October 26, 2015
MS Scientific Research Foundation funded multi-site study makes breakthrough in identifying type of white blood cell involved in MS
Research into understanding and treating multiple sclerosis (MS) has largely been centered on a type of white blood cell known as the T cell or T lymphocyte. T cells are in charge of protecting the body against harmful infections, but in the case of MS T cells have been identified as important culprits in the improper immune response against the myelin sheath surrounding nerve fibres. Extensive research into which types of T cells attack myelin and how they can be controlled has led to important advancements in the MS field; however, mounting evidence has pointed to another white blood cell that appears to also be playing a major role in MS. The B cell or B lymphocyte is similar to a T cell in that it functions to eliminate disease, but unlike T cells, B cells produce antibodies that protect the body against future infection. Whether B cells contribute to MS through interaction with T cells, other immune cells, or through antibodies is still not fully understood.
In 2014 the MS Scientific Research Foundation awarded a $3.6 million grant to Dr. Amit Bar-Or (McGill University), Dr. Jennifer Gommerman (University of Toronto) and Dr. Alexandre Prat (University of Montreal) to explore the various roles of B cells in MS based on findings in the clinic and from cellular and animal studies. Their goal is to understand which B cells are good and which ones are bad, in order to block the bad ones while allowing the good ones to remain active in fighting disease. Their work recently led to a breakthrough discovery – a specific type of highly inflammatory B cell that appeared to be a major driver of MS and was found in reduced levels in people who received B-cell depletion treatment. The study was published in Science Translational Medicine.
The researchers conducted a series of laboratory experiments using blood samples from people with relapsing-remitting MS and healthy volunteers. They also collected blood samples from people who received treatment which targets and destroys disease-producing B cells. Using these samples they analyzed and compared levels of inflammatory molecules called cytokines, and in particular measured levels of B cells that release a cytokine called granulocyte macrophage colony-stimulating-factor (GM-CSF). GM-CSF is commonly associated with other immune cells as a growth stimulator, but has also been linked to certain B cells and could explain their inflammatory nature.
The researchers found an increased number of pro-inflammatory B cells containing GM-CSF in untreated people with MS compared to healthy controls. In cell culture experiments, they found that this specific type of B cell interacted with and turned on other inflammatory cells that are known to activate disease-causing T cells. Treatment with the B cell targeting therapy rituximab reduced the levels of B cells containing GM-CSF and resulted in reduced inflammatory activity in people with MS by blocking the release of pro-inflammatory cytokines. The diminished inflammatory response persisted in treated individuals long after treatment and even when new B cells were formed.
This study marks an important advancement in the MS community’s understanding of the immune players in MS, notably the specific types of B cells that are involved which, until now, were not well defined. This also serves as an example of research with translational potential, as these findings will have enormous implications for how MS is treated. Publication of these findings coincides with the recently announced results from ORATORIO – a phase III clinical trial that included 732 participants with primary progressive MS. The participants received either ocrelizumab (a treatment that targets B cells) or placebo. Results showed that treatment with ocrelizumab reduced disability progression, lesion size, brain volume loss, and improved mobility. The remarkable potential for B cell treatments to treat MS and improve quality of life speaks to the importance of understanding how certain types of B cells contribute to both relapsing and progressive MS disease, why people who receive B cell treatments do better overall, and how B cells treatments can be fine-tuned to yield the greatest benefit while avoiding harmful side effects.
Li R et al (2015). Proinflammatory GM-CSF–producing B cells in multiple sclerosis and B cell depletion therapy. Science Translat Med. 7(310):310ra166