Intricate niche of cells and tissues in the brain may be fueling inflammation in progressive MS
The disease process underlying progressive MS remains a complex, largely unsolved area of research. People living with progressive MS often respond poorly to current MS immune-modifying therapies, suggesting that progressive MS is less an inflammatory disease and more a neurodegenerative disease.
In relapsing-remitting MS, inflammation appears to play a much more prominent role; however, new research evidence is surfacing which shows that inflammation may also be involved in progressive MS, albeit in a different way. Researchers postulate that inflammatory cells may be “setting up shop” inside the brain, causing ongoing damage to nerve cells. This could explain neurodegeneration in progressive MS, and researchers from the University of Toronto led by Dr. Jennifer Gommerman have provided compelling findings supporting this possibility. Their study, funded by the MS Society of Canada and MS Scientific Research Foundation, was published this month in the journal Immunity. Lead author of the paper, Dr. Natalia Pikor, was a recipient of an MS Society Doctoral Award.
Study Methods and Results
The study involved mice that exhibited MS-like symptoms, as well as blood cells extracted from people living with MS and non-MS controls. In the mice, researchers observed the location and composition of so-called “tertiary lymphoid tissues”, which are a collection of white blood cells that they believe are residing within the brain and contributing to harmful inflammation in MS. In particular they looked within the meninges, the part of the brain that appears to be rich in inflammatory B cells in people with progressive MS.
In mice they found that, at the start of the disease, T cells dominated within the meninges, and at the peak of the disease, there was a mix of B and T cells. Specifically, they found that T helper 17 or Th17 cells (a type of T cell) were highly active in this area of the brain, causing demyelination. This echoes previous studies showing that Th17 cells are major players in autoimmune disease.
Using the same mice they looked at changes in the cellular environment within the meninges. They discovered the formation of a network of supportive fibers, which created a net that can collect more Th17 cells and preserve inflammation. When analyzing human blood samples, the researchers found increased levels of inflammatory cytokines that are associated with Th17 cells. This confirmed the mouse findings and linked them to the human disease.
For years it was demonstrated that, in MS, immune cells are activated outside of the central nervous system (CNS), and then travel into the CNS where they cause damage. New research shows that inflammation may also be occurring within the CNS, independent of the new waves of immune cells coming in. In their latest study funded by the MS Society, Dr. Gommerman and her team provide a detailed description of this compartmentalized inflammation that could help explain what happens in progressive MS.
Overall, the study strengthens the MS research community’s understanding of the inflammatory nature of MS, by identifying where exactly inflammation is taking place and how it is maintained. The MS Society looks forward to seeing how this work will inform development of therapies for progressive MS that block the effects of culprits such as the Th17 cells.
Pikor N et al. (2015) Integration of Th17 and Lymphotoxin-beta receptor-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation. Immunity [epub ahead of print].