Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Amit Bar-Or

Abstract

Multiple Sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), which leads to accumulating neurological disability. Available therapies can ease symptoms and may decrease new episodes of injury, but they broadly target the immune system and can lead to adverse effects. Although T cells are implicated in MS, the particular subsets and their antigenic targets remain largely unknown. Elucidating these could guide development of more selective and safer treatments. In this dissertation, we focus on pediatric-onset MS, which offers us a window of opportunity into the earliest biological events of this disease. We use a range of cell-based assays including cell culture, flow cytometry and single-cell level proteogenomic analyses to assess the phenotype and functional profiles of circulating immune cells within high quality cryopreserved peripheral blood mononuclear cells isolated from well-characterized children with MS and compare them to samples isolated from other CNS inflammatory disease controls, as well as healthy children. The research presented in this dissertation provides novel insights into early MS disease-implicated T cells and explores mechanisms by which both previously implicated, as well as newly identified cell populations may contribute to disease pathogenesis. In Chapter 2, we identify an imbalance between effector T cells and regulatory T cells as a distinguishing characteristic in children with MS and implicate a particular pro-inflammatory memory T cell subset that co-expresses the ‘CNS-homing’ CCR2 and CCR5 chemokine receptors, which is present at a higher frequency in children with MS and exhibits exaggerated pro-inflammatory responses. In Chapter 3, we evaluate spontaneous activation and antigen-specificities of T cells (including the implicated CD4 T cells) to CNS (myelin) and Epstein-Barr Virus antigens, as well as determine how these abnormal T-cell responses are impacted in patients undergoing treatment with an effective MS therapy. In Chapter 4, we explore the single cell proteogenomic profile of T cells (with a focus on the implicated CCR2+CCR5+ CD4 T cells and memory T cells more generally) and discuss the potential implication of differential expression profiles detected in cells of children with MS, as well as the more recently recognized inflammatory demyelinating condition defined by presence of circulating anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (MOG-associated disease; MOGAD). Collectively, the data in this dissertation broadens our understanding of T cell profiles and responses in these unique patient cohorts, as well as provides insights into the potential interactions with other cell types and their targets involved in early MS pathogenesis. We hope that this work will help develop better biological measures of disease state and could ultimately lead to the development of potentially novel biomarkers and therapeutic targets.

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