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Transforming immune cells in the brain take on a wide variety of functions / Changes in multiple sclerosis mapped for the first time / Study in the journal Nature refutes textbook opinion

A team of researchers led by the University Medical Center Freiburg has completely remapped the brain's own immune system in humans and mice. The scientists were able to show for the first time that all phagocytes in the brain, known as microglial cells, have the same origin but develop differently depending on their task. Until now, different cell types had been assumed. The discovery was made using a new, high-resolution method for examining individual cells and is important for understanding neurodegenerative diseases. The researchers from Freiburg, Göttingen, Berlin, Bochum, Essen and Ghent (Belgium) were also able to demonstrate in detail how the human immune system changes in multiple sclerosis, which is important for future therapeutic approaches. The study was published in the journal Nature on February 13, 2019.

"We were able to show that there is only one type of microglial cell in the brain," says project leader Prof. Dr. Marco Prinz, Medical Director of the Institute of Neuropathology at the Freiburg University Medical Center. "These immune cells are very versatile all-rounders and not specialists, as was previously the textbook opinion," summarizes Prof. Prinz.

Versatile all-rounders instead of specialists

As the immune cells in the blood cannot reach the brain and spinal cord due to the so-called blood-brain barrier, the brain needs its own immune defense: the microglia cells. These scavenger cells of the brain are formed early in embryonic development and later eliminate invading germs and dead nerve cells. They are also involved in the maturation and lifelong malleability of the brain. Until now, it was unclear whether there are subtypes for the various functions in the healthy and diseased brain.

The researchers led by Prof. Prinz and the first authors of the study, Dr. Takahiro Masuda, Dr. Roman Sankowski and Dr. Ori Staszewski from the Institute of Neuropathology at the Freiburg University Medical Center, compared the different immune cells in the brain in detail. They did this both in a mouse model and on human brain tissue that had been removed from patients during epilepsy surgery.

Using a new method for examining single cell analyses, the researchers were able to determine the origin and function of the cells in detail. To do this, they used a microscope to examine many immune cells from different brain regions and stages of development. Using a molecular biological method, they also analyzed the RNA protein blueprints of the cells. This showed that all microglial cells had the same origin, but developed differently depending on the developmental phase and region of the brain and the function to be performed.

Hope for patients with multiple sclerosis

Misdirected microglia also play a role in several brain diseases. In particular, microglial cells are thought to play a crucial role in the development of Alzheimer's disease, multiple sclerosis (MS) and some psychiatric disorders such as autism. In the healthy brain, microglia form a uniform network around the nerve cells, which can change in a matter of minutes during illness and can form many new phagocytes to combat damage.

"We now have a high-resolution immune cell atlas of the human brain for the first time. This also allows us to understand how these cells change in diseases such as multiple sclerosis," says Prof. Prinz. "In MS patients, we were able to find microglial cells in a state that is specific to multiple sclerosis. Our hope is that cells in this state can be specifically switched off in the future."

"It is extremely exciting to see how flexible the microglial cells can be," says Prof. Prinz. The investigations in the mouse model put the researchers on the right track. However, first author Dr. Masuda was also able to show that human microglial cells are significantly more complex than those of laboratory animals. "The individual changes in the human brain also leave their mark on the microglial cells in the course of life," says Dr. Masuda.

Original title of the study: Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

DOI: 10.1038/s41586-019-0924-x

Link to the study: https: //www.nature.com/articles/s41586-019-0924-x

Image source: Takahiro Masuda / University Medical Center Freiburg

Caption: Single-cell analysis of microglial cells: Each dot shows a cell and the color signals how strongly certain immunologically important genes are activated in different cells.

Contact: 
Prof. Dr. Marco Prinz 
Institute of Neuropathology 
Freiburg University Medical Center 
Phone: 0761 270-51060 
marco.prinz@uniklinik-freiburg.de

Further information: 
<link neuropathologie.html>https://www.uniklinik-freiburg.de/neuropathologie.html</link> Institute of Neuropathology, Freiburg University Medical Center