Master of Science
Microbiology and Immunology
Kerfoot, Steven M.
While the role of autoimmune T cells has been extensively studied in anti-myelin
autoimmunity, little is known about the function of B cells in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). B cells form clusters with T cells in the meninges directly adjacent to demyelinating lesions. Previous studies have shown that disease progression is dependent on the depletion of specific populations of B cells, but it is not clear which contributes to pathology or how. The purpose of this thesis is to characterize the population of meningeal B cells to determine how they differ from other subsets, with the goal to identify potential pathogenic functions in a murine model of anti-myelin autoimmunity. Single-cell profiling of cells found in the CNS suggests that mature meningeal B cells upregulate interferon-induced genes and downregulate genes associated with MHC Class II molecules compared to naive follicular B cells. Characterizing the inflammatory and regulatory properties of individual B cell subsets will inform pathogenic B cell population targets in MS and other autoimmune diseases with similar B cell profiles.
Summary for Lay Audience
The immune system is composed of white blood cells (WBCs) that protect the body against harmful substances. B cells and T cells belong to a group of WBCs that recognize and mount targeted immune responses against antigens that are uniquely recognized by them. There are several mechanisms used by the body to eliminate or inactivate T and B cells that recognize self-antigen. If self-reactive B and T cells escape elimination, they can become activated and cause autoimmune disease in which the body mistakenly attacks healthy cells. MS is an autoimmune disease that affects the brain and spinal cord and results in ongoing inflammation, tissue damage, and loss of proper nerve function. Although damage is primarily driven by T cells that attack the myelin sheath surrounding neurons, B cells was found to be important in disease pathogenesis. A common and effective treatment for people affected by MS involves targeting a subset of mature B cells. However, of the many B cell subpopulations, it is not clear which contributes to MS pathology or how. B cells may present antigens to activate T cells, secrete molecules that increase inflammation and/or produce antibodies that attack the body. The purpose of this thesis is to characterize how B cells found in the spinal cord differ from B cells found in the lymph node that have not yet been activated by analyzing their gene expression profile, with the goal to identify potential pathogenic functions. Sequencing technologies used to study the genes expressed by individual B cells in a mouse model of MS led to the discovery that B cells in the spinal cord upregulate genes that mitigate inflammation and downregulate genes that are involved in antigen-presentation.
Chowdhury, Lika, "Characterizing the Function of B Cells that Accumulate in the Inflamed Central Nervous System in Anti-Myelin Autoimmunity" (2022). Electronic Thesis and Dissertation Repository. 9140.
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