T-bet+ CXCR3+ B cells drive hyperreactive B-T cell interactions in multiple sclerosis

Area of Science:

• Immunology
• Neuroscience
• Pathogenesis of Autoimmune Diseases

Background:

• Multiple sclerosis (MS) is a chronic autoimmune disease targeting the central nervous system (CNS).
• Self-peptide-dependent autoproliferation (AP) of B and T cells is a critical factor in MS pathogenesis.
• Understanding the cellular interactions driving MS is essential for developing targeted therapies.

Purpose of the Study:

• To investigate the role of B and T cell clusters in the autoproliferation (AP) process during MS.
• To identify specific B cell subsets involved in sustaining T cell responses in MS.
• To elucidate the mechanisms by which B cells contribute to CNS inflammation in MS.

Main Methods:

• Analysis of pro-inflammatory B-T cell-enriched cell clusters (BTECs) formed during AP.
• Characterization of T-bet+CXCR3+ B cells and their interaction with Th1 cells.
• Assessment of epigenetic modifications and receptor-ligand interactions in B cells.
• Evaluation of B cell clonal evolution and gene expression profiles, including interferon-gamma (IFN-γ) related genes.

Main Results:

• Pro-inflammatory BTECs, mirroring germinal center reactions, form during B and T cell AP in MS.
• T-bet+CXCR3+ B cells were identified as a key subset amplifying and sustaining Th1 cell responses via IFN-γ.
• These T-bet+CXCR3+ B cells are prevalent in inflamed meningeal tissue and exhibit epigenetic changes and receptor-ligand interactions with self-reactive T cells.
• AP+ CXCR3+ B cells demonstrated significant clonal evolution, progressing from memory cells to somatically hypermutated plasmablasts with increased IFN-γ gene expression.

Conclusions:

• T-bet+CXCR3+ B cells play a significant role in MS pathogenesis within both the peripheral immune system and the CNS.
• These B cells are implicated in both early relapsing-remitting MS and the chronic progressive stages of the disease.
• Targeting T-bet+CXCR3+ B cells may offer a therapeutic strategy for multiple sclerosis.