Intrathecal B cells in multiple sclerosis

Abstract

Multiple sclerosis is a chronic, inflammatory, neurodegenerative disease that affects the central nervous system and has no known cure. The pathology of the disease is characterized by immune cell infiltration of the central nervous system, and B cells seem to play a significant role in this process. B cells have been shown to form tertiary lymphoid structures in the meninges; they may produce cytokines and neurotoxic factors and could act as antigen-presenting cells and activate pathogenic T cells. B cells are also known to differentiate into antibody-secreting cells that produce intrathecal IgG, a hallmark of MS. The main goal of this thesis was to gain insights into the mechanisms underlying B-cell responses in treated and treatment-naïve multiple sclerosis patients. To this end, we characterized the B-cell receptor repertoire, clonal relationships, and transcriptional profiles of B-lineage cells found in the cerebrospinal fluid of multiple sclerosis patients. Utilizing single-cell full-length mRNA sequencing, we conducted a detailed study of B-lineage cells, dissecting their phenotypes and revealing specific patterns of paired heavy- and light-chain gene usage. Next, by combining sequencing data with mass spectrometry analysis of IgG from the same patients, we found that the intrathecal IgG-producing B cells are heterogeneous and include highly proliferating and more differentiated cells primarily focused on immunoglobulin production. Finally, we also examined the B cell composition and phenotypes in the cerebrospinal fluid of multiple sclerosis treated with dimethyl fumarate. Our results support the theory that memory B cells are a potential mechanistic target of dimethyl fumarate. This work sheds light on the role of B cells in the context of the intrathecal immunoglobulin repertoire in multiple sclerosis. It also discusses the consequences of our results in light of immunomodulatory treatment options for patients suffering from multiple sclerosis.