Identifying novel soluble biomarkers in relapsing-remitting multiple sclerosis

Blandford, Stephanie Nicole (2022) Identifying novel soluble biomarkers in relapsing-remitting multiple sclerosis. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Relapsing-remitting multiple sclerosis (RRMS) is a chronic immune-mediated inflammatory disease characterized by central nervous system (CNS) demyelination and axonal damage. Under current guidelines, a multiple sclerosis (MS) diagnosis most often occurs over the course of months and requires clinical assessment, magnetic resonance imaging (MRI), and a lumbar puncture. While clinically useful diagnostic, prognostic, and disease monitoring biomarkers do exist, they share commonalities with many other autoimmune and/or neurodegenerative disorders. As a result, this process leaves patients waiting for critical healthcare services. The objective of this thesis is to identify novel candidate biomarkers in blood plasma of MS patients and elucidate pathophysiological disease mechanisms in RRMS. Blood plasma represents an accessible body fluid harboring many immune-related molecules that may inform on RRMS disease status and ongoing systemic pathological mechanisms. In this thesis, interleukin-1 receptor antagonist (IL-1RA) was identified as a plasma-based biomarker for increased disability in RRMS that is released from macrophages and microglia in active areas of lesions during activation of an inflammasome. Blood plasma of RRMS cases was also used to investigate the patterns of circulating extracellular vesicles (EVs). It was determined that RRMS cases have higher levels of immune cell derived EVs in circulation compared to healthy controls, and that this was unrelated to numbers of circulating parent cell populations. Finally, cerebrospinal fluid samples were analysed for 27 cytokines, and identified few differences in RRMS compared to non-inflammatory neurological disease controls. CXCL10 levels were significantly increased but were not associated with its most welliii known function of immune cell chemotaxis. Instead, an alternative pathological mechanism whereby CXCL10 leads to downregulation of glutamate transporters on astrocytes was identified. This thesis highlights the wealth of information to be gained from studying body fluid-based biomarkers of ongoing inflammatory activity in RRMS and identifies three exploratory biomarkers for which future studies will be based on. These future works should focus on determining the sensitivity and specificity of these molecules in MS prospectively, longitudinally and across the disability and disease spectrum. Furthermore, future studies will work any functional mechanisms that are modulated by IL-1RA, immune cell derived EVs and CXCL10.

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