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

Background One of the major challenges in addressing multiple sclerosis is to understand its progression trajectory. The pathological process transitions from acute phases predominantly driven by inflammation to progressive clinical profiles where neurodegeneration takes precedence. The factors mediating this heterogeneity remain unresolved. However, it is known that sex plays a crucial role; females are two to three times more likely to suffer from multiple sclerosis, while males suffer from more rapid neurodegeneration with greater severity. Results We profiled 48,919 central nervous system and 336,934 peripheral immune cells, covering the multiple sclerosis spectrum. We generated cell-type specific landscapes, including gene signatures from differentially expressed genes, functional profiling, pathway activation, and cell-cell communication networks for females, males, and their sex differential profiles. Among our findings, we revealed that female neurons may exhibit protective mechanisms against neurodegeneration. 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 progressive forms, with males exhibiting cytolytic profiles that may promote neurodegeneration. Complete results can be explored in the user-friendly interactive webtool https://bioinfo.cipf.es/cbl-atlas-ms/. Conclusions We identified cell-type specific sex differences in brain and immune cells that vary in the spectrum of multiple sclerosis progression. We consider this molecular description of sex differences to be valuable resources to promote future targeted approaches to specific molecular mechanisms considering the sex of the individual.