Our immune system connects the blood-brain barrier with schizophrenia

Like a strict bodyguard for the central nervous system, the blood-brain barrier stores anything that could lead to disease and dangerous inflammation – at least when everything is functioning normally.

This may not be the case for people with schizophrenia and other mental disorders, suggest new findings from a team led by researchers from the School of Veterinary Medicine, Perelman School of Medicine and Children’s Hospital of Philadelphia (CHOP). In these individuals, a more permissive barrier appears to allow the immune system to improperly engage the central nervous system, the researchers showed. The inflammation that develops probably contributes to the clinical manifestations of neuropsychiatric conditions.

“Our hypothesis was that if the immune function of the blood-brain barrier is impaired, the resulting inflammation will affect the central nervous system,” says Jorge Iván Alvarez, assistant professor at Penn Vet and senior author at the paper, published in the journal Brain. “With that in mind, we think these findings could also be used to understand how the blood-brain barrier and neurological processes affect not only schizophrenia but also mental disorders in general.”

The research team continued a study focusing on a rare condition called 22q11.2 deletion syndrome (22qDS), in which people are born who lack a small portion of DNA from chromosome 22. About a quarter of people with this syndrome develop schizophrenia. Penn and CHOP have a community of researchers who study the condition, often as a way to study the mysteries of schizophrenia more deeply.

However, this disorder was not in the focus of the Alvarez laboratory, until he gave a speech in CHOP about his professional field – the blood-brain barrier – and then approached it.

“We started talking about the fact that in this deletion syndrome, one of the missing genes is very important for the function of the blood-brain barrier,” says Alvarez.

That student, Stewart Anderson of CHOP, studied 22qDS and together he and Alvarez began collaborating to assess whether the blood-brain barrier and its effect on the immune system play a role in the condition.

As a first step, the group used a technique by which stem cells from patients with 22qDS diagnosed with schizophrenia, as well as healthy controls, persuade them to develop into blood-brain barrier endothelial cells, cells that make up a tightly regulated “wall”. In experiments led by Vet School doctoral student Alexis Crockett, they found that barrier function in cells derived from 22qDS patients was more impaired than those derived from healthy controls, which were more restrictive. They confirmed these findings in mice bred to have a 22qDS version, finding that their blood-brain barrier was also permeable compared to normal mice.

The brain is usually considered “immunologically privileged,” meaning that monitoring by immune cells and immune mediators in the central nervous system regulates not only the physical blockage of the blood-brain barrier but also endothelial cells that express a lower level of immune signaling molecules.

To determine if 22qDS compromised this immune privilege, the researchers re-examined the patient’s stem cells induced to grow into blood-brain barrier cells and their mouse model. In both cases, they observed damage to the immune privileged properties of the barrier, with multiple immune cells and proinflammatory molecules being able to cross it.

As final confirmation of their findings, the researchers examined post-mortem brain tissue from three patients with 22qDS and three controls. Similar to their work on cultured cells and the mouse model, they found evidence of impairment of the physical and immune protective function of the blood-brain barrier.

“This was a process of corroboration, which replicated all these observations in human tissues,” says Alvarez.

The paper adds a growing body of evidence to suggest that schizophrenia and certain other neuropsychiatric conditions may be in part neuroinflammatory disorders. It is also the first study to evaluate blood-brain barrier function in 22qDS, making an important link between neuroinflamma due to barrier dysfunction and neuropsychiatric disorders.

“Since 25% of patients with 22q develop schizophrenia, it may be possible that these mechanisms that take place in 22q are applicable to idiopathic schizophrenia,” Alvarez says. “And when 22q patients are studied in detail, up to 80% find they have some form of mental disorder, so these findings can extend to other disorders,” including perhaps depression or autism, he says.

In future work, Alvarez and colleagues will further explore the role of the blood-brain barrier, narrowing down what processes are involved in increased barrier permeability, including a look at astrocytes, cells that typically improve barrier function.

Further insight into the link between inflammation and neuropsychiatric illness, Alvarez says, may one day lead to therapies that deal with inflammation by manipulating the immune response.

Reference: Crockett AM, Ryan SK, Vásquez AH et all. Interruption of the blood-brain barrier in deletion syndrome 22q11.2. The brain. 2021; (awab055). doi: 10.1093 / brain / awab055

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