B-cell depletion therapy recruits gut cells to fight MS, study suggests

Therapies to remove harmful immune B-cells that drive inflammation in multiple sclerosis (MS) may also work by mobilizing protective, gut-derived B-cells into the bloodstream and nervous system, a new study shows.

Researchers also found that higher levels of molecules thought to drive such protective functions in B-cells were linked to better clinical outcomes in patients on B-cell-depleting treatment, pointing to a previously unrecognized mechanism behind the effectiveness of this type of therapy.

“Our research shows that B cell depletion changes the levels of factors that regulate B cells and is associated with an increased migration of protective gut-derived B cells,” Anne-Katrin Pröbstel, MD, PhD, the study’s senior author at the University of Basel in Switzerland, said in a university news story. “Interestingly, higher levels of these B cell-regulating factors were linked to better outcomes in patients with MS.”

The study, “Anti-CD20 B cell depletion is associated with elevated mucosal-originating circulating regulatory IgA B cells in multiple sclerosis,” was published in Science Translational Medicine.

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Some B-cell types actually help calm immune responses

MS is a chronic inflammatory disease in which immune cells mistakenly attack the myelin sheath, the protective coating that surrounds nerve fibers. This damage disrupts communication between the brain and the body, giving rise to the disease symptoms.

Among the immune cells involved, B-cells have been identified as important drivers of disease activity. As a result, B-cell-depleting therapies, particularly those targeting the CD20 protein at the surface of most B-cells, have become a major treatment approach for MS.

While anti-CD20 therapies are known to be highly effective, scientists don’t fully understand which specific B-cell types and associated regulating factors are responsible for the clinical benefit. In fact, some B-cells types, called regulatory B-cells, actually help to calm immune responses, including the type of autoimmune responses seen in MS.

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Regulatory B-cells may have migrated into brain and spinal cord

To address this gap, Pröbstel and colleagues in Switzerland, Germany, the Netherlands, Canada, and the U.S. measured gene activity and protein levels in blood, cerebrospinal fluid (CSF), and intestinal tissue samples from people with MS over time.

The CSF is the fluid surrounding the brain and spinal cord. Intestinal sampling across multiple sites was performed in one MS patient on anti-CD20 treatment and one patient not on such therapies.

The team combined patient findings with immune data from an MS animal model given an anti-CD20 treatment.

In both blood and CSF samples, the analysis showed that anti-CD20 treatment was linked to an increase in regulatory B-cells producing IgA, a type of antibody associated with mucosal tissues like the gut.

Importantly, researchers found matching genetic “fingerprints” of B-cells in both the gut and bloodstream, suggesting that these IgA-producing regulatory B-cells were migrating from the gut into the bloodstream and potentially into the brain and spinal cord.

In addition, experiments found that higher levels of two signaling proteins thought to help drive regulatory functions in B-cells — BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand)  — were associated with better clinical outcomes in people with MS undergoing anti-CD20 treatment.

These findings suggest that anti-CD20 therapy may work in part by recruiting beneficial B-cells from the gut, rather than only by removing harmful B-cells, “opening previously unknown therapeutic avenues for MS,” the researchers wrote.