T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis

Area of Science:

• Neuroimmunology
• Autoimmune Diseases
• T-cell immunology

Background:

• Multiple sclerosis (MS) pathogenesis is not fully understood due to undefined autoantigens.
• Identifying specific autoantigens is crucial for developing antigen-specific tolerance therapies.
• Understanding T-cell responses in MS can elucidate disease heterogeneity and improve clinical management.

Purpose of the Study:

• To investigate T-cell specificities in multiple sclerosis (MS) patients.
• To identify novel autoantigens targeted by T-cells in MS.
• To correlate T-cell specificities with clinical and biological features of MS.

Main Methods:

• Analyzed CD4+ T-cell proliferative responses and interferon-gamma (IFN-γ) release from cerebrospinal fluid (CSF) of MS patients against various autoantigens.
• Performed ex vivo immunophenotyping and transcriptome analysis of T-cell subsets from CSF and blood.
• Assessed CSF biomarkers of inflammation and neurodegeneration, clinical data, MRI features, and HLA class II alleles.

Main Results:

• Identified patients responding to GDP-l-fucose synthase and myelin oligodendrocyte glycoprotein (35-55) peptides.
• Observed an expansion of effector memory Th1 CD4+ T-cells in GDP-l-fucose synthase responders, with associated cytotoxicity gene expression.
• Found significant differences in biomarkers, imaging, HLA alleles, and lumbar puncture timing among patients with distinct T-cell specificities.

Conclusions:

• T-cell specificity is strongly associated with MS pathogenesis and disease heterogeneity.
• These findings support improved patient classification in clinical practice.
• The results guide the development of antigen-specific tolerization strategies for MS.