Targeting B-cells in Cerebrospinal Fluid May Lead to More Effective MS Therapies, Study Suggests

Immune B-cells are more abundant and have a pro-inflammatory profile in the cerebrospinal fluid (CSF), the fluid that bathes the central nervous system,  compared to blood in people with relapsing-remitting multiple sclerosis (RRMS), a study reports.

The results suggest that therapeutic strategies targeting the CSF B-cells could constitute a new and effective approach to manage MS symptoms, especially in treatment-resistant patients.

The study “A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis” was published in Proceedings of the National Academy of Sciences journal, and led by researchers at Weill Institute for Neurosciences, University of California, San Francisco (UCSF).

B-cells are important in the immune system as they are responsible for producing antibodies and recruiting other immune cells when fighting infections. These cells also keep a “memory” of past infections, generating a faster and stronger response upon re-stimulation with “foreign” invaders.

Previous research has shown that B-cells are one of the players triggering the destruction of the myelin sheath, the protective coating around nerve fibers; its loss is the hallmark of MS.

As so, MS therapies have focused on decreasing the number of memory B-cells in the central nervous system (CNS, brain and spinal cord). These therapies succeeded in reducing relapses. However, according to the UCSF researchers, they do not completely eliminate the myelin-targeting B-cells found in the CNS, and in certain patients the disease continues to progress.

“The success of these therapies is nearly unprecedented in medicine, but the exact role of these B cells in MS is still poorly understood,” Akshaya Ramesh, PhD, the study’s first author, said in a UCSF press release. “We wanted to understand if certain populations of B cells play a particularly important role in the disease and might be targeted by future therapies.”

“A longstanding question in the field of MS has been simply this: what are B cells doing in the spinal fluid of MS patients and why are they so difficult to remove even with our best available B cell removal treatments?” added Ryan Schubert, MD, study co-author.

To understand the uniqueness of CSF B-cells and how they contribute to neurodegeneration, the team analyzed B-cells isolated from both the blood and spinal fluid of 24 participants. These included patients diagnosed with RRMS  (16 patients), clinically isolated syndrome (two patients), healthy controls (three participants), and people diagnosed with other neurological diseases (three participants).

All MS patients had participated in the UCSF ORIGINS study or the Expression, Proteomics, Imaging, Clinical (EPIC) study.

Researchers used two cutting-edge technologies — single-cell RNA-sequencing and single-cell immunoglobulin sequencing — to profile all the RNA molecules and antibodies produced in each individual cell. They also performed a bulk analysis of all RNAs in blood and CSF B-cells from an additional seven RRMS patients. (RNA molecules include those used as templates to make proteins, which carry out various functions in a cell.)

The analysis revealed that, compared to B-cells in the blood, those in the CSF had a strikingly different cellular profile. Moreover, in RRMS patients, B-cells were 13 times more abundant in the CSF compared to healthy controls.

Researchers also assessed which subtypes of B-cells were found in CSF. B-cells can be classified as naive, memory and plasmablast/plasma cells. The results showed that the CSF of RRMS was enriched in memory B-cells and plasmablast/plasma cells (mature and previously activated B-cells) compared to the those in the blood.

Bioinformatic analysis revealed that B-cells found in the CSF were activated in key pathways that help explain their role in MS. Compared to blood B-cells, those in the CSF had a significant enrichment of inflammatory pathways, as well as in cholesterol metabolism, which has been linked to play a role in MS.

“By identifying particular B-cell biological pathways that are more pronounced in in the spinal fluid of patients with MS, we hope to provide guideposts for development of next-generation B cell therapies,” said Michael Wilson, MD, associate professor of neurology at UCSF Weill Institute for Neurosciences, and the study’s lead author.

The analysis indicated that memory B-cells and plasma blast/plasma cells in CSF of RRMS are polarized toward an inflammatory phenotype compared to B-cells circulating in the blood.

“We see that B cells in the spinal fluid specifically turn on genes that increase their chance of surviving as they encounter brain and spinal fluid tissue, perpetuating a cycle of injury and resulting in the characteristic feature of MS — demyelination,” said Schubert.

Researchers also found that the majority of the B-cells in the CSF were positive for IgM and IgG1 immunoglobulins (antibodies). Moreover, the sequences of these Igs were less diverse in RRMS patients, indicating that these potentially could be used as targets for tailored therapeutics.

“If we could do that, we could design therapies to selectively deplete B cells that are reacting to this particular antigen or group of antigens,” Wilson said. “It would be the first opportunity to really go after the root cause of the disease.”

Researchers also observed that expansion of B-cells in the CSF of RRMS patients was associated with the increase of gadolinium-positive regions in MRI scans (Gadolinium is a contrast agent used to identify MS active lesions.)

These results link the increase of B-cells in the CSF of MS patients to the active destruction of myelin and the breakdown of the blood-brain barrier, a highly selective semipermeable membrane that shields the CNS from blood circulation.

“Taken together, these data support the targeting of activated resident B cells in the CNS as a potentially effective strategy for control of treatment-resistant chronic disease” the team concluded.