Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Jelcic I

PROVIDER: S-EPMC6191934 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Publications

Memory B Cells Activate Brain-Homing, Autoreactive CD4<sup>+</sup> T Cells in Multiple Sclerosis.

Jelcic Ivan I Al Nimer Faiez F Wang Jian J Lentsch Verena V Planas Raquel R Jelcic Ilijas I Madjovski Aleksandar A Ruhrmann Sabrina S Faigle Wolfgang W Frauenknecht Katrin K Pinilla Clemencia C Santos Radleigh R Hammer Christian C Ortiz Yaneth Y Opitz Lennart L Grönlund Hans H Rogler Gerhard G Boyman Onur O Reynolds Richard R Lutterotti Andreas A Khademi Mohsen M Olsson Tomas T Piehl Fredrik F Sospedra Mireia M Martin Roland R

Cell 20180830 1

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<sup>+</sup> 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 ...[more]

PMID: 30173916

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Project description:Cell-permeable formulations of metabolites, such as fumaric acid esters, have been used as highly effective immunomodulators in patients with multiple sclerosis and yet their mechanism of action remains elusive. Since fumaric acid esters are metabolites, and cell metabolism is highly intertwined with the epigenetic regulation of gene expression, we investigated whether this metabolic-epigenetic interplay could be leveraged for therapeutic purposes. To this end we recruited 47 treatment-naïve and 35 fumaric acid ester-treated patients with multiple sclerosis, as well as 16 glatiramer acetate-treated patients as a non-metabolite treatment control. Here we identify a significant immunomodulatory effect of fumaric acid esters on the expression of the brain-homing chemokine receptor CCR6 in CD4 and CD8 T cells of patients with multiple sclerosis, which include T helper-17 and T cytotoxic-17 cells. We report differences in DNA methylation of CD4 T cells isolated from untreated and treated patients with multiple sclerosis, using the Illumina EPIC 850K BeadChip. We first demonstrate that Krebs cycle intermediates, such as fumaric acid esters, have a significantly higher impact on epigenome-wide DNA methylation changes in CD4 T cells compared to amino-acid polymers such as glatiramer acetate. We then define a fumaric acid ester treatment-specific hypermethylation effect on microRNA MIR-21, which is critical for the differentiation of T helper-17 cells. This hypermethylation effect was attributed to the subpopulation of T helper-17 cells using a decomposition analysis and was further validated in an independent prospective cohort of seven patients before and after treatment with fumaric acid esters. In vitro treatment of CD4 and CD8 T cells with fumaric acid esters supported a direct and dose-dependent effect on DNA methylation at the MIR-21 promoter. Finally, the upregulation of miR-21 transcripts and CCR6 expression was inhibited if CD4 or CD8 T cells stimulated under T helper-17 or T cytotoxic-17 polarizing conditions were treated with fumaric acid esters in vitro. These data collectively define a direct link between fumaric acid ester treatment and hypermethylation of the MIR-21 locus in both CD4 and CD8 T cells and suggest that the immunomodulatory effect of fumaric acid esters in multiple sclerosis is at least in part due to the epigenetic regulation of the brain-homing CCR6+ CD4 and CD8 T cells.

Dataset Information

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

Publications

Memory B Cells Activate Brain-Homing, Autoreactive CD4<sup>+</sup> T Cells in Multiple Sclerosis.

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Dataset Information

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

Publications

Memory B Cells Activate Brain-Homing, Autoreactive CD4<sup>+</sup> T Cells in Multiple Sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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