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Critical role of WASp in germinal center tolerance through regulation of B cell apoptosis and diversification

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Descatoire_2022_Cell_Rep_Critical_role_WASp_GC_tolerance_CC.pdf (3.244Mb)
Date
08/03/2022
Author
Descatoire, Marc
Fritzen, Remi
Rotman, Samuel
Kuntzelman, Genevieve
Leber, Xavier Charles
Droz-Georget, Stephanie
Thrasher, Adrian J.
Traggiai, Elisabetta
Candotti, Fabio
Keywords
Wiskott-Aldrich syndrome
Germinal center B cells
Autoimmunity
QH301 Biology
QR180 Immunology
DAS
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Abstract
A main feature of Wiskott-Aldrich syndrome (WAS) is increased susceptibility to autoimmunity. A key contribution of B cells to development of these complications has been demonstrated through studies of samples from affected individuals and mouse models of the disease, but the role of the WAS protein (WASp) in controlling peripheral tolerance has not been specifically explored. Here we show that B cell responses remain T cell dependent in constitutive WASp-deficient mice, whereas selective WASp deletion in germinal center B cells (GCBs) is sufficient to induce broad development of self-reactive antibodies and kidney pathology, pointing to loss of germinal center tolerance as a primary cause leading to autoimmunity. Mechanistically, we show that WASp is upregulated in GCBs and regulates apoptosis and plasma cell differentiation in the germinal center and that the somatic hypermutation-derived diversification is the basis of autoantibody development.
Citation
Descatoire , M , Fritzen , R , Rotman , S , Kuntzelman , G , Leber , X C , Droz-Georget , S , Thrasher , A J , Traggiai , E & Candotti , F 2022 , ' Critical role of WASp in germinal center tolerance through regulation of B cell apoptosis and diversification ' , Cell Reports , vol. 38 , no. 10 , 110474 . https://doi.org/10.1016/j.celrep.2022.110474
Publication
Cell Reports
Status
Peer reviewed
DOI
https://doi.org/10.1016/j.celrep.2022.110474
ISSN
2211-1247
Type
Journal article
Rights
Copyright 2022 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Description
This project was supported by grant 310030-179251 from the Suisse National Science Foundation (SNF) (to F.C.), funds from the BLACKSWAN Foundation (BSF-005) (to M.D.), and the Wellcome Trust (to A.J.T.).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/25042

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