C4A copy number
Schizophrenia has strong heritability—around 80%—and genomic variation in C4A copy number is the largest single common genetic risk factor identified to date. Individuals differ in how many C4A gene copies they carry; more copies are associated with higher C4A expression and increased levels of the activation fragment C4-ana in plasma. Prior work by the authors linked C4A gene copy number to plasma C4-ana in people with schizophrenia.
Neutrophils produce C4A
In the current study, the team analyzed extensive gene-expression datasets and tested fresh blood from anonymous donors. Gene-expression profiling shows which genes are actively transcribed in specific cell types. The authors found that neutrophils and monocytes express C4A, and subsequent assays confirmed neutrophils as a prominent source of C4 protein.
Importantly, neutrophils from patients with schizophrenia showed higher transcriptional activity for C4A than neutrophils from controls. Yet intact C4A protein levels were paradoxically lower in patients’ neutrophils, while plasma concentrations of C4-ana were elevated—consistent with active consumption and activation of C4A in the bloodstream.
These observations suggest neutrophils manufacture substantial amounts of C4A that are then rapidly activated or used elsewhere in the body. The precise sites and mechanisms of C4A consumption remain to be identified.
If neutrophils contribute directly to disease mechanisms, therapeutics that modulate neutrophil activation in blood could alter disease trajectories without needing to cross the blood-brain barrier. Similarly, neutrophil-based measures combined with genetic and clinical data could become part of an early diagnostic strategy.
“We do not have a complete explanation for schizophrenia yet, but identifying how pieces like C4A and neutrophils fit together will accelerate progress,” Kalinowski said.
Funding: The study 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 and brain interact continuously. Stanford researchers discovered that neutrophils make C4A, a protein that in the brain promotes synaptic pruning. When neutrophils overproduce C4A, the brain’s pruning process can become excessive, potentially removing critical synapses and impairing cognition.
A: Clozapine reduces hallucinations and delusions and also lowers neutrophil counts, but it has serious systemic side effects. Demonstrating that neutrophils are a direct source of harmful C4A creates the possibility of designing targeted therapies that block this immune pathway in blood without the broad, dangerous effects seen with some antipsychotics.
A: Potentially, yes. Neutrophil activation markers, C4A gene copy number, and plasma C4-ana create measurable signals that may be combined with clinical information to build predictive tools. Early detection of immune changes could enable interventions before severe cognitive or psychotic symptoms develop.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by 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., 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
A lack of highly effective disease-modifying therapies for schizophrenia motivates the study of new aspects of its biology, including innate immune mechanisms outside the brain. Activation of the complement protein C4 is associated with symptoms and outcomes in schizophrenia, but its activation does not consistently track with expected changes across the complement cascade, suggesting alternative cellular sources for C4 protein.
Analyzing fresh whole blood from anonymous donors and large public gene-expression datasets, the authors show that C4 protein expression is concentrated in neutrophils and monocytes. They compared C4 protein in neutrophils, classical monocytes, and plasma with individuals’ C4A gene copy number.
Using digital droplet PCR to quantify gene copy number, Western blotting to measure C4 protein in neutrophils and plasma, and flow cytometry for classical monocytes, they observed a strong positive correlation between C4A gene copy number and neutrophil C4 protein specifically in the schizophrenia group (Spearman’s rho = 0.63, 95% BCa CI: 0.12 to 0.89, P = 0.012).
These results indicate convergence of innate immune mechanisms in schizophrenia and suggest that innate immunity warrants further investigation as a potential therapeutic target.