Memory B Cells Activate Brain-Homing, Autoreactive CD4⁺ T Cells in Multiple Sclerosis

Area of Science:

• Neuroimmunology
• Autoimmunity
• Immunogenetics

Background:

• Multiple sclerosis (MS) is an autoimmune disease resulting from genetic and environmental factors.
• The precise mechanisms by which these factors generate autoreactive T cells remain unclear.
• The HLA-DR15 haplotype is a significant genetic risk factor for MS.

Purpose of the Study:

• To investigate the role of HLA-DR15 in T cell autoreactivity in multiple sclerosis.
• To elucidate the involvement of B cells in T cell self-reactivity.
• To identify specific autoantigens targeted in MS.

Main Methods:

• Assessed T cell autoproliferation in patients with the HLA-DR15 haplotype.
• Investigated B cell mediation of T cell autoproliferation in a HLA-DR-dependent manner.
• Utilized anti-CD20 therapy to deplete B cells and observed its effect on T cell autoproliferation.
• Employed T cell receptor deep sequencing to characterize autoproliferating T cells.
• Used unbiased epitope discovery to identify target autoantigens.

Main Results:

• T cell autoproliferation was elevated in patients carrying the HLA-DR15 haplotype.
• Memory B cells mediated T cell autoproliferation in a HLA-DR-dependent manner.
• Anti-CD20 treatment reduced T cell autoproliferation both in vitro and in vivo.
• Autoproliferating T cells were enriched for brain-homing phenotypes.
• RASGRP2 was identified as a target autoantigen expressed in the brain and B cells.

Conclusions:

• The HLA-DR15 haplotype is associated with increased T cell self-reactivity in MS, mediated by B cells.
• B cell depletion, particularly with anti-CD20, can reduce T cell autoproliferation.
• RASGRP2 represents a potential autoantigen target in MS pathogenesis.
• These findings offer insights into pathogenic B-T cell interactions and potential therapeutic strategies for MS.