26 September 2018

Immune cells now new suspects in schizophrenia

Clinical Psychiatry

Specialised white blood cells have been caught breaching the blood-brain barrier in schizophrenia brains for the first time.

The major discovery by Professor Cyndi Shannon Weickert from Neuroscience Research Australia (NeuRA) appears to have opened up a whole new potential avenue for treatment, and the research group is now seeking funding to trial anti-inflammatory drugs in people with schizophrenia. 

It was previously thought that these immune cells couldn’t cross the blood-brain barrier, and so they were largely ruled out as a potential neurobiological mechanism for schizophrenia.

But this study, involving 74 post-mortem samples from the NSW Brain Tissue Resource Centre, showed that white blood cells infiltrated schizophrenia brains (which already showed inflammation of the resident glial cells of the brain) at a much higher rate than in non-schizophrenia brains.

Historically, schizophrenia researchers have largely focused their attention on three cell suspects: neurons, glial cells, and endothelial cells. Now, there’s a fourth player in the brain pathology of schizophrenia: immune cells called macrophages.

“Usually the monocytes are circulating in the blood looking for foreign agents,” said Dr Tertia Purves-Tyson, a research fellow at NeuRA’s Schizophrenia Research Laboratory who was not involved in the study.

“Monocytes can get taken into other tissues but the brain was always thought to be immune privileged. But what they showed [in this study] was that monocytes can get across the blood-brain barrier. Once they are across the barrier they are called macrophages.”

Macrophages are immune cells that ingest foreign bodies through phagocytosis. 

Once across the blood-brain barrier, macrophages are in close enough proximity to the neurons to do damage, which may explain some of the symptoms of schizophrenia in some patients.  

“We have seen the resident glial cells in the brain become inflamed in some people with schizophrenia and produce distress signals,” Dr Purves-Tyson said. 

“We think these signals cause the cells of the blood vessel walls, the endothelial cells, to change and produce more cell adhesion proteins (such as ICAM1).”

These adhesion proteins cause immune cells to stick to the side of the blood vessels and transmigrate across the blood-brain barrier. 

Around 40% of patients with schizophrenia have a “high inflammatory biotype”. This subgroup would be the target of any future clinical trials that repurpose anti-inflammatory drugs as an adjunct therapy, Dr Purves-Tyson said.

One limitation of the study was that all the tissue samples came from patients that had been treated with antipsychotics – medication that could change inflammation.

However, a previous study of anti-psychotic-naïve patients in the UK showed greater immune system activity in the brains of people with schizophrenia, Dr Purves-Tyson said.

This study focused on the resident glial cells, that could produce immune factors, rather than looking at immune cells that crossed the blood-brain barrier. 

However, the rise in immune system activity inside the brain was likely to be tied to a broader inflammatory response, Dr Purves-Tyson said.

Glial cells in the brain produced inflammatory proteins that acted like emergency sirens, which might call macrophages to the brain, she said. 

Molecular Psychiatry 2018, 14 September