Annals of clinical and translational neurology · 2026
Innate Immune Reprogramming Mediated by Endogenous Retroelement Dysregulation Drives Multiple Sclerosis Progression.
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Xiao Li-Mei, Zhao Qiu-Ping, Li Run-Yun, Chen Wei, Song Huan-Huan, Chen Wan-Jin, Fu Ying
Аннотация
BACKGROUND: Skewed myelopoiesis in the bone marrow has been identified as a key driver of multiple sclerosis (MS) progression. Interestingly, SARS-CoV-2 infection, which has a severe impact on MS patients, can also induce similar skewed myelopoiesis. This shared phenotype raises the question of whether a common mechanism underlies the skewed myelopoiesis in both diseases. Previous studies in mice have demonstrated that the dysregulation of endogenous retroelements (EREs) in HSPCs leads to skewed myelopoiesis. Building on this, we sought to determine whether ERE dysregulation contributes to the skewed myelopoiesis observed in MS and after COVID-19, which remains challenging.
METHODS: We undertook a joint investigation of two public single-cell/nuclei cohorts respectively representing MS and following COVID-19. Both cohorts were processed through an identical bioinformatic pipeline to ensure comparable assessment of gene and ERE expression.
RESULTS: We observed enhanced myelopoiesis in the bone marrow of MS patients compared to healthy controls, along with downregulation of the ERE repressor H3.3 and concomitant EREs overexpression. Notably, a similar epigenetic and transcript feature was found in post-COVID-19 individuals.
CONCLUSION: The H3.3low/EREhigh signature may not only explain the common skewed myelopoiesis in MS and post-COVID-19 conditions, but also provide a mechanistic link between infection and the innate immune reprogramming that drives MS progression. This offers a novel therapeutic insight for MS.
METHODS: We undertook a joint investigation of two public single-cell/nuclei cohorts respectively representing MS and following COVID-19. Both cohorts were processed through an identical bioinformatic pipeline to ensure comparable assessment of gene and ERE expression.
RESULTS: We observed enhanced myelopoiesis in the bone marrow of MS patients compared to healthy controls, along with downregulation of the ERE repressor H3.3 and concomitant EREs overexpression. Notably, a similar epigenetic and transcript feature was found in post-COVID-19 individuals.
CONCLUSION: The H3.3low/EREhigh signature may not only explain the common skewed myelopoiesis in MS and post-COVID-19 conditions, but also provide a mechanistic link between infection and the innate immune reprogramming that drives MS progression. This offers a novel therapeutic insight for MS.