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Summary: <\/strong>A new study uncovered a startling bridge connecting schizophrenia to the body\u2019s peripheral immune system. Researchers discovered that neutrophils, the most abundant white blood cells in the human body, function as active factories for C4A, an immune system complement protein previously thought to be produced primarily in the liver. Long recognized as the single strongest common genetic risk factor for schizophrenia, C4A drives excessive \u201csynaptic pruning\u201d in the brain, destroying vital neural connections.<\/p>\n The study reveals that neutrophils in schizophrenia patients launch an aggressive surge of C4A production, which is immediately consumed or activated in the bloodstream. This milestone discovery raises the possibility of diagnosing and treating a severe brain disorder entirely through the peripheral blood, completely bypassing the blood-brain barrier.<\/p>\n Key Facts<\/strong><\/p>\n Source: <\/strong>Stanford<\/p>\n The most common white blood cells in your body \u2014 immune cells called neutrophils \u2014 can make a protein nobody knew they were making, Stanford Medicine investigators have discovered. That unexpected sighting joins a growing list of hints tying schizophrenia, a disorder of the brain, to events occurring elsewhere in our bodies.<\/strong><\/p>\n The findings are summarized in a\u00a0paper\u00a0published online May 11 in\u00a0Proceedings of the National Academy of Science<\/em>.<\/p>\n The newly noticed neutrophil nexus, as a source of the protein called C4A, links a long list of other observations that are somewhat puzzling when looked at in isolation: For example, large-scale population-genetic studies have identified C4A, already known to be produced mainly in the liver, as a pronounced risk factor in schizophrenia.<\/p>\n People with schizophrenia tend to have increased numbers of neutrophils in their blood. And the most effective medication for schizophrenia inhibits neutrophils.<\/p>\n \u201cConnecting such seemingly disparate relationships could give us a better understanding of schizophrenia and, eventually, better treatments and diagnostics for it,\u201d said\u00a0Agnes Kalinowski,\u00a0MD, PhD, a clinical assistant professor of psychiatry and behavioral sciences.<\/p>\n Kalinowski, a researcher as well as a practicing psychiatrist focusing on schizophrenia, is the\u00a0PNAS<\/em>\u00a0study\u2019s lead author. The senior author is\u00a0Alexander Urban, PhD, associate professor of psychiatry and behavioral sciences and of genetics.<\/p>\n Schizophrenia affects one in every 100 persons globally almost without variation by geography or ethnicity. Its most noticeable symptoms are hallucinations, delusions and fixations. A fundamental feature of the disease is cognitive impairment: inability to think clearly, reduced working memory, disorganized thinking and behavior.<\/p>\n Current treatments for schizophrenia are palliatives, Kalinowski said. They don\u2019t stop disease progression or restore motivation or cognitive sharpness. \u201cThe best drug we\u2019ve got now is clozapine,\u201d she said. \u201cIt reduces manifestations such as hallucinations, fixations and delusions. That can be life-changing. But it has side effects ranging from weight gain to heart attack risk.\u201d<\/p>\n Intriguingly, another of clozapine\u2019s major side effects \u2014 or\u00a0is<\/em>\u00a0it a \u201cside\u201d effect? \u2014 \u00a0is that it depletes the numbers of circulating neutrophils, she noted.<\/p>\n C4A: a neutrophil-brain connection?<\/strong><\/p>\n You may not have heard much about neutrophils, but you\u2019ve probably seen them. They account for a good half of a healthy person\u2019s circulating white blood cells.<\/p>\n These short-lived kamikaze warriors have a tough life. They\u2019re the first immune cells to arrive on the scene of bacterial infections. There they gobble up microbial pathogens; spew out toxic bactericidal substances; and extrude gooey microbe-trapping webs made of long stringy molecules, including their own DNA. Neutrophils routinely die on the job \u2014 their life expectancies range from less than a day to a week \u2014 only to become the main cellular ingredient of pus.<\/p>\n C4A is one of the 50 or so proteins aligned in a close, complex collaboration in our bloodstreams called the complement system. This ancient evolutionary kernel of our modern immune system, which traces back to the sponges of some 500 million years ago, can rapidly recognize various inflammatory events such as microbial invasions.