Twin study dissects CXCR3⁺ memory B cells as non-heritable feature in multiple sclerosis

Area of Science:

• Immunology
• Neuroimmunology
• Genetics

Background:

• Multiple sclerosis (MS) pathogenesis involves B cells, influenced by genetic and environmental factors.
• Monozygotic twin studies offer a unique model to dissect these complex interactions.
• Identifying specific B cell subsets affected by non-heritable factors is crucial for understanding MS.

Purpose of the Study:

• To analyze B cell subset differences in monozygotic twins discordant for MS.
• To investigate the functional characteristics and therapeutic modulation of identified B cell subsets.
• To explore the role of these B cells in MS pathogenesis.

Main Methods:

• Analysis of B cell subsets in blood samples from monozygotic twins with and without MS.
• Utilized publicly available datasets for B cell subset analysis.
• Verified functional characteristics by examining therapy effects and analyzing unrelated individuals.

Main Results:

• Frequencies of CXCR3+ memory B cells were significantly reduced in MS-affected twins compared to their healthy siblings.
• Treatment with natalizumab (anti-VLA-4 antibody) was associated with the reversal of these reduced frequencies.
• CXCR3+ memory B cells exhibit CNS-homing potential, evidenced by elevated CXCL10 in MS cerebrospinal fluid and in vitro differentiation into antibody-secreting cells.

Conclusions:

• Circulating CXCR3+ memory B cells are influenced by non-heritable environmental factors in individuals who develop MS.
• Environmental triggers, such as Epstein-Barr virus, are implicated in the activation of these B cells.
• CXCR3+ memory B cells may enter the CNS via CXCL10, differentiate into antibody-secreting cells, and contribute to MS.