Abstract
AbstractCircumstantial evidence suggests that B cells may instruct T cells to break tolerance. Here, to test this hypothesis, we used a murine model in which a single B cell clone precipitates an autoreactive response resembling systemic lupus erythematosus (SLE). The initiating clone did not need to enter germinal centers to precipitate epitope spreading. Rather, it localized to extrafollicular splenic bridging channels early in the response. Autoantibody produced by the initiating clone was not sufficient to drive the autoreactive response. Subsequent epitope spreading depended on antigen presentation and was compartmentalized by major histocompatibility complex (MHC). B cells carrying two MHC haplotypes could bridge the MHC barrier between B cells that did not share MHC. Thus, B cells directly relay autoreactivity between two separate compartments of MHC-restricted T cells, leading to inclusion of distinct B cell populations in germinal centers. Our findings demonstrate that B cells initiate and propagate the autoimmune response.
Funder
Novo Nordisk Fonden
Lundbeckfonden
LEO Pharma Research Foundation
Det Frie Forskningsråd
Carlsbergfondet
Danmarks Grundforskningsfond
U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases
Sean N Parker Center COVID-19 Research Fund Henry Gustav Floren Trust
EC | Horizon 2020 Framework Programme
John and Birthe Meyer Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary