Rituximab-resistant splenic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
14 04 2021
14 04 2021
Historique:
received:
23
04
2020
revised:
29
10
2020
accepted:
22
03
2021
entrez:
15
4
2021
pubmed:
16
4
2021
medline:
13
7
2021
Statut:
ppublish
Résumé
Rituximab (RTX), an antibody targeting CD20, is widely used as a first-line therapeutic strategy in B cell-mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Here, we characterize the cellular basis responsible for disease relapse in secondary lymphoid organs in humans, taking advantage of the opportunity offered by therapeutic splenectomy in patients with relapsing immune thrombocytopenia. By analyzing the B and plasma cell immunoglobulin gene repertoire at bulk and antigen-specific single-cell level, we demonstrate that relapses are associated with two responses coexisting in germinal centers and involving preexisting mutated memory B cells that survived RTX treatment and naive B cells generated upon reconstitution of the B cell compartment. To identify distinctive characteristics of the memory B cells that escaped RTX-mediated depletion, we analyzed RTX refractory patients who did not respond to treatment at the time of B cell depletion. We identified, by single-cell RNA sequencing (scRNA-seq) analysis, a population of quiescent splenic memory B cells that present a unique, yet reversible, RTX-shaped phenotype characterized by down-modulation of B cell-specific factors and expression of prosurvival genes. Our results clearly demonstrate that these RTX-resistant autoreactive memory B cells reactivate as RTX is cleared and give rise to plasma cells and further germinal center reactions. Their continued surface expression of CD19 makes them efficient targets for current anti-CD19 therapies. This study thus identifies a pathogenic contributor to autoimmune diseases that can be targeted by available therapeutic agents.
Identifiants
pubmed: 33853929
pii: 13/589/eabc3961
doi: 10.1126/scitranslmed.abc3961
pmc: PMC7610758
mid: EMS123362
pii:
doi:
Substances chimiques
Antibodies, Monoclonal, Murine-Derived
0
Rituximab
4F4X42SYQ6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Research Council
ID : 693267
Pays : International
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Références
Proc Natl Acad Sci U S A. 2002 May 14;99(10):6955-60
pubmed: 12011454
Genome Biol. 2019 Dec 23;20(1):296
pubmed: 31870423
Bioinformatics. 2017 Apr 15;33(8):1179-1186
pubmed: 28088763
Annu Rev Immunol. 2009;27:267-85
pubmed: 19302041
Arthritis Rheum. 2006 Aug;54(8):2377-86
pubmed: 16869000
Nat Rev Immunol. 2009 Dec;9(12):845-57
pubmed: 19935804
Blood. 2011 Sep 1;118(9):2530-40
pubmed: 21768293
Blood. 2015 Oct 29;126(18):2098-109
pubmed: 26289642
Immunity. 2018 Jan 16;48(1):174-184.e9
pubmed: 29343437
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Blood. 2017 Jun 22;129(25):3389-3391
pubmed: 28468795
Curr Opin Immunol. 2018 Dec;55:75-80
pubmed: 30388513
Clin Immunol. 2007 Feb;122(2):139-45
pubmed: 17008130
Am J Hematol. 2019 Dec;94(12):1314-1324
pubmed: 31489694
Blood. 2018 Apr 5;131(14):1545-1555
pubmed: 29378696
Blood Adv. 2019 Dec 10;3(23):3829-3866
pubmed: 31794604
JCI Insight. 2020 Jul 23;5(14):
pubmed: 32573488
Int J Cancer. 2018 Jan 15;142(2):322-333
pubmed: 28921505
Immunity. 2019 Nov 19;51(5):840-855.e5
