Like most autoimmune diseases, multiple sclerosis (MS), is more prevalent in women than men, thought to be due to more robust immune responses in women. The effects of sex hormones on the immune response have been extensively studied by our lab and others, but effects of sex chromosomes are widely unknown. Sex chromosomes can elicit gene expression differences between males and females via expression of Y genes, X gene dosage effects, or parent-of-origin differences in DNA methylation of X genes, also called parental imprinting. We previously showed that sex chromosomes modulate immune responses in the animal model of MS experimental autoimmune encephalomyelitis (EAE), however, the mechanisms remained unknown. Chapter 2 of this dissertation identified parent-of-origin differences in DNA methylation of X chromosome genes as a mechanism by which sex chromosomes alter gene expression in immune cells. Through a series of RNA sequencing experiments using the "four core genotypes" model, we discovered a cluster of X genes with higher expression in XY than XX genotypes in CD4+ T lymphocytes. Additionally, DNA methylation studies in X monosomic mice revealed parent-of-origin differences in DNA methylation in which the paternal X is hypermethylated compared to the maternal X and autosomes, which is consistent with higher expression of X genes in XY compared to XX. This work demonstrated how parental imprinting of X chromosome genes can lead to sex differences in gene expression during immune responses. While women are more susceptible to MS, disability progression tends to be worse in men, thought to be due to a more neurodegenerative response to immune attack. This identifies males as a superior target for understanding mechanisms of neurodegeneration. In Chapter 3 of this dissertation, I take a cell-specific and region-specific gene expression approach to investigate the neurodegenerative response in the hippocampus during injury. Through transcriptomics studies in hippocampal astrocytes, I found upregulated expression of genes involved in MHC class I (MHC I) signaling. Since MHC I has an important role in synaptic plasticity, I hypothesize that astrocyte MHC I signals to microglia and neurons to induce aberrant synaptic pruning in adult mice with disease (EAE). I will test this hypothesis with time- and cell-specific conditional knock out of B2m to reduce MHC I cell surface expression in astrocytes during EAE. Additional studies utilizing gonadectomy will determine the effects of sex hormones on MHC I gene expression. Together, these projects seek to fundamentally understand complex mechanisms in MS susceptibility and progression, and how sex affects these aspects of disease. Further understanding of these mechanisms may lead to identifying natural disease modifiers and new translatable targets for neuroinflammatory therapeutics.