What Is Neuroimmunology?

One of the most promising areas of growth in the medical world within the last century has been the emergence of a field many people may have never heard of: neuroimmunology.

Neuroimmunology is a subspecialty of neurology that examines how the immune system affects the nervous system. Broadly speaking, the nervous system refers to the central nervous system (brain and spinal cord) and peripheral nervous system (a network of nerves that runs throughout the body, connecting the central nervous system to limbs and organs).

To specialize in neuroimmunology, neurologists typically complete one year of additional clinical training or two to three years of additional training if their focus will be in research. Neuroimmunologists treat a wide array of conditions, primarily autoimmune disorders, including those involving nerve damage and certain brain infections.

“We've had an explosion of treatment options for known neuroimmune diseases, but we are also uncovering new aspects of diseases that we previously did not know had a neuroimmunology connection,” says Erin Longbrake, MD, PhD, a Yale Medicine neuroimmunologist. “If we can better understand those connections, that will provide us with better clues to treating them, giving patients a better quality of life.”

An evolving understanding of the interactions between the immune and nervous systems has led to dramatic breakthroughs in the treatment of multiple sclerosis (MS). More recently, researchers have been investigating the role the immune system plays in Parkinson’s disease, a chronic and progressive brain disorder in which nerve cells in the brain die, leading to stiffness, movement problems, and tremors.

Below, Dr. Longbrake and David A. Hafler, MD, chair of Neurology at Yale Medicine, talk more about the field of neuroimmunology and how it is evolving.

The immune system protects the body and prevents infection by identifying and attacking harmful bacteria, viruses, parasites, and cancer cells. In the brain, the immune system plays an important role in protecting it from infection, regulating inflammation, and repairing damaged tissue.

However, the immune system sometimes goes haywire. For example, in MS, the immune system mistakenly attacks the myelin sheath, a protective layer that forms around nerves, including those in the central nervous system. Because the myelin sheath is crucial for the efficient transmission of electrical signals in the central nervous system, any harm to it can disrupt how the nerves send signals to other parts of the body, causing a range of neurological symptoms.

In MS, this leads to problems with vision, muscle weakness, balance issues, numbness, and trouble with thinking and memory.

According to Dr. Longbrake, MS is the condition neuroimmunologists treat most frequently, accounting for about 75% of cases. But neuroimmunologists manage other demyelinating diseases, or conditions that involve damage to the myelin sheath.

In addition to MS, some of the most well-known demyelinating diseases are:

• Neuromyelitis optica is a rare demyelinating disease that was once thought to be a type of MS but is now recognized as a distinct condition. It is characterized by the immune system mistakenly attacking the optic nerves and spinal cord, which can lead to vision loss, weakness or paralysis of the limbs, and a dysfunctional bladder or bowel.

• MOGAD, which stands for myelin oligodendrocyte glycoprotein-associated disease, is a condition in which the immune system attacks a protein located on the outer surface of myelin sheaths in the central nervous system. This can lead to vision problems, weakness, sensory loss, paralysis, severe headaches, and cognitive problems.

Neuroimmunologists also manage autoimmune encephalitis, an umbrella term for a group of inflammatory brain disorders caused by the immune system mistakenly attacking brain tissue. Symptoms can vary widely but often include confusion, seizures, memory disturbances, mood changes or psychosis, and movement disorders.

Additionally, neuroimmunologists treat neurologic complications from other autoimmune diseases. For example, if someone has lupus (a disease in which the immune system produces antibodies against its own cells and tissues, leading to widespread inflammation and tissue damage) and the disease appears to be affecting the brain, they might see a neuroimmunologist, who can manage their neurological symptoms.

As the field of neuroimmunology has evolved, so have treatment options and approaches. In 1993, the FDA approved the first disease-modifying MS treatment—interferon beta-1b (Betaseron®), a daily injection that reduces inflammation and modulates the immune response to decrease the frequency and severity of MS relapses, or flare-ups of symptoms.

“There was then an explosion of treatment options starting around 2010,” Dr. Longbrake says. “We now have 20-odd medications approved for multiple sclerosis and other treatments that we use off-label for other diseases.”

Today, treatments include infusions, injections, and pills, most of which are immunomodulatory, meaning they can enhance or suppress the immune system’s activity.

The biggest breakthrough of them all, Dr. Hafler says, has been the development of MS medications ocrelizumab (brand name: Ocrevus®) and ofatumumab (brand name: Kesimpta®). Both of these drugs work by depleting circulating B cells, a type of immune cell that activates infection-fighting T cells, which mistakenly attack the myelin sheath.

These medications are 98% effective at stopping relapses, Dr. Hafler says. “Using these medications early on is so effective that some speculate that we are approaching a ‘cure’ for the condition, but time will tell how long-lasting the effects are in preventing progression,” he says.

This is important because some of the greatest brain damage in neuroimmune diseases occurs in its early stages, which makes timely and aggressive treatment vital, he adds.

“We want to go in early and prevent the initial damage that leads to neurodegeneration,” says Dr. Hafler.

As the field of neuroimmunology advances, researchers are broadening their net and finding other examples of neurological diseases that may turn out to have an immune component. For example, Parkinson’s disease appears to be affected by immune system dysfunction and inflammation in spinal fluid, notes Dr. Hafler.

“We are soon starting a clinical trial at Yale looking at how immunotherapies may prevent the onset of Parkinson's disease,” Dr. Hafler says. “So we're now expanding our view of neuroimmunology.”

Yale (and other academic medical institutions) now offer numerous clinical trials testing treatments that could help with MS and other neuroimmune conditions, Dr. Longbrake says. She says she is excited about work focused on the use of chimeric antigen receptor (CAR-T cell therapy), a form of immunotherapy that uses modified T-cells within a patient’s body to kill cancer cells.

“CAR-T cells are approved for treating certain cancers, like leukemia and lymphomas, and some early case studies suggest they were quite effective for autoimmune conditions like lupus. Now, CAR-T cells are being introduced into clinical trials for aggressive cases of multiple sclerosis,” Dr. Longbrake says.