Innate Immune Reprogramming Mediated by Endogenous Retroelement Dysregulation Drives Multiple Sclerosis Progression

Area of Science:

• Immunology
• Genetics
• Neurology

Background:

• Skewed myelopoiesis is a key driver of multiple sclerosis (MS) progression.
• SARS-CoV-2 infection can induce myelopoiesis similar to that seen in MS.
• Dysregulation of endogenous retroelements (EREs) in hematopoietic stem and progenitor cells (HSPCs) can cause skewed myelopoiesis.

Purpose of the Study:

• To investigate if ERE dysregulation contributes to skewed myelopoiesis in MS and post-COVID-19.
• To identify common mechanisms underlying skewed myelopoiesis in both conditions.

Main Methods:

• Joint analysis of two public single-cell/nuclei cohorts (MS and post-COVID-19).
• Application of an identical bioinformatic pipeline for gene and ERE expression assessment.

Main Results:

• Enhanced myelopoiesis observed in MS patients compared to controls.
• Downregulation of the ERE repressor H3.3 and overexpression of EREs found in MS.
• Similar epigenetic and transcript features identified in post-COVID-19 individuals.

Conclusions:

• The H3.3 low/ERE high signature may explain common skewed myelopoiesis in MS and post-COVID-19.
• This signature provides a mechanistic link between infection and innate immune reprogramming in MS.
• Offers novel therapeutic insights for MS progression.