Immune dysfunction contributes to comorbid depression in patients with multiple sclerosis

Area of Science:

• Neuroimmunology
• Genetics
• Immunology

Background:

• Depression affects 30% of multiple sclerosis (MS) patients, worsening outcomes.
• The immunopathogenesis of MS-associated depression is not well understood.
• Investigating immune dysfunction in MS depression using integrated genomic and single-cell data.

Purpose of the Study:

• To explore the genetic correlation and potential causal links between MS and depression.
• To identify shared genetic loci and immune pathways involved in both conditions.
• To characterize immune cell phenotypes and functions in MS patients with and without depression.

Main Methods:

• Genome-wide association study (GWAS) summary statistics from MS and depression cohorts.
• Linkage disequilibrium score regression (LDSC), Mendelian randomization (2SMR), and multi-trait analysis of GWAS (MTAG).
• Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from MS patients.

Main Results:

• Significant positive genetic correlation found between MS and depression (rg=0.108, P=0.035).
• Shared genetic loci identified in the MHC region, enriched for antigen processing/presentation pathways.
• Expansion of GZMB+ effector CD8+ T cells observed in MS with depression, targeting neuronal antigen 5-HT1F via HLA-B.

Conclusions:

• Integrative evidence suggests CD8+ T cell-mediated targeting of 5-HT1F-expressing neurons underlies depression in MS.
• Highlights a potential neuroimmune mechanism contributing to MS-associated depression.
• Supports further investigation into T cell-mediated autoimmunity in the context of MS and depression.