Yale experts make strides in Multiple Sclerosis research
Scientists at Yale School of Medicine have investigated the connection between inflammation and autoimmune diseases, particularly Multiple Sclerosis, and its impact on disease progression and quality of life.
Eric Wang, Staff Photographer
Researchers at the Yale School of Medicine have found that B-cell depleting drugs can help reduce symptoms of inflammation in patients with multiple sclerosis.
Multiple sclerosis, or MS, is an autoimmune neurodegenerative condition in which a patient’s overactive immune system attacks their nerves, causing neurologic dysfunction. Professor of neurology and immunobiology David Hafler, assistant professor of neurology Erin Longbrake, assistant professor of neurology Tomokazu Sumida and professor of rheumatology, pathology and epidemiology Richard Bucala ’79 have paved the way in MS research. Their work has focused on potential treatments for this debilitating inflammatory disease.
“The working model for MS is that you have autoreactive T-cells recognizing brain antigens, particularly myelin antigens, that get activated in a genetically susceptible host,” Hafler said.
T-cells are a type of immune cell that recognizes particular antigens – or proteins that are present on the surface of cells – before targeting them and killing them. Autoreactive T-cells essentially cause autoimmune disease because they recognize antigens on the body’s own cells, rather than the foreign cells of disease which need to be destroyed.
Thus, T-cells play a central role in MS. According to Hafler, T-cells recognize cellular signatures called antigens like those on the myelin sheath and then cause inflammation by secreting inflammatory cytokines. The myelin sheath is important for increasing the speed of signals sent between the brain and different parts of the body, so destroying these cells makes this essential communication in MS slower and more difficult.
Genetic susceptibility is a key component of MS. Hafler’s lab identified 233 common genes and eight rare mutations that are associated with disease risk.
For decades, Hafler’s work has been pivotal in the field of multiple sclerosis. In fact, in the 1980s, his lab was the first to identify autoreactive T-cells in patients with MS.
“It was the first demonstration of autoreactive T-cells in humans for any self-antigens,” Hafler said. “The surprising thing back then was, not only did we find autoreactive T-cells in patients with MS, but [we] also found them in healthy individuals. They were [present with a] lower frequency but they were present, and that was a conundrum that we dealt with for decades … We finally figured … that the difference [between] patients with MS [and healthy individuals] … [is that] in healthy individuals, T-cells are autoreactive but they are secreting … a suppressive cytokine that turns off immune responses.”
Hafler added that these T-cells then recruit other cells –– scavenger cells –– to destroy the myelin sheath. In comparison, healthy individuals’ “T-cells are not setting up an inflammatory response.”
B-cells, like T-cells, are the immune system’s other main cells. They produce antibodies to fight off infections. Antibodies, like T-cells, recognize antigens on foreign cells and kill those cells that invade the body, which typically come from infectious disease.
“One of the big breakthroughs in the field is drugs that deplete B-cells — in particular, Ocreluzimab [Ocrevus], the FDA-approved drug we use,” Hafler said. “The drug Rituxan for rheumatoid arthritis was tried in a number of different autoimmune models and it worked very well in rheumatoid arthritis. Eventually, it was tried in multiple sclerosis … and we’ve been using it for five years in our clinic with absolutely spectacular results.”
Rituxan and Ocrevus are both B-cell depleting monoclonal antibodies.
Anti-inflammatory medications don’t target the underlying cause of MS, but work to reduce symptoms and increase the quality of life in patients suffering from the disease. According to Bucala, the symptoms of MS are caused by inflammatory cells and immune cells infiltrating the brain. These cells then release mediators that destroy the surrounding neurons and the neural connections.
“If you can reduce those inflammatory mediators by blocking [their] action or by blocking [their] production, then there’s less tissue damage,” Bucala said. “There’s less brain damage that occurs. They’re not curative, in the sense the disease never returns, but the symptoms — the pain, the disability — are reduced. And the progression of the disease is slowed.”
In addition to slowing the disease progression, research is paving the way for earlier diagnosis of MS.
Patients with MS are usually diagnosed much after its main, debilitating symptoms, or immunopathology, start to show.
“[When] the immune system becomes dysregulated and starts to damage the central nervous system, [the] damage that is caused most likely begins well in advance of someone actually having symptoms of multiple sclerosis,” Longbrake noted. “We can’t actually make a diagnosis of MS until someone has a symptom of the disease. But we do know that at the time that those first symptoms develop, it’s pretty clear that there’s been underlying damage taking place for … probably, years.”
Even without any concrete symptoms, neurological damage can be seen in people who haven’t yet received a diagnosis. According to Longbrake, while MS patients are still asymptomatic, some of them exhibit brain lesions that appear to be MS. If these individuals are studied closely, they may have subtle cognitive problems.
Longbrake noted that their study is interested in the concept of preclinical MS and diagnosing the disease closer to its onset.
“We are learning that within those five years leading up to a diagnosis … [they] start to access healthcare systems more frequently,” Longbrake said. “We know that with MS, treating early gives you the best long-term outcomes. The natural extension of that observation is to say — if you treat it before the symptoms actually became noticeable, could the disease be prevented altogether?”
Experts estimate that there are around one million people in the United States living with MS.