<\/p>\n In response, a bucket brigade of events ensues. One by one, the component proteins become activated and bind to the next protein in the brigade, activating it. C4A\u2019s activation gets tripped off when a small fragment of it, called C4-ana, gets snipped off.<\/p>\n Activated complement, the result of that bucket brigade, engages in tasks such as punching holes in bacterial cells\u2019 outer membranes; curiously, it\u2019s consistently seen in blood samples from people with schizophrenia.<\/p>\n C4A pops up in more places than just our blood. In the brain, it engages in a very different capacity. It has been implicated in a process called synaptic pruning, in which the brain periodically rids itself of excessive nerve-cell-to-nerve-cell contact points called synapses.<\/p>\n A healthy adult human brain has an estimated 100 trillion to 500 trillion synapses. During early brain development, that number rockets even higher, resulting in many unnecessary, redundant and even obfuscating connections. Like an editor slashing out extraneous verbiage in a potentially great story, synaptic pruning ordinarily enhances cognitive coherence. It occurs in waves during fetal development, early childhood and adolescence.<\/p>\n But this can go too far. The schizophrenic brain\u2019s outermost layer, the cerebral cortex, crucial to high-level mental functioning, has been shown to contain some 30% fewer synapses than a healthy brain does, and to be thinner than normal.<\/p>\n Researchers have found a link between brain thickness and circulating neutrophil counts, Kalinowski said.<\/p>\n A major schizophrenia risk factor<\/strong><\/p>\n Risk factors for schizophrenia include high levels of emotional stress or severe fever in early childhood (before age 5) and daily marijuana use, especially during adolescence.<\/p>\n But these environmental factors are dwarfed by the genetic ones.<\/p>\n \u201cThe heritability of schizophrenia is very strong \u2014 about 80%,\u201d Kalinowski said. The biggest single hereditary risk factor involves C4A.<\/p>\n Genes are recipes for proteins. Our genomes typically carry two copies of each gene \u2013 one inherited from Mom, one from Dad. But over the course of evolution, some of our genes have undergone mutations called duplications, resulting in more copies of those genes in some people\u2019s genomes.<\/p>\n That\u2019s the case for C4A: Some of us have two copies of the gene for it, while others may have several. The number of C4A-gene copies in a person\u2019s genome is the strongest common genetic risk factor associated with schizophrenia.<\/p>\n Nobody\u2019s been able to say why. But C4A\u2019s concentration in schizophrenia patients\u2019 plasma (blood\u2019s contents after its resident cells have been removed) has been found to track with the number of copies of the C4A gene in those patients\u2019 genomes.<\/p>\n Schizophrenic patients\u2019 symptom intensity correlates with their brain levels of C4A, inferred from its measured levels in their cerebrospinal fluid.<\/p>\n In 2021, Kalinowski and Urban co-authored a\u00a0paper\u00a0in\u00a0Translational Psychiatry<\/em>\u00a0showing a strong connection between the number of copies of the gene for C4A in the genomes of people with schizophrenia and the amount, in their plasma, of C4-ana, that small snippet of C4A that gets excised to kick-start C4A\u2019s activation.<\/p>\n C4-ana can be thought of as a kind of footprint of activated C4A\u2019s presence.<\/p>\n Neutrophils make C4A<\/strong><\/p>\n In the new\u00a0PNAS<\/em>\u00a0study, Kalinowski, Urban and their colleagues looked at a massive gene-expression database. Gene expression analyses measure, gene by gene, the intensity of their participation in an early step in individual cells\u2019 production of proteins.<\/p>\n Our genomes contain roughly 20,000 genes. But only a small, selected set of any single cell\u2019s genes are actively engaged in directing the production of proteins, depending on what type of cell it is (nerve, skin, heart, etc.) and what state it\u2019s in (healthy or diseased, agitated or at peace, young and frisky or old and cranky). The investigators also tested blood samples from 10 anonymous volunteers.<\/p>\n They saw that neutrophils can and do make C4A.