Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
10
06
2021
accepted:
16
06
2022
pubmed:
29
7
2022
medline:
10
8
2022
entrez:
28
7
2022
Statut:
ppublish
Résumé
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.
Identifiants
pubmed: 35902638
doi: 10.1038/s41590-022-01271-6
pii: 10.1038/s41590-022-01271-6
pmc: PMC9355881
doi:
Substances chimiques
DNA-Binding Proteins
0
Homeodomain Proteins
0
Nuclear Proteins
0
RAG2 protein, human
0
RAG-1 protein
128559-51-3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1256-1272Subventions
Organisme : NIAID NIH HHS
ID : R01 AI153830
Pays : United States
Organisme : NIAID NIH HHS
ID : K08 AI103035
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA AI001222
Pays : United States
Organisme : NIAID NIH HHS
ID : P01 AI061093
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI100887
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Nat Immunol. 2002 Sep;3(9):822-9
pubmed: 12154359
Front Immunol. 2020 Oct 21;11:574738
pubmed: 33193364
J Allergy Clin Immunol. 2018 Jun;141(6):2303-2306
pubmed: 29477728
Annu Rev Immunol. 2020 Apr 26;38:315-340
pubmed: 31986068
Front Immunol. 2020 Sep 29;11:1954
pubmed: 33117328
Immunobiology. 2002 Dec;206(5):502-13
pubmed: 12607725
JCI Insight. 2021 Oct 8;6(19):
pubmed: 34622798
J Exp Med. 2016 Mar 7;213(3):355-75
pubmed: 26926994
Nat Immunol. 2019 Aug;20(8):1071-1082
pubmed: 31263277
Blood. 2013 Feb 28;121(9):1595-603
pubmed: 23223361
Ann N Y Acad Sci. 2011 Dec;1246:1-10
pubmed: 22236425
Nat Rev Immunol. 2009 Jul;9(7):491-502
pubmed: 19521398
Immunol Rev. 2019 Mar;288(1):136-148
pubmed: 30874345
J Immunol. 2016 Aug 15;197(4):1023-8
pubmed: 27430719
Sci Immunol. 2016 Dec 16;1(6):
pubmed: 28783691
J Allergy Clin Immunol. 2003 Nov;112(5):973-80
pubmed: 14610491
Nat Rev Immunol. 2016 Apr;16(4):234-46
pubmed: 26996199
J Immunol. 2004 Oct 1;173(7):4479-91
pubmed: 15383579
Nucleic Acids Res. 2012 Sep 1;40(17):e134
pubmed: 22641856
J Allergy Clin Immunol. 2014 Apr;133(4):1124-33
pubmed: 24418478
Nat Immunol. 2015 Jul;16(7):755-65
pubmed: 26006014
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):E3216-24
pubmed: 23922396
Front Pediatr. 2019 Jul 05;7:235
pubmed: 31334206
J Allergy Clin Immunol. 2014 Apr;133(4):1211-5
pubmed: 24331380
J Exp Med. 2004 Aug 16;200(4):411-23
pubmed: 15314072
J Clin Invest. 2015 Nov 2;125(11):4135-48
pubmed: 26457731
Cell. 2020 Oct 1;183(1):143-157.e13
pubmed: 32877699
Am J Surg Pathol. 2016 Jul;40(7):958-67
pubmed: 27158760
Blood. 2011 Aug 4;118(5):1305-15
pubmed: 21543762
J Allergy Clin Immunol. 2014 Apr;133(4):1099-108
pubmed: 24290284
Eur J Immunol. 2006 Apr;36(4):810-6
pubmed: 16541472
Sci Immunol. 2021 Oct 15;6(64):eabh0891
pubmed: 34623902
Science. 2003 Sep 5;301(5638):1374-7
pubmed: 12920303
Methods Mol Biol. 2012;882:569-604
pubmed: 22665256
J Exp Med. 2013 Nov 18;210(12):2773-89
pubmed: 24145511
J Exp Med. 1993 Apr 1;177(4):1009-20
pubmed: 8459201
J Immunol. 2015 Jul 1;195(1):71-9
pubmed: 26034175
N Engl J Med. 2008 May 8;358(19):2030-8
pubmed: 18463379
Clin Immunol. 2005 Apr;115(1):70-3
pubmed: 15870023
J Clin Invest. 2013 Oct;123(10):4283-93
pubmed: 24051380
Front Immunol. 2013 Nov 15;4:358
pubmed: 24298272
J Allergy Clin Immunol. 2013 Oct;132(4):969-71.e1-2
pubmed: 23891352
J Exp Med. 2010 Jul 5;207(7):1541-54
pubmed: 20547827
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
J Allergy Clin Immunol. 2017 Dec;140(6):1739-1743.e7
pubmed: 28864286
J Allergy Clin Immunol Pract. 2018 Sep - Oct;6(5):1769-1771.e2
pubmed: 29410113
Bioinformatics. 2015 Oct 15;31(20):3356-8
pubmed: 26069265
Sci Rep. 2016 Jun 01;6:27030
pubmed: 27249108
Clin Infect Dis. 2017 Jan 1;64(1):83-86
pubmed: 27810866
Front Immunol. 2018 Sep 28;9:2206
pubmed: 30323809
Cytometry A. 2015 Jul;87(7):636-45
pubmed: 25573116
Eur J Immunol. 2003 Sep;33(9):2391-7
pubmed: 12938215
Immunity. 2018 Oct 16;49(4):725-739.e6
pubmed: 30314758
Blood. 2003 Jun 1;101(11):4500-4
pubmed: 12560217
Science. 1990 Jun 22;248(4962):1517-23
pubmed: 2360047
Immunity. 2004 Apr;20(4):441-53
pubmed: 15084273
J Allergy Clin Immunol Pract. 2019 Jul - Aug;7(6):1970-1985.e4
pubmed: 30877075
Immunity. 2004 Jun;20(6):785-98
pubmed: 15189742
Front Immunol. 2019 Oct 18;10:2458
pubmed: 31681331
J Exp Med. 2010 Jul 5;207(7):1525-40
pubmed: 20547828
Blood. 2009 Jul 2;114(1):105-8
pubmed: 19414857
Front Pediatr. 2019 Apr 16;7:122
pubmed: 31058115
Nat Rev Immunol. 2017 May;17(5):281-294
pubmed: 28368006
J Clin Invest. 2005 Nov;115(11):3140-8
pubmed: 16211094
Nucleic Acids Res. 2011 Jul;39(Web Server issue):W499-504
pubmed: 21665923
J Immunol. 1991 Jun 15;146(12):4385-91
pubmed: 1710250