X-chromosome linked genes associated with myeloid cell CNS trafficking contributes to female–male differences in the disease outcome for neuroinflammatory diseases

Abstract

Certain diseases such as Multiple Sclerosis (MS), a chronic demyelinating disease, affect more women than men, despite males appearing to be predisposed to infections and malignancies. X-linked genes contribute to increased MS susceptibility. Currently, an immense body of research exists that explores the complexity surrounding underlying risk factors for MS development including X-chromosome-linked inflammatory processes. Female–male disparities in disease susceptibility have been found at both the gene and chromosomal level. Genes such as CXORF21 and DDX3X can escape X-chromosome inactivation (XCI) and contribute to various disease pathogenesis. Additionally, blocking immune cell entry to the central nervous system (CNS) can have a major impact on MS. Prior research on MS has shown that immune cells such as T cells and dendritic cells (DCs) infiltrate the CNS. Due to persistent tissue stress, these cells may induce local inflammation and autoimmunity, subsequent neurodegeneration, and both the onset and progression of MS. Chemokines are signaling proteins which regulate leukocyte trafficking to the site of injury, contributing to cell recruitment, CNS inflammation, and disease severity. Some chemokine receptors (CXCR3) are X-linked and may escape XCI. This review provides an account of the contribution of x-linked genes in MS in relation to the chemotaxis of myeloid cells into CNS and subsequent neuroinflammation. The impact of the X-chromosome on autoimmunity, including XCI and the expression of X-linked genes is evaluated. Collectively, the analyses from this review seek to advance both our understanding of MS and advocate for more patient-specific therapies.