<\/p>\n What\u2019s more, neutrophils\u2019 C4A protein-production intensity in individuals with schizophrenia correlated with their clinical measures. Was C4A from schizophrenia patients\u2019 neutrophils getting into the brain and revving up synaptic pruning in these individuals?<\/p>\n \u201cIt turns out neutrophils are able to be little factories for C4A,\u201d Kalinowski said. \u201cAnd neutrophils from schizophrenic patients are initiating far more CA4 production than healthy controls\u2019 neutrophils are.\u201d<\/p>\n Paradoxically, they\u2019re holding on to less of it: There was no difference in the amount of this protein itself in plasma, and there was\u00a0less<\/em>\u00a0of it in neutrophils from schizophrenic patients than in neutrophils from controls. Yet levels of C4-ana \u2014 the telltale marker of C4A\u2019s activation \u2014 were higher in schizophrenic patients\u2019 plasma.<\/p>\n This all suggests to Kalinowski that the protein is being made in abundance in neutrophils but is somehow getting consumed.<\/p>\n \u201cSchizophrenia patients\u2019 neutrophils appear to be exhausting their initially plentiful C4A supplies,\u201d she said. \u201cSomething, somewhere, is using it up. We don\u2019t know exactly where that\u2019s happening, but we\u2019re hoping to find out.\u201d<\/p>\n The study raises the possibility that neutrophils may play a direct role in schizophrenia. If they do, then maybe blocking their activity could interfere with the disease process.<\/p>\n \u201cDrugs that block neutrophil activation wouldn\u2019t need to penetrate the blood-brain barrier, because they\u2019d be working in our peripheral bloodstream,\u201d Kalinowski said.<\/p>\n Neutrophil assessments could also be part of a diagnostic, Kalinowski said. \u201cBeing able to extract a diagnostic signal from something in blood, in combination with clinical information, would be game-changing.\u201d<\/p>\n Might looking for elevated neutrophil counts predict the onset of symptoms?<\/p>\n \u201cWe don\u2019t have a full explanation of schizophrenia yet, but we\u2019re putting together the jigsaw puzzle,\u201d Kalinowski said. \u201cFiguring out where each piece goes helps you snap the rest of them into place more quickly.\u201d<\/p>\n Funding: <\/strong>The study was funded by the Stanford Department of Medicine\u2019s Translational Research and Applied Medicine Program and the Stanford Department of Psychiatry and Behavioral Sciences.<\/p>\n A<\/strong>: It sounds completely disconnected, but your immune system and your brain are constantly speaking to one another. Stanford researchers discovered that neutrophils act like little peripheral factories producing a protein called C4A. In the brain, C4A is responsible for \u201csynaptic pruning\u201d, acting like a brutal editor that slashes away redundant nerve connections to sharpen thinking. In schizophrenia patients, these immune cells pump out way too much C4A, sending the brain\u2019s editing process into overdrive and wiping out up to 30% of critical cognitive synapses.<\/p>\n<\/div>\n A<\/strong>: The gold-standard drug we have right now is clozapine, and it can be completely life-changing at reducing hallucinations and delusions. Intriguingly, it also depletes your body\u2019s circulating neutrophils. The problem is that clozapine is a heavy-handed palliative treatment with severe, dangerous side effects ranging from massive weight gain to life-threatening heart attack risks. By explicitly proving that neutrophils are the root source of the toxic C4A protein, scientists can now design highly specific drugs to block this immune pathway without the devastating full-body side effects.<\/p>\n<\/div>\n A<\/strong>: Yes, and that is precisely why this discovery is a massive game-changer for early psychiatry. Because a patient\u2019s neutrophil counts and their C4A genetic copy numbers leave a distinct, measurable chemical signature right inside their blood plasma, clinicians hope to build a digital diagnostic dashboard. Spotting these hyper-active immune changes early could allow doctors to predict the onset of cognitive symptoms and intervene long before hallucinations or psychological breakdown ever occur.<\/p>\n<\/div>\n<\/div>\n Author:\u00a0<\/strong>Bruce Goldman<\/a>\n
Key Questions Answered:<\/h3>\n
Editorial Notes:<\/h3>\n
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About this genetics and schizophrenia research news<\/h2>\n
Source:\u00a0<\/strong>Stanford<\/a>
Contact:\u00a0<\/strong>Bruce Goldman \u2013 Stanford
Image:\u00a0<\/strong>The image is credited to Neuroscience News<\/p>\n