Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity

Zhang, Y; Morris, R; Brown, GJ; Lorenzo, AMD; Meng, X; Kershaw, NJ; Kiridena, P; Burgio, G; Gross, S; Cappello, JY; Shen, Q; Wang, H; Turnbull, C; Lea-Henry, T; Stanley, M; Yu, Z; Ballard, FD; Chuah, A; Lee, JC; Hatch, AM; Enders, A; Masters, SL; Headley, AP; Trnka, P; Mallon, D; Fletcher, JT; Walters, GD; Šestan, M; Jelušić, M; Cook, MC; Athanasopoulos, V; FULCHER, DA; Babon, JJ; Vinuesa, CG; Ellyard, JI

Author(s): Zhang, Y; Morris, R; Brown, GJ; Lorenzo, AMD; Meng, X; Kershaw, NJ; Kiridena, P; Burgio, G; Gross, S; Cappello, JY; Shen, Q; Wang, H; Turnbull, C; Lea-Henry, T; Stanley, M; Yu, Z; Ballard, FD; Chuah, A; Lee, JC; Hatch, AM; Enders, A; Masters, SL; Headley, AP; Trnka, P; Mallon, D; Fletcher, JT; Walters, GD; Šestan, M; Jelušić, M; Cook, MC; Athanasopoulos, V; FULCHER, DA; Babon, JJ; Vinuesa, CG; Ellyard, JI;
Details: Publication Year 2024-04-01,Volume 221,Issue #4,Page e20221080
Journal Title: Journal of Experimental Medicine
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.
Publisher: Rockefeller University Press
Keywords: Animals; Humans; Mice; *Autoimmunity/genetics; B-Cell Activating Factor/metabolism; B-Lymphocytes; *Lupus Erythematosus, Systemic/genetics; Precursor Cells, B-Lymphoid
Research Division(s): Inflammation; Structural Biology; Blood Cells And Blood Cancer
PubMed ID: 38417019
Publisher's Version: https://doi.org/10.1084/jem.20221080
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-03-04 01:53:21

Last Modified: 2024-03-04 01:56:12