Single-Cell RNA-Seq and Clonal Analysis of B Cells in MS
Abstract
Multiple sclerosis (MS) is a chronic neurological disease that often begins in early adulthood and is now known to affect over 600,000 people in the U.S. and over 2.3 million people worldwide. MS is believed to be the result of an immune attack on the central nervous system (CNS) myelin sheath. B cells are a subset of blood lymphocytes that are highly implicated in the development of MS attacks. B cells are characterized by the CD20 marker. Two FDA-approved therapies that lyse cells bearing CD20 (ocrelizumab and ofatumumab) have a profound benefit on relapsing-remitting MS (RRMS) by significantly reducing relapses and MRI activity, and reduce disability progression in primary progressive MS (PPMS). This proposal is trying to study which B cells are causing pathology in MS, the targets of these B cells, and what makes these cells different in MS. This study is relevant because identifying the specific B cells causing MS disease would give us a more specific target for treatments. Elucidating B cells exact roles in MS might open a new personalized therapeutic approach to patients with MS. B cells in the spinal fluid, the colorless body fluid found in the brain and spinal cord, are the cells that are more likely to cause disease. Our preliminary data support this by showing differences in B cell composition in the spinal fluid and blood of people with MS. This project aims to analyze individual B cells in people with MS to determine differences between the blood and the spinal fluid and between brain tissue of people who died with MS and people with other neurological diseases who died of other causes. The data that I have accumulated, confirming that inflammatory B cells are found in the spinal fluid of people with MS. In contrast, healthy people do not have them. To address these aims, I will use advanced technologies to analyze B cells in people with MS, clues to what activates and sustains the immune response in MS. Further, I will also study the complementarity-determining regions (CDRs). CDRs are crucial for recognizing toxins or other foreign substances, which induce an immune response in the body, especially the production of antibodies. Our goal is to understand the early-stage pathogenic B cell population in the blood that are similar to B cells found in the spinal fluid and brain lesions of people with MS and find new therapeutic targets to block them in the periphery. While effective anti-CD20 therapies have been approved for RRMS and PPMS, the B cell pathological roles and functions still need to be understood. A better understanding of B cell sub-populations in people with MS, particularly in the relevant body compartment (for example, spinal fluid and brain), is vital to develop more effective and better targeted B cell depletion strategies. Cutting-edge experimental methods, combined with this proposal s aims, will be applied to discover new B cell molecules to be used as a potential target for therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110672
Entities
People
- Claudia Cantoni
Organizations
- United States Army
- Washington University in St. Louis