Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis
Article
Jelcic, I, Al Nimer, F, Wang, J et al. (2018). Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis
. 175(1), 85-100.e23. 10.1016/j.cell.2018.08.011
Jelcic, I, Al Nimer, F, Wang, J et al. (2018). Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis
. 175(1), 85-100.e23. 10.1016/j.cell.2018.08.011
Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies. Memory B cells drive proliferation of self-reactive brain-homing CD4+ T cells, which recognize autoantigens expressed in B cells and in brain lesions with target potential in multiple sclerosis.
