Multiple Sclerosis Is Associated with Immunoglobulin Germline Gene Variation of Transitional B Cells

Area of Science:

• Immunology
• Autoimmune Diseases
• B-cell Biology

Background:

• Regulatory B cells (Breg) are vital for immune response regulation and preventing autoimmune diseases.
• Disrupted Breg anti-inflammatory functions can accelerate immunopathology, particularly in autoimmune conditions.
• The precise mechanisms, specificity, and B-cell receptor (BCR) structure of Breg cells remain largely unknown.

Purpose of the Study:

• To investigate the BCR repertoire of transitional Breg (tBreg) cells in multiple sclerosis (MS) patients.
• To identify potential differences in tBreg BCR structure between MS patients and healthy individuals.
• To explore the association between tBreg BCR repertoire variations and MS disease severity.

Main Methods:

• Utilized next-generation sequencing (NGS) to analyze the BCR repertoire of the CD19+CD24highCD38high tBreg subpopulation.
• Compared immunoglobulin germline distribution in tBreg cells from MS patients and healthy donors.
• Correlated BCR repertoire variations with clinical MS phenotypes (highly active MS vs. benign MS).

Main Results:

• Demonstrated a significant difference in immunoglobulin germline distribution within the tBreg subpopulation between MS patients and healthy controls.
• Observed a stronger variation in immunoglobulin germline distribution in highly active MS (HAMS) patients compared to benign MS (BMS) patients.
• Indicated that alterations in the Breg immunoglobulin repertoire occur early in B-cell maturation, at the transitional stage.

Conclusions:

• The study provides the first evidence of distinct BCR repertoires in tBreg cells of MS patients.
• Deviations in the Breg repertoire suggest an early role in MS pathogenesis.
• These findings highlight tBregs as a potential target for understanding and treating MS.