Monocyte Macrophage Biomarkers of Multiple Sclerosis in an Underrepresented Minority Population

Multiple Sclerosis (MS) is an autoimmune, inflammatory disease of the central nervous system and is one of the most common causes of neurological disability in young adults. Historically, this disease was predominantly studied in White individuals of European ancestry because of high disease prevalence in these populations. However, more recent work suggested Black American woman have the highest incidence of MS in the United States. In addition, Black and Hispanic Americans are at increased risk of developing more severe neurological disability. The work for this thesis focused on identification of differential DNA methylation and transcriptomics of peripheral myeloid cells because these biomarkers may best reflect the impact of environment determinants. Donor samples were from the UI Health Neuroimmunology Biobank, and approximately 55% of donors identify as Black or African American and 25% as Hispanic or Latino. Analysis of differential expression of mRNA splice variants in human macrophages revealed that splice variants of ATP5MPL, HSP90B1, PPP1R10, and SCN10A were associated with MS. These genes regulate cellular stress responses, and ATP5MPL and SCN10A were further characterized in their regulatory roles of mitochondrial respiration. Whole blood methylomic analysis of differential DNA methylation identified novel biomarkers of MS and revealed associations with pathways that regulate cellular proliferation and differentiation and host responses to GI pathogens. Single cell RNAseq analysis of human macrophages showed expansion of a potentially proinflammatory cellular subset in MS. Taken together, these results suggest novel mechanisms of MS pathogenesis that may increase the risk of severe forms of MS. The working model is that environmental regulators of cellular stress in myeloid cells mediate epigenetic modifications that lead to chronic inflammatory activation of macrophages and increased risk of disease susceptibility and severe clinical phenotypes of MS.