The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by...

Area of Science:

• Neuroimmunology
• Molecular Genetics
• Autoimmune Diseases

Background:

• Multiple Sclerosis (MS) is an autoimmune disorder impacting the central nervous system.
• Current MS therapies often target peripheral blood cells.
• Previous work identified low expression of EOMES and TBX21 (ET) transcription factors in MS blood.

Purpose of the Study:

• To replicate and validate the observation of low ET gene expression in a new MS cohort.
• To investigate the heritability and longitudinal stability of this molecular phenotype.
• To explore correlations between ET expression, immune cell subsets, genetic risk factors, and treatment responses in MS.

Main Methods:

• Gene expression analysis in blood samples from MS patients and controls.
• Longitudinal assessment of ET expression over time.
• Correlation analysis with immune cell populations (e.g., CD56+ cells).
• Genotyping for MS risk SNPs (EOMES, TBX21, HLA-DRB1*1501) and EBNA-1 antibody titers.
• Analysis of ET expression changes in response to various MS therapies (natalizumab, glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate).

Main Results:

• Low ET gene expression was replicated in a new MS cohort with statistical significance.
• ET expression demonstrated significant longitudinal stability and high heritability (h(2)=0.48 for EOMES).
• Genes correlated with ET expression were involved in cell migration, further defining the MS phenotype.
• Lower Eomes or T-bet protein levels and/or under-representation of CD56+ cells were observed in MS.
• ET expression correlated with HLA-DRB1*1501 genotype but not with EOMES/TBX21 risk SNPs or EBNA-1 titers.
• Natalizumab normalized ET expression to healthy control levels, while other therapies showed variable effects.

Conclusions:

• Low, stable, and heritable ET gene expression is a validated molecular phenotype in MS.
• This phenotype is associated with specific immune cell subset alterations and genetic factors (HLA-DRB1*1501).
• Therapeutic responses regarding ET expression vary, with natalizumab showing normalization and others exhibiting variability.