Major schizophrenia breakthrough finds immune cells on the wrong side of the tracks
For so long schizophrenia was seen as a disorder exclusively of the mind, but new lines of research are uncovering evidence that its machinations may venture well beyond the brain. In what is being labeled one of the biggest breakthroughs in schizophrenia research of recent times, scientists have detected heightened immune cell activity in the brains of sufferers, providing a brand new target for further research into its causes, diagnosis and treatment.
Old habits die hard
The idea that schizophrenia is not only an illness of the mind, but of the whole body, actually originated more than 100 years ago. An influential German psychiatrist named Emil Kraepelin posited that the disorder was actually a broad metabolic disease that affects the entire body, though his voice was soon drowned out by influential figures in the field of psychoanalysis.
Professor Cyndi Shannon Weickert's twin brother was diagnosed with schizophrenia at aged 17. As a neuroscientist, now at Neuroscience Research Australia, she has dedicated her life's work to discovering its cause. She explained to us one of the reasons for the long-held scientific aversion to studying the interplay between the immune system and brains of schizophrenia sufferers.
"We were taught as neuroscientists that the brain was 'immune privileged,'" she tells New Atlas. "What that was taken to mean by some researchers was the immune cells would just kind of cruise by on the vascular highway, but not really cross the blood brain barrier and interact with the resident cells of the brain."
Modern research technology is giving scientists fresh impetus to examine these links. A study published earlier in the year looking at 30 years of data, taken from over one million people, found a strong link between stress disorders like PTSD and autoimmune diseases.
Another meta-study in July involving more over 25 million individuals found people with autoimmune disorders were around 40 percent more likely to develop psychotic disorders, like schizophrenia. A 2017 genetic study at the University of Pennsylvania, meanwhile, uncovered eight genes that appeared to be implicated in both rheumatoid arthritis and schizophrenia.
Now Weickert is joining the chorus.
Wrong side of the tracks
Vessels carry blood into and around the brain to provide it with constant nourishment, and it is here that the blood brain barrier plays a crucial role. It closely guards the brain tissue from pathogens and toxins in the bloodstream that threaten to cross over and cause it harm, and it was thought that immune cells, too, were unable to escape its watchful eye.
As such, three types of brain cells have largely been associated with schizophrenia: the neurons, the glial cells that support them, and the endothelial cells that pack tightly inside the blood vessel walls. But now, after studying the inflamed brains of deceased schizophrenia patients with modern molecular techniques, Weickert believes that one suspect may have gone undetected this whole time.
"I found a molecular signature of inflammation, and that was the smoke," she tells us. "And the deeper that we dug we actually found, underlying that smoke, some changes that were consistent with the brain vessels becoming stickier. And then we thought, well what kind of immune cells could be captured and be encouraged to transmigrate across the blood brain barrier into the tissue?"
Weickert and her team turned to RNA sequencing to narrow the field and searched for signatures indicative of immune cell infiltration and high inflammation. This path led them to the macrophage, a type of immune cell with a reputation for having quite the appetite.
"Once the cells go into the tissue they differentiate into macrophages, which are known as 'big eaters,'" Weickert explains. "That's how they got their name, because they are very active cells that are able to destroy microbes, microorganisms and tissue or damaged cells."
The scientists found that in some people with schizophrenia, the glial cells become inflamed and emit distress signals that alter the state of the endothelial cells, prompting them to extend sticky tentacles. Immune cells that would normally pass innocently by are being snaffled by these tentacles and drawn across to a place that they shouldn't be.
"This is a major breakthrough, we have found immune cells on the brain side of the endothelial wall, in greater amounts in people with schizophrenia and inflammation," says Weickert. "So why is this important, you may ask? You can liken this to an unsolved crime case, all of a sudden a new suspect arrives at the scene of the crime. And here's the twist, it has always been at the scene of the crime, but has gone undetected by scientists for the last 100 years."
This suggests that the pathology for schizophrenia may have been hiding in the immune cells all along, and that those cells may have been contributing to the symptoms of the disease. To explore these possibilities, Weickert is hoping neuroscientists can work with immunologists to develop new treatments and better understand its root causes.
"What we're really interested in doing is dampening down this inflammation to see if its going to bring about clinical benefit." she tells us. "Now, what's important to realize here is that not everyone with schizophrenia is in a state of inflammation at any one time. We find about 40 percent of people with schizophrenia can have elevated cytokines in the brain or in their blood. So we think those are the ones that are going to be responsive to anti-inflammatories, it makes sense that those that are inflamed are the ones that you would want to treat."
The drugs used to treat schizophrenia today don't take aim at the underlying causes of the disease, they are instead designed to relieve some symptoms, and none of them target the immune system. This new knowledge may act as springboard for the development of new kinds of drugs that dampen down the immune system, and/or block the entry of the immune cells into the brain tissue.
New clinical trials are already underway at Neuroscience Research Australia involving both neuroscientists and immunologists, and Weickert says they are beginning to produce "encouraging" results, which they hope to publish before the end of the year.
The new research was published in the journal Molecular Psychiatry, and you can hear from Weickert in the video below.
Source: Neuroscience Research Australia