When Controls Fail

The central nervous system, composed of the brain and the spinal cord, is our body’s control center. It regulates numerous vital functions such as respiration and the interplay between organs, as well as muscular coordination and our sensory organs. This important switchboard needs especially good defenses against malignant invaders like viruses, bacteria and other pathogens. The central nervous system lies behind the almost impenetrable blood-brain barrier, where it is protected like a safe inside a Swiss bank. The blood-brain barrier shields the brain from pathogens and toxins, but also from one’s own antibodies and immune cells. Numerous turnstiles and security guards regulate what gains entry into the central nervous system. Everything depends on the utmost precision because any immune cells that erroneously get waved through can trigger autoimmune reactions – immune responses that attack the body’s own tissues. Autoimmune reactions in the brain can cause serious harm and can severely impair thinking and memory, for example.

This is the focus of immunologist Sarah Mundt’s research. Using a mouse model, she wants to examine how immune cells are able to penetrate into the central nervous system and aims to discover what part regulation mechanisms play in the process. With her current research project, which is supported by the UZH Alumni Research Talent Development Fund (“Fonds zur Förderung des akademischen Nachwuchses”, FAN), Mundt wants to contribute to attaining a better understanding of how the central nervous system interacts with the immune system. “Diseases of the central nervous system are especially frightening because victims lose control over themselves, over the very essence of their being, and over basic functions such as walking, seeing and thinking. Through my research, I would like to pave the way for better therapies and more effective drugs to be developed,” the immunologist says. Diseases have always fascinated her, Mundt adds, which is why she originally wanted to become a physician. Through her research, she hopes to help as many people as possible who are suffering from a disease of the central nervous system involving the immune system. The spectrum of such disorders includes dementia, Parkinson’s disease and arguably the most well-known example, multiple sclerosis (MS). Some two-and-a-half million people worldwide suffer from MS, around 10,000 alone in Switzerland.

If pathogens evade the blood-brain barrier and infiltrate the brain, they must be combated immediately. Microglia perform this task as the first line of defense. These immune cells reside in brain tissue and carry out the same function that scavenger cells (macrophages) do in the rest of the body’s immune system: they eliminate cell debris and devour pathogens. If microglia get overwhelmed by the attack by pathogens and require backup reinforcements, the blood-brain barrier becomes more permeable and allows select T cells to enter the brain.

Around half of our immune cells are T cells. These white blood corpuscles form part of the body’s so-called adaptive immune defense. They stand on the lookout for pathological changes and eliminate them with pinpoint precision. In a healthy organism, T cells rarely turn up inside the central nervous system, but since they help defend against pathogens and malignant cells, they perform a vital protective function there.

Mundt is investigating how protective T cells that defend against pathogens, but also autoreactive T cells that attack the body’s own tissues, are able to migrate into the central nervous system and how they are regulated there. “It is still unknown in what instances autoreactive T cells are able to gain entry into the brain, but we conjecture that diseases like MS can be triggered by a natural malfunction of one of the control entities,” the UZH researcher explains. It is known that T cells need special permission to migrate into the central nervous system. “Little research has been done on immunoregulatory mechanisms of this kind in the central nervous system even though they have a significant impact on diseases like cancer, infections and autoimmunity,” Mundt says.

In her earlier research work, Mundt demonstrated that dendritic cells can grant autoreactive T cells permission to enter the brain if they are activated enough. Autoreactive T cells recognize their target tissue via proteins presented by dendritic cells and infiltrate the central nervous system, where they then recruit other immune cells such as monocytes. The problem, though, is that the chemical messengers of the recruited immune cells and the mechanisms triggered by them that destroy pathogens and remove them from the body harm the nervous system and cause inflammation. This enables different types of autoimmune disorders to manifest, depending on which cell structure the autoreactive T cell is programmed to target.

Mundt’s research proceeds on the assumption that dendritic cells normally block autoreactive T cells from gaining entry into the brain. Regulatory T cells and immune checkpoints may also play a role here. Immune checkpoints are receptors on the membranes of immune cells that temper their reactivity and thus regulate the immune response. Conversely, one treatment approach in cancer therapy is to employ immune checkpoint inhibitors to activate the body’s immune system to combat tumors. The drawback of this method of treatment is that autoimmune reactions often arise in the course of therapy, some of which affect the central nervous system. “From that, we conclude that immune checkpoints may be involved in some way in allowing entry into the central nervous system, but these hypotheses have to be validated through specific experiments,” Mundt says.

Using a mouse model, the immunologist is investigating whether it really is the control entities that malfunction in MS and why that happens. Her experiments employ genetically altered mice that do not become ill despite them harboring a particularly large number of reactive T cells arrayed against the central nervous system. To find out why these mice do not fall ill, Mundt is examining how regulating control entities such as dendritic cells, immune checkpoints, and regulatory T cells interact with the autoreactive T cells in the mice’s brains. “The latest technologies like spectral flow cytometry and single-cell RNA sequencing make it possible to do that today,” Mundt explains. Using those technologies, she and her research team were able to detect a reduced incidence of autoreactive T cells in the central nervous system and to observe that they really do exhibit different cell characteristics compared to other T cells. “The dangerous autoreactive cells appear either to get locked out of the central nervous system or to get reprogrammed, or virtually defused, in situ there so that they can no longer attack it.”

In the next step, Mundt will genetically modify individual cell types and their specific functions in an effort to ascertain with greater precision what role regulatory T cells and dendritic cells play in controlling autoreactive immune cells. Mundt and her team would also like to figure out what impact certain risk factors for MS, such as (viral) infections, pregnancy or hormones, have on the control of autoreactive T cells. “Hopefully this knowledge will help us in the future to better understand and treat other autoimmune diseases of the central nervous system as well.”