Zhang, Yaoyuan;
Morris, Rhiannon;
Brown, Grant J;
Lorenzo, Ayla May D;
Meng, Xiangpeng;
Kershaw, Nadia J;
Kiridena, Pamudika;
... Ellyard, Julia I; + view all
(2024)
Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity.
Journal of Experimental Medicine
, 221
(4)
, Article e20221080. 10.1084/jem.20221080.
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Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.
| Type: | Article |
|---|---|
| Title: | Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1084/jem.20221080 |
| Publisher version: | http://dx.doi.org/10.1084/jem.20221080 |
| Language: | English |
| Additional information: | © 2024 Zhang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
| Keywords: | Autoimmunity, Lymphocyte biology, Tolerance |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10188531 |
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