Inflammation and autoimmune diseases – including multiple sclerosis (MS)—often go hand in hand. While this may be unsurprising, given that inflammation is an integral part of physiology that seeks to protect the body after deviations from its normal state, such as those created by injury or infection, excessive inflammation is problematic. For patients with MS and other autoimmune diseases, inflammation can diminish quality of life by degrading otherwise healthy parts of the body.
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Researchers at Yale School of Medicine are paving the way to better understanding how to treat MS and other neuroinflammatory diseases. Among them is David A. Hafler, MD, William S. and Lois Stiles Edgerly Professor of Neurology, professor of immunobiology, and chair of the Department of Neurology, who has studied MS and neuroinflammation from the time he was a freshman in college.
Other leaders include Erin Longbrake, MD, PhD; assistant professor of neurology and director of clinical research in neuroimmunology; Tomokazu Sumida, PhD, assistant professor of neurology, who has recently established his own, independent laboratory; and Richard Bucala, MD, PhD, Waldemar Von Zedtwitz Professor of Medicine (Rheumatology) and professor of pathology and of epidemiology (microbial diseases).
“While it was always clear that MS was an inflammatory autoimmune disease, one of the major surprises in the field of medicine has been the role of inflammation in different diseases, particularly neurodegenerative diseases,” Hafler says. “We now understand it plays a critical part.”
MS and the Body’s Immune System
MS is an autoimmune disease that occurs when dysregulated immune cells, known as T-cells, attack the body, specifically brain cells. As the overactive immune system degrades or destroys nerves in the brain and spine, individuals begin experiencing episodes of neurologic dysfunction such as loss of vision or the ability to walk.
While symptoms from these episodes, or relapses, may be temporary, MS is an unpredictable disease that when untreated often leads to lifelong disability. It usually develops during early adulthood and can progress through the lifespan. “Scientists have made tremendous progress in treating the condition,” Hafler says. “In 1970, there was no treatment for the disease, while now, there are incredibly effective treatments that have evolved, particularly depletion of B cells.”
“The immune system is supposed to be the body’s armed forces, protecting it from external attacks by germs or pathogens,” says Longbrake. “In MS, it gets its orders confused and causes harm.”
Longbrake says MS brain lesions are caused by inflammatory damage to nerves. This damage leads to neurologic deficits like weakness, numbness, or memory problems. Inflammation of the central nervous system is linked to the initial appearance of the disease as well as relapses. And “more smoldering inflammation,” she continues, causes the disease to progress over time. Medications are effective at lowering the amount of inflammation, and are most effective when used early in the disease, though they aren’t guaranteed to put every symptom into remission.
Yale Researchers Lead in Understanding and Treating MS
Yale is home to some of the world’s leading experts who have linked MS to inflammation. Hafler, for example, came to Yale in 2009 from Harvard, he says, because Yale’s immunobiology department is one of the best in the country. His decades of research have led to identification of the genes that cause MS and the development of new therapies.
When he first started, he knew that MS was an inflammatory disease, but didn’t know if inflammation was a primary or secondary cause. His lab was the first to identify that in patients with MS, there are T-cells in the immune system that can degrade myelin, a substance that coats and insulates nerves. While these cells are present in both healthy people and patients with MS, they occur at a much higher frequency in MS.
“Our lab didn’t just identify myelin-reactive T-cells, but also defined the nature of these cells—showing that they are highly inflammatory and likely to cause disease,” Hafler says.
More recently, Hafler’s lab has been using a new technology called single cell RNA sequencing analysis to study inflammatory cells in the spinal fluid of patients with MS. Through this technique, his team is able to study cells at the single-cell level and characterize them. They are using the technology to measure the frequency of autoreactive T-cells—which play a key role in autoimmune disease—in the spinal fluid of MS patients. He is finding that the frequency is “very high,” but that using a treatment known as B-cell depletion therapy in MS patients is turning off the reactive T-cells.
While most patients respond to B-cell depletion, there is a small subset of patients who fail to respond to treatment. Sumida, who originally studied a pathway linking cardiovascular disease and immune cell activation in Japan, brought his expertise in immunology to Hafler’s lab in 2015. He is currently studying the T- and B-cells of these patients to try and understand why B-cell depletion therapy is effective in some individuals, but not others. “Our research will help us predict which immune systems will likely respond to B-cell depletion therapy, as well as help us better understand how the therapy works,” Sumida says.
When asked about the next steps needed to better understand the link between MS and inflammation, Hafler says he plans on continuing his work identifying trigger antigens, including environmental triggers, for autoimmune disease.
A study in his lab led by Sumida published in 2018 in Nature Immunology, for instance, found that salt induces inflammation and high-salt environments could trigger the onset of the condition. The team discovered that high concentrations of salt in the brain tissue could cause T-cells to become “incredibly inflamed,” says Hafler. A follow up study published in PNAS showed that patients with MS have a higher salt load in their tissues.
“High salt environments are also one of the major risk factors in cardiovascular disease,” says Sumida. “I’m envisioning applying this knowledge to learning how to explore immune cell function not only in MS, but also in the future to cardiovascular disease.”
MS Research May Benefit Other Neuroinflammatory Conditions
Yale is also home to numerous clinical trials for evaluating MS treatment. Longbrake, for instance, is interested in identifying and treating the earliest stages of MS and is the principal investigator of many of the trials. She is most excited about her research on radiologically-isolated syndrome (RIS), a condition in which individuals have brain lesions identical to those seen in MS patients, yet have no symptoms of the disease.
Viewing RIS as a pre-clinical form of MS, she is leading a clinical trial to see if using a short course of B-cell depletion therapy can prevent inflammation and immune-mediated damage to the brain and spine, thus preventing or delaying the onset of MS. “The most important thing we need to understand is the first steps in the cascade when things begin to become pathologic,“ she says. “This will be one of the most impactful studies we will see in multiple sclerosis.”
”The researchers hope their work will not only benefit MS patients, but also those struggling with other neuroinflammatory diseases, including Parkinson’s and Alzheimer’s disease. “Our work can be the hub for a lot of phenomena we see in the context of disease,” says Sumida. “It can help us gain a broader view of how autoimmune diseases develop.
Targeting Inflammation to Treat Autoimmune Diseases
Other Yale experts have also made strides in MS research. When a 2011 study found a polymorphic gene was linked with the severity of lupus, another autoimmune disease, the researchers, including senior author Bucala, grew interested in its association with MS. This particular gene is linked to the production of the cytokine MIF, an inflammatory hormone, and 20% of the population has a high-production form of the gene—the form connected to greater severity of multiple autoimmune diseases.
The 2011 finding led to another study in 2017 in which the researchers obtained DNA from 200 MS patients, and found that the more severe, progressive form of MS was also associated with the high-production form of the MIF gene. “Our study identified an important genetic susceptibility to severe MS,” says Bucala.
This finding has clinical applications for MS treatment. Ibudilast, an anti-inflammatory drug that targets MIF, was originally approved in Japan for the treatment of asthma. Bucala’s team’s finding sparked clinical trials of Ibudilast for progressive MS, which have so far yielded promising results.
The collaborative nature at Yale, says Bucala, is a special feature of the medical school that allows research on inflammation in MS and other autoimmune diseases to thrive. “Many investigators at Yale have worked on fundamental inflammatory mechanisms,” he says. “We’re all one campus working together and talking among ourselves. There’s a lot of thought into how our fundamental findings can be translated to medicine and therapeutics.”
Source: Yale University