The Mystery of Multiple Sclerosis: What Does the Immune System Have to Do With It?

by: Katie Foulger

Affecting one million Americans per year, of an unknown cause, with no treatment plans in place — the disease Multiple Sclerosis (MS) truly is an enigma. MS is an autoimmune disease that directly affects the central nervous system (CNS), consisting of the brain and spinal cord. The immune system malfunctions and begins to attack the body’s own nerve cells’ insulating layer in the brain and spinal cord, called the ‘myelin’. Eventually, this causes a loss in motor control and degeneration of communication between the body and brain over the course of the patient’s life. 

The initial trigger of the disease was not entirely clear, however, after collective research over many years, there is a consensus that B-cells do have a significant role in onset and progression. B-cells are ‘memory cells’ in the immune system that circulate and recognize previously encountered pathogens and produce antibodies. The hypothesis that these cells are what triggers MS was confirmed as post depleting these B-cells in test MS patients, their symptoms of numbness/paralysis were significantly reduced. This has been further confirmed by studies comparing healthy CNS fluid and MS Patients via microarrays and RNA-sequencing, essentially comparing the sequence of the genetic code. 

However, it has been found that these B-cells of MS patients are stubborn, and even after numerous depletion treatments they still linger in the cerebrospinal fluid (CSF), fluid that supplies only the central nervous system of the patients, allowing the disease to progress. Understanding why and what makes these B-cells so stubborn by comparing early-stage MS spinal fluid to untreated MS patient’s spinal fluid could show us a biological pathway that would guide B-cell therapies forward; this could later lead to targeted immunotherapy that follows these specific pathways to halt disease progression. 

Pioneering research in this field, the UCSF Weill Institute for Neurosciences, led by Stephen Hauser, in 2020 has successfully profiled gene activity in the CNS of MS patients to understand how exactly these B-cells promote neurodegeneration. Dr. Akshaya Ramesh, PhD, one of the study’s lead authors explains, “The success of these therapies is nearly unprecedented in medicine, but the exact role of these B cells in MS is still poorly understood, 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.”

In summation, the goal of this research was to clarify which of the roles B-cells play within the body were malfunctioning and if specific populations were causing the disease. Normally, B-cells are responsible for secreting proinflammatory cytokines/chemokines, presenting autoantigens to T cells, and producing pathogenic antibodies. While checking these functions, researchers also checked if they were acting as reservoirs for viruses that trigger demyelination of the neural cells. 

The virus hypothesis was quickly nullified as no viral transcripts were detected, including those from Epstein–Barr viruses. In an attempt to understand the other roles B-cells play, the researchers used numerous comprehensive gene profiling techniques; MS gene transcripts were compared to healthy controls to determine the differences. This was done by raw sequencing reads using IDseq, a technology that combines antibody-based protein detection and DNA-sequencing via these DNA-tagged antibodies, as well as a further calculation of Z-Score (how far the MS patients were from the average value) comparison relative to the template/un-affected CSF controls. Single-cell RNA sequencing (scRNA-Seq) was done on the CSF and blood on subjects with relapsing-remitting MS, other neurologic diseases, and healthy controls, in an attempt to explore the rest of the roles of B-Cells in a more specific way.

The second stage of the experiment was to then perform single-cell immunoglobulin sequencing on a subset of these subjects. Paired CSF and blood B cell subsets were isolated using fluorescence-activated cell sorting for bulk RNA sequencing (RNA-Seq, different from scRNA-seq). The conclusion of all three of these independent analyses was that the CSF of MS patients contained a large number of earlier activated, mature B-cells. These B-cells showed increased activation of the genetic nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways, which are both linked to inflammation and cholesterol metabolism; cholesterol metabolism plainly correlates to degeneration of the fatty-layer myelin, a key characteristic of MS. Specific cytokine and chemokine receptors (essentially what controls genetic pathway signaling to the nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways) were also up-regulated in CSF memory B cells, while SMAD/TGF-β1 signaling was also down-regulated in CSF plasmablasts/plasma cells.

Furthermore, it was found that the inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis that characterize MS were found in positive correlation with the B-cells following these overactive genetic pathways. These B-cells are clonally expanded or proliferate extensively (share an affinity with and specificity of the same parent antigen) following these pathways, increasing the reach of the disease. Surprisingly, it was found that these B-cells and similar Ig heavy-chain sequences also persisted in other patients with unrelated neurological/immune diseases. 

In addition to now knowing the pathway these B-cells follow, researchers have also been able to sequence the proteins on their surfaces. Soon what triggered MS itself in the patient will be able to be deduced. With new information about the receptor coupled with the information researchers now have about the pathways that the B-cells themselves follow, they may be able to design specifically targeted drugs. This is the difference between a ‘chemotherapy’ esque approach and a vaccine-like approach, minimizing the damage on an already injured nervous system.

Selectively depleting B cells based on the particular antigen/group of antigens would be the first opportunity to target the root cause of the disease alone. Continuing to clarify the expression of the B-cells and their subtypes may help us further understand disease pathogenesis, as well as provide disease-specific guidance on B-cell therapeutics that could be applicable to a variety of diseases even beyond MS.

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