Single cell landscape of sex differences in the progression of multiple sclerosis

One of the major challenges in addressing multiple sclerosis is to understand the progression trajectory of patients. The pathological process evolves from acute phases predominantly driven by inflammation transitioning to progressive profiles where neurodegeneration takes precedence. It remains unresolved why this course is highly heterogeneous among patients. Currently we know that sex variable plays a crucial role in its understanding. Females are 2-3 times more likely to suffer from multiple sclerosis while males progression is faster with greater severity. We investigate the potential molecular mechanisms underlying these sex-differential clinical traits analysing transcriptomic data at single cell resolution. 48,919 central nervous system and 336,934 peripheral immune cells, covering the multiple sclerosis spectrum, enabled us to provide the comprehensive landscape of sex differences by cell type. This includes signatures in gene expression patterns, functional profiling, pathways activation and cell-cell communication networks for females, males and their sex-differential profiles. Complete results can be explored in the user-friendly interactive webtool https://bioinfo.cipf.es/cbl-atlas-ms/. Among these findings, we unveiled that female neurons may exhibit protective mechanisms against excitotoxicity, glial cells dysregulated widely stress response genes in a sex-differential manner, and female oligodendrocytes increase expression of axon-myelin contact genes suggesting strong potential for myelin recovery. In the inflammatory-predominant forms, female immune cells present an inflammatory core driven by the AP-1 transcription factor, while male adaptive immune cells exhibit higher mitochondrial impairment. Conversely, larger differences are reported in CD8+ T cells, with females displaying homeostasis recovery patterns and males exhibiting cytolytic profiles. We consider that the molecular description of sex differences in multiple sclerosis progression may be a valuable resource for prevention and diagnosis through biomarker research and the development of personalised therapeutic strategies.