Escape From X Chromosome Inactivation as a Driver of Plasmacytoid DC Heterogeneity in Health and Disease

Decades of experimental work have helped define the heterogeneity of the various cell types that compose the immune system. The different cell types arise from distinct hematopoietic stem and progenitor cells in a coordinated fashion during ontogeny, providing a set of diverse cells that contribute to host defense. Cells can also differentiate into different subsets in response to the cytokine and tissue environment, creating a level of cellular heterogeneity that helps direct the nature and magnitude of the immune response. Here we are discussing a variation whereby cellular heterogeneity arises due to the expression of X-linked immune genes that escape X chromosome inactivation, giving an advantage to a subset of cells more prone to respond to stimulation by external (pathogens) but also internal signals (i.e., mechanosensing). Interestingly, these inflammatory subsets are much more likely to be differentially enriched in patients with autoimmunity or inflammatory diseases which are well known to be predominant in females. We are using plasmacytoid dendritic cells (pDCs) as a model cell type, as these cells are a rare but critical subset of innate immune cells, with a rapid and massive capacity to produce type I IFNs (IFN-I) upon sensing of nucleic acids from pathogens, but also from the self, and these cells have been linked to the pathogenesis of many autoimmune diseases.