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Rogue B Cells May Drive Inflammation in Multiple Sclerosis

A new study has uncovered a type of B cell that may fuel inflammation in patients with multiple sclerosis. The findings help explain the long-standing question of why an experimental therapy that removes these immune cells from the body is effective against the disease. Selectively eliminating the pool of rogue B cells, while sparing healthy B cells, may offer a more targeted approach for treating multiple sclerosis and potentially other autoimmune disorders, researchers say.

The study appears in the 21 October issue of Science Translational Medicine.

"It opens up a window into an exciting new biology that we hadn't appreciated before," said senior author Amit Bar-Or of McGill University. "Some [B cells] may be bad in MS and some may actually be beneficial."

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The researchers uncovered the rogue group of B cells in blood drawn from patients with multiple sclerosis. | Flickr/Steven Kenny, East Kent Hospitals University NHS Trust, Wellcome Images/ CC BY-NC-ND 2.0

The subset of pro-inflammatory B cells may also serve as a potential marker of disease relapse and patients' response to treatment, said Bar-Or.

Multiple sclerosis is traditionally viewed as a T cell-driven disease. In this autoimmune disorder, the immune system, primarily T cells as well as immune cells called myeloid cells, are thought to destroy myelin, a fatty substance that insulates and protects nerve fibers.

B cell depletion therapy, which removes B cells from the blood, can keep relapses at bay in multiple sclerosis patients. The success of this treatment in clinical trials has put the spotlight on B cells as key players in the disease. B cells are best known for their ability to make antibodies, and abnormal antibodies are common in multiple sclerosis patients.

However, the B cell depletion treatment has little effect on the abnormal antibodies found in these patients. This "striking and surprising observation" led Bar-Or and colleagues to suspect functions for B cells beyond antibody production, he said. B cells fulfill other important roles, including secretion of cytokines, small signaling proteins that can either quench or promote inflammation.

Analyzing B cells in blood samples from multiple sclerosis patients and healthy individuals, and studying patients' immune responses before and after B cell depletion therapy, Bar-Or's team identified a subpopulation of B cells that releases a powerful pro-inflammatory cytokine called GM-CSF, which is known to drive inflammation in the brain.

Compared to healthy individuals, untreated multiple sclerosis patients had abnormally abundant and more readily activated GM-CSF-producing B cells. These B cells stimulated myeloid cells in a dish to secrete pro-inflammatory cytokines, which in turn can activate pro-inflammatory T cells.

After undergoing B cell depletion therapy, multiple sclerosis patients experienced fewer flare-ups of their symptoms and showed reduced inflammation in their blood. The results suggest that by partially eliminating the rogue B cell pool, the therapy may have blunted inflammation triggered by myeloid cells and T cells. These benefits persisted for months after treatment and even as patients formed new B cells.

While B cell depletion therapy has proven highly effective in advanced clinical trials, its long-term safety remains to be seen. The therapy "may be taking some of the good with the bad, so by getting a better sense of who the bad guys are, we can hopefully develop treatments that are as effective and potentially even safer," said Bar-Or.

Author

Jean Mendoza

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