Researchers at the University of Toronto (UToronto) and the University of California San Francisco (UniCalSF) have discovered that the intestine is the source of immune cells that reduce brain inflammation in people with multiple sclerosis (lat. Sclerosis multiplex, MS) and that increasing the number of these cells blocks inflammation entirely in a preclinical model of the disease. The cells in question are plasma cells – white blood cells that originate as B cells in the bone marrow but change their behavior when triggered by microbes in the gut. Studying mice and samples from human MS patients, the researchers found that plasma cells that reside in the gut and produce Immunoglobulin A (IgA) antibodies appear to migrate to the central nervous system and produce an anti-inflammatory effect during MS flare-ups.
MS is an autoimmune disease, driven by other types of immune cells (including B and T cells) that attack myelin, the protective coating that surrounds nerve fibers. Recent clinical studies have shown drugs that target B cells mitigate MS, while those that target plasma cells make the disease worse. The current study offers an explanation for these divergent results. According to Jen Gommerman, Ph.D., a professor of immunology at the University of Toronto, scientists already knew what was and was not working in the clinic. But here they have uncovered the molecular and cellular mechanism at play. It’s a kind of reverse translation approach, which highlights the importance of the gut-brain axis in MS and other autoimmune conditions.
Canada and the U.S. have among the highest rates of MS in the world, with around three in every thousand individuals affected. Symptoms can include fatigue, poor coordination, tingling, organ problems and cognitive impairment. There is no cure, although quicker diagnoses and better drugs have improved outcomes significantly in the last 15 years. The lead authors on the study are postdoctoral fellows Olga Rojas, Ph.D., and Elisa Porfilio, Ph.D., from the Gommerman lab at the University of Toronto and Anne-Katrin Pröbstel, MD, from the Baranzini lab at UCSF. They recently presented their research at the same conference and realized their results aligned. The researchers began to collaborate, and Anne-Katrin Pröbstel and colleagues in the Baranzini lab were able to show that the Gommerman lab’s findings in mice had parallels to human MS patients.
Specifically, the UCSF team found evidence that IgA was decreased in fecal samples from patients with active MS neuroinflammation, suggesting that the inflammation-suppressing cells had been recruited to help fight the patients’ disease. One promising aspect of the new research is that increasing the number of IgA plasma cells that migrate from the gut to the brain eradicated neuroinflammation in mice. A therapeutic approach might aim to expand the number of these cells in the gut, enabling a plentiful supply that could move to the brain and dampen inflammation.
Until now, no one has really studied these IgA-producing plasma cells in the context of disease, but scientists are now examining them in detail in patients with MS to begin to understand how they might manipulate them to help treat neuroinflammatory disease. A key next step for the researchers is to figure out what microbes in the gut promote the generation of immunosuppressive IgA plasma cells. If scientists can understand what these cells are reacting to, they can potentially treat MS by modulating gut commensals. That might be easier than getting drugs into the brain, which is a strategy that hasn’t always worked in MS.