Persistent virus-specific and clonally expanded antibody-secreting cells respond to induced self-antigen in the CNS.
Antibody-secreting cells
Autoimmunity
CNS tolerance
Multiple sclerosis
Viral infection
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
06
09
2022
accepted:
02
01
2023
revised:
20
12
2022
pubmed:
26
1
2023
medline:
16
2
2023
entrez:
25
1
2023
Statut:
ppublish
Résumé
B cells contribute to the pathogenesis of both cellular- and humoral-mediated central nervous system (CNS) inflammatory diseases through a variety of mechanisms. In such conditions, B cells may enter the CNS parenchyma and contribute to local tissue destruction. It remains unexplored, however, how infection and autoimmunity drive transcriptional phenotypes, repertoire features, and antibody functionality. Here, we profiled B cells from the CNS of murine models of intracranial (i.c.) viral infections and autoimmunity. We identified a population of clonally expanded, antibody-secreting cells (ASCs) that had undergone class-switch recombination and extensive somatic hypermutation following i.c. infection with attenuated lymphocytic choriomeningitis virus (rLCMV). Recombinant expression and characterisation of these antibodies revealed specificity to viral antigens (LCMV glycoprotein GP), correlating with ASC persistence in the brain weeks after resolved infection. Furthermore, these virus-specific ASCs upregulated proliferation and expansion programs in response to the conditional and transient induction of the LCMV GP as a neo-self antigen by astrocytes. This class-switched, clonally expanded, and mutated population persisted and was even more pronounced when peripheral B cells were depleted prior to autoantigen induction in the CNS. In contrast, the most expanded B cell clones in mice with persistent expression of LCMV GP in the CNS did not exhibit neo-self antigen specificity, potentially a consequence of local tolerance induction. Finally, a comparable population of clonally expanded, class-switched, and proliferating ASCs was detected in the cerebrospinal fluid of relapsing multiple sclerosis (RMS) patients. Taken together, our findings support the existence of B cells that populate the CNS and are capable of responding to locally encountered autoantigens.
Identifiants
pubmed: 36695896
doi: 10.1007/s00401-023-02537-5
pii: 10.1007/s00401-023-02537-5
pmc: PMC9925600
doi:
Substances chimiques
Autoantigens
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
335-355Informations de copyright
© 2023. The Author(s).
Références
Nat Immunol. 2019 Jun;20(6):756-764
pubmed: 31110315
J Comp Neurol. 2015 Aug 15;523(12):1840-63
pubmed: 25732325
Proc Natl Acad Sci U S A. 2020 Sep 15;117(37):22932-22943
pubmed: 32859762
Glia. 2006 Jul;54(1):11-20
pubmed: 16575885
Science. 2021 Jul 23;373(6553):
pubmed: 34083450
Nat Immunol. 2020 Aug;21(8):938-949
pubmed: 32572242
Nat Rev Neurol. 2012 Nov 5;8(11):613-23
pubmed: 23045237
Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):15994-9
pubmed: 26647186
Nat Biotechnol. 2015 May;33(5):495-502
pubmed: 25867923
Front Immunol. 2015 Sep 15;6:470
pubmed: 26441975
