Academic Journal
Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity
| العنوان: | Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity |
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| المؤلفون: | Zhang, Yaoyuan, Morris, Rhiannon, Brown, Grant J., Lorenzo, Ayla May D., Meng, Xiangpeng, Kershaw, Nadia J., Kiridena, Pamudika, Burgio, Gaétan, Gross, Simon, Cappello, Jean Y., Shen, Qian, Wang, Hao, Turnbull, Cynthia, Lea-Henry, Tom, Stanley, Maurice, Yu, Zhijia, Ballard, Fiona D., Chuah, Aaron, Lee, James C., Hatch, Ann-Maree, Enders, Anselm, Masters, Seth L., Headley, Alexander P., Trnka, Peter, Mallon, Dominic, Fletcher, Jeffery T., Walters, Giles D., Šestan, Mario, Jelušić, Marija, Cook, Matthew C., Athanasopoulos, Vicki, Fulcher, David A., Babon, Jeffrey J., Vinuesa, Carola G., Ellyard, Julia I. |
| المساهمون: | National Computational Infrastructure, National Collaborative Research Infrastructure Strategy, National Health and Medical Research Council, Australian Government |
| المصدر: | Journal of Experimental Medicine ; volume 221, issue 4 ; ISSN 0022-1007 1540-9538 |
| بيانات النشر: | Rockefeller University Press |
| سنة النشر: | 2024 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1084/jem.20221080 |
| DOI: | 10.1084/jem.20221080/1924734/jem_20221080.pdf |
| الاتاحة: | http://dx.doi.org/10.1084/jem.20221080 https://rupress.org/jem/article-pdf/doi/10.1084/jem.20221080/1924734/jem_20221080.pdf |
| Rights: | http://www.rupress.org/terms/ ; https://creativecommons.org/licenses/by-nc-sa/4.0/ |
| رقم الانضمام: | edsbas.7550B98C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1084/jem.20221080 |
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