pubmed: 31606264
Blood. 2014 Jan 30;123(5):669-77
pubmed: 24227819
Arthritis Rheumatol. 2015 May;67(8):2046-55
pubmed: 25916583
Nat Immunol. 2015 Jul;16(7):755-65
pubmed: 26006014
Cell. 2017 Aug 24;170(5):913-926.e19
pubmed: 28841417
Blood. 2014 Oct 23;124(17):2666-74
pubmed: 25224411
Nat Methods. 2019 Dec;16(12):1289-1296
pubmed: 31740819
J Autoimmun. 2015 Aug;62:22-30
pubmed: 26112660
J Exp Med. 2008 Jun 9;205(6):1331-42
pubmed: 18519648
Nat Commun. 2017 Oct 2;8(1):755
pubmed: 28970470
Blood. 2014 Oct 30;124(18):2858-66
pubmed: 25232056
Elife. 2015 May 08;4:
pubmed: 25955968
Methods Mol Biol. 2012;882:569-604
pubmed: 22665256
Nat Methods. 2014 Jun;11(6):637-40
pubmed: 24747814
Nature. 2020 Oct;586(7827):127-132
pubmed: 32866963
Blood. 1994 Feb 15;83(4):1024-32
pubmed: 8111044
Nat Rev Nephrol. 2016 Apr;12(4):232-40
pubmed: 26923204
Nat Methods. 2017 Nov;14(11):1083-1086
pubmed: 28991892
J Clin Pharmacol. 2005 Jul;45(7):792-801
pubmed: 15951469
Blood. 2011 Oct 20;118(16):4394-400
pubmed: 21876120
Blood. 2009 Mar 12;113(11):2386-93
pubmed: 19005182
Cell Mol Life Sci. 2012 May;69(10):1625-34
pubmed: 22481437
Blood. 2005 Apr 1;105(7):2933-40
pubmed: 15591116
Nat Immunol. 2013 Aug;14(8):867-75
pubmed: 23812095
Immunol Lett. 2012 Mar 30;143(1):44-52
pubmed: 22285696
Bioinformatics. 2014 Jul 1;30(13):1930-2
pubmed: 24618469
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19643-8
pubmed: 19064921
Nat Commun. 2011 Sep 06;2:465
pubmed: 21897376
Nat Protoc. 2019 Feb;14(2):482-517
pubmed: 30664679
Front Immunol. 2017 Sep 14;8:1157
pubmed: 28959265
J Immunol Methods. 2008 Jan 1;329(1-2):112-24
pubmed: 17996249
Rheumatology (Oxford). 2019 Jun 1;58(6):1075-1085
pubmed: 30649469
Blood. 2016 Sep 29;128(13):1711-22
pubmed: 27535994
Am J Transplant. 2013 Jun;13(6):1503-11
pubmed: 23570303
J Clin Invest. 2013 Jan;123(1):432-42
pubmed: 23241960
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
J Immunol. 2015 Oct 15;195(8):3716-24
pubmed: 26355154
Br J Clin Pharmacol. 2017 Aug;83(8):1773-1781
pubmed: 28230269
Front Immunol. 2018 Sep 05;9:2026
pubmed: 30233601
Arthritis Res Ther. 2013;15 Suppl 1:S3
pubmed: 23566754
Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4658-63
pubmed: 20176942
Sci Rep. 2018 Sep 25;8(1):14338
pubmed: 30254311
Bioinformatics. 2015 Oct 15;31(20):3356-8
pubmed: 26069265
Nat Methods. 2017 Sep 29;14(10):935-936
pubmed: 28960196
J Immunol. 2011 Sep 15;187(6):3438-47
pubmed: 21841127
Blood. 2014 Nov 20;124(22):3228-36
pubmed: 25293768
Blood. 2013 Oct 24;122(17):3020-9
pubmed: 23821660
Am J Transplant. 2007 Feb;7(2):402-7
pubmed: 17241113
Cell Syst. 2016 Oct 26;3(4):385-394.e3
pubmed: 27693023
Curr Opin Rheumatol. 2014 Mar;26(2):228-36
pubmed: 24126901
Blood. 2012 Jun 21;119(25):5989-95
pubmed: 22566601
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
Blood. 2015 Jan 29;125(5):762-6
pubmed: 25498911
Sci Transl Med. 2019 Mar 6;11(482):
pubmed: 30842314
Sci Adv. 2020 Jul 24;6(30):eaba6493
pubmed: 32754637
Arthritis Rheum. 2007 Sep;56(9):3044-56
pubmed: 17763423
Genome Biol. 2015 Dec 10;16:278
pubmed: 26653891
Genome Biol. 2016 Apr 28;17:77
pubmed: 27121950
J Biol Chem. 2008 Jun 20;283(25):16971-84
pubmed: 18426802
J Immunol. 2002 Apr 1;168(7):3675-82
pubmed: 11907134
Arthritis Rheum. 2006 Feb;54(2):613-20
pubmed: 16447239