Multiple sclerosis is the most common inflammatory disease of the central nervous system, affecting around 2.8 million people worldwide. Symptoms include difficulty moving, weakness, muscle spasms, stiffness, depression and general aches and pains. So far there is no cure. Instead, treatments focus on helping patients to manage their symptoms, control flare-ups, and slow the progression of the disease. Neuroscientists at the University of Virginia Health have discovered a possible way to interrupt the chronic inflammation which is responsible for multiples sclerosis.

The new study identifies a major contributor to the hyperactive autoimmune response and neuroinflammation that are hallmarks of MS. Blocking this pivot in an MS research model reduced inflammation and gave researchers a prime target in developing new treatments for multiple sclerosis and other autoimmune diseases. The research was conducted by Andrea Merchak, a graduate student in neuroscience, and her colleagues in the lab of Alban Gaultier from the University of Virginia School of Medicine’s Department of Neuroscience and its Center for Brain Immunology and Glia, or BIG.

The Role of the Gut Microbiome in Multiple Sclerosis

Scientists are constantly trying to understand the causes of MS, and research has already shown that the gut microbiome is involved. The new findings from the University of Virginia School of Medicine back this up by finding that an immune system controller found in “barrier tissues” like the gut plays a crucial role in the disease. According to the scientists, these regulators reprogram the gut microbiome to promote harmful, chronic inflammation. By modulating the microbiome (a collection of microorganisms that naturally live within us), we are making advances in understanding how the immune response can get out of hand in autoimmunity. This information can be used to find early interventions.

The experts blocked the activity of the regulator, called the aryl hydrocarbon receptor, in immune cells called T-cells, resulting in a dramatic impact on the production of bile acids and other metabolites in the microbiomes of laboratory mice. When this receptor was down, the inflammation decreased and the mice recovered.

These results suggest that doctors may one day be able to take a similar approach to disrupting harmful inflammation in people with MS. However, that will require a lot more research. According to the scientists, it is important to better understand the interactions between the immune system and the microbiome. Still, this new research lays an important foundation for future efforts to target the microbiome to reduce the inflammation that causes multiple sclerosis and other autoimmune diseases.

Due to the complexity of the intestinal flora, probiotics are difficult to use clinically. This receptor can be easily targeted with drugs, so this could be a more reliable way to promote a healthy gut microbiome. The researchers believe that fine-tuning the immune response using the microbiome could save patients from dealing with the powerful side effects of immunosuppressive drugs.

Protein Produced in the Liver and Multiple Sclerosis

In an animal model of multiple sclerosis (MS), reducing the amount of a protein made in the liver significantly protected against the development of the disease’s characteristic symptoms and promoted recovery in symptomatic animals. The findings, published by Science Translational Medicine, could lead to new treatment strategies for this neurological disorder and other conditions characterized by chronic inflammation.

In 1997, researchers discovered a protein called reelin secreted in the brain. Subsequent work showed that Reelin appears to help the brain organize itself during development and helps form connections between brain cells in adulthood. However, as the researchers learned more about Reelin, they discovered that large amounts of it are produced in the liver and that cells lining blood vessels have receptors for this protein.

A 2016 study by Joachim Herz, M.D., director of the Center for Transnational Neurodegeneration Research and a professor in the Departments of Molecular Genetics, Neurology and Neurotherapy, and Neuroscience at UTSW, and his colleagues showed that reducing circulating levels of Reelin in mice protected them from Atherosclerosis. When they looked more closely at the mechanism behind this phenomenon, they found that Reelin appears to regulate the production of adhesion molecules on the walls of blood vessels that trap circulating monocytes, a type of inflammation-causing immune cell. When the scientists decreased Reelin in animal models, levels of these adhesion molecules also decreased, preventing them from trapping monocytes and causing inflammation.

Lowering Reelin Levels to Treat Multiple Sclerosis Effectively

Wondering if reelin plays a similar role in other inflammatory diseases, Herz worked with Laurent Calvier, Ph.D., an instructor in the Department of Molecular Genetics at UTSW, and their colleagues to investigate the role of this protein in multiple sclerosis. They began by studying blood levels of Reelin in patients with relapsing-remitting MS, the most common form of the disease. They found that Reelin levels in patients in remission were about the same as in patients without the disease, while levels in patients in relapse were elevated. These results suggest that circulating Reelin levels are correlated with the severity and stages of MS, and that lowering Reelin levels may be a new avenue to treat MS.

In further investigations, the researchers worked with mice affected by a disease called experimental autoimmune encephalomyelitis (EAE), a disease modeled after human MS. When these animals were genetically engineered to control Reelin production, they found that removing this protein significantly reduced or even eliminated the paralysis associated with the disease, in contrast to mice with normal Reelin levels. These effects appeared to result from the lack of monocyte adhesion to the blood vessel walls of the engineered animals, preventing entry into the central nervous system.

Also Possible With Other Diseases

Researchers had further success in preventing paralysis when unaltered animals with EAE received antibodies that inactivated Reelin. This strategy was effective even in animals that were already showing symptoms of the disease—a situation that more closely mimics human patients diagnosed with MS—reducing the severity of the paralysis and promoting healing.

Herz and Calvier suggest that reducing the ability of immune cells to pool and cause inflammation by altering Reelin levels could represent a new strategy for treating patients with MS, a disease for which there are multiple effective drugs. However, they can have significant side effects. In addition, reducing Reelin may alter the course of several other diseases characterized by chronic inflammation, including psoriasis, Crohn’s disease and rheumatoid arthritis. In preparation for future human clinical trials, researchers are working to humanize a monoclonal antibody, Reelin can remove from human blood.