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

Autor:	Zhang Y; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Morris R; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Brown GJ; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Lorenzo AMD; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Meng X; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Kershaw NJ; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Kiridena P; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Burgio G; Division of Genome Sciences and Cancer, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Gross S; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Cappello JY; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Shen Q; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Francis Crick Institute , London, UK., Wang H; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Francis Crick Institute , London, UK., Turnbull C; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Lea-Henry T; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; The Canberra Hospital , Garran, Australia., Stanley M; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Yu Z; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Ballard FD; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Chuah A; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Lee JC; Francis Crick Institute , London, UK.; Department of Gastroenterology, Division of Medicine, Institute for Liver and Digestive Health, University College London, London, UK., Hatch AM; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; The Canberra Hospital , Garran, Australia., Enders A; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Masters SL; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Headley AP; Concord Repatriation General Hospital , Concord, Australia., Trnka P; Queensland Children's Hospital , South Brisbane, Australia., Mallon D; Fiona Stanley Hospital , Murdoch, Australia., Fletcher JT; The Canberra Hospital , Garran, Australia., Walters GD; The Canberra Hospital , Garran, Australia., Šestan M; Department of Pediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia., Jelušić M; Department of Pediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia., Cook MC; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; The Canberra Hospital , Garran, Australia.; Cambridge Institute for Therapeutic Immunology and Infectious Diseases, University of Cambridge , Cambridge, UK., Athanasopoulos V; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Fulcher DA; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia., Babon JJ; Walter and Eliza Hall Institute of Medical Research , Parkville, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Australia., Vinuesa CG; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Francis Crick Institute , London, UK., Ellyard JI; Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Acton, Australia.; Centre for Personalised Immunology, John Curtin School of Medical Research, The Australian National University, Acton, Australia.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2024 Apr 01; Vol. 221 (4). Date of Electronic Publication: 2024 Feb 28.
DOI:	10.1084/jem.20221080
Abstrakt:	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. (© 2024 Zhang et al.)
Databáze:	MEDLINE
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