Header

UZH-Logo

Maintenance Infos

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.

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.

Statistics

Citations

Dimensions.ai Metrics
18 citations in Web of Science®
18 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

20 downloads since deposited on 06 Dec 2018
20 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Gastroenterology and Hepatology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:General Biochemistry, Genetics and Molecular Biology
Language:English
Date:1 September 2018
Deposited On:06 Dec 2018 13:48
Last Modified:13 Feb 2019 11:32
Publisher:Cell Press (Elsevier)
ISSN:0092-8674
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.cell.2018.08.011
PubMed ID:30173916

Download

Download PDF  'Memory B Cells Activate Brain-Homing, Autoreactive CD4+ T Cells in Multiple Sclerosis'.
Preview
Content: Published Version
Filetype: PDF
Size: 12MB
View at publisher
Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)