Science. 2021 Jul 23;373(6553):
pubmed: 34083447
Nat Rev Neurol. 2020 Nov;16(11):601-617
pubmed: 33005040
Eur J Immunol. 2022 Feb;52(2):297-311
pubmed: 34727578
Neurotherapeutics. 2022 Apr;19(3):823-831
pubmed: 35060089
Eur J Immunol. 2010 Mar;40(3):654-63
pubmed: 20077405
NAR Genom Bioinform. 2021 Apr 14;3(2):lqab023
pubmed: 33884369
Nat Immunol. 2019 Jan;20(1):97-108
pubmed: 30510223
Cell Rep. 2020 Jan 21;30(3):905-913.e6
pubmed: 31968262
Science. 2022 Jan 21;375(6578):296-301
pubmed: 35025605
Nat Neurosci. 2022 May;25(5):555-560
pubmed: 35301477
Sci Transl Med. 2015 Jan 7;7(269):269rv1
pubmed: 25568072
Nature. 2020 Nov;587(7834):472-476
pubmed: 33149302
Acta Neuropathol. 2018 Mar;135(3):337-361
pubmed: 29368213
Ann Neurol. 2009 Dec;66(6):833-42
pubmed: 20033986
Nat Rev Immunol. 2021 Dec;21(12):798-813
pubmed: 33976421
Nature. 2016 Feb 24;533(7602):278
pubmed: 26909581
J Neurosci. 2013 Nov 6;33(45):17587-96
pubmed: 24198349
Nat Rev Drug Discov. 2021 Mar;20(3):179-199
pubmed: 33324003
J Exp Med. 2016 Jul 25;213(8):1571-87
pubmed: 27377586
Genes Immun. 2022 Sep;23(6):183-195
pubmed: 36028771
Ann Clin Transl Neurol. 2017 Sep 27;4(10):756-761
pubmed: 29046884
Ann Neurol. 2013 Jan;73(1):120-8
pubmed: 23225603
Clin Exp Immunol. 1983 Dec;54(3):641-7
pubmed: 6317243
Ann Neurol. 2006 Jun;59(6):880-92
pubmed: 16718690
Immunity. 2021 Dec 14;54(12):2784-2794.e6
pubmed: 34626548
Cell Rep. 2021 Jun 22;35(12):109286
pubmed: 34161770
Oncogene. 2016 Dec 8;35(49):6330-6340
pubmed: 27270442
J Immunol. 2005 Nov 1;175(9):5875-84
pubmed: 16237080
J Exp Med. 2006 Apr 17;203(4):1007-19
pubmed: 16585265
iScience. 2020 Sep 25;23(9):101519
pubmed: 32905040
Nat Commun. 2021 Feb 12;12(1):1009
pubmed: 33579927
Nat Rev Immunol. 2022 Aug;22(8):513-524
pubmed: 34903877
Eur J Immunol. 2022 Apr;52(4):550-565
pubmed: 35094395
J Clin Invest. 2010 May;120(5):1368-79
pubmed: 20440079
Proc Biol Sci. 2021 Feb 24;288(1945):20202793
pubmed: 33622131
Sci Immunol. 2022 Jan 28;7(67):eabf5314
pubmed: 35089815
Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4663-8
pubmed: 16537369
J Clin Invest. 2021 Jun 1;131(11):
pubmed: 34060477
Nat Clin Pract Neurol. 2008 Apr;4(4):202-14
pubmed: 18334978
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Immunity. 2014 Dec 18;41(6):886-97
pubmed: 25526304
Arch Immunol Ther Exp (Warsz). 2008 Mar-Apr;56(2):77-83
pubmed: 18373241
Immunity. 2022 Apr 12;55(4):718-733.e8
pubmed: 35349789
Sci Transl Med. 2022 Apr 13;14(640):eabl6058
pubmed: 35417190
Neurol Neuroimmunol Neuroinflamm. 2016 Mar 09;3(2):e212
pubmed: 27027096
Front Immunol. 2019 Feb 08;10:201
pubmed: 30800132
Ann Neurol. 1998 Feb;43(2):236-43
pubmed: 9485065
Annu Rev Immunol. 2022 Apr 26;40:195-220
pubmed: 35044795
Nat Neurosci. 2017 Feb;20(2):136-144
pubmed: 28092660
J Immunol. 2014 Mar 15;192(6):2551-63
pubmed: 24510966
Nat Immunol. 2021 Jul;22(7):880-892
pubmed: 34099917
Biochem Biophys Res Commun. 2021 Jun 25;559:183-190
pubmed: 33945996
Viral Immunol. 2020 May;33(4):282-293
pubmed: 32023188
J Neuropathol Exp Neurol. 2008 Dec;67(12):1113-21
pubmed: 19018243
Nat Immunol. 2018 Jul;19(7):696-707
pubmed: 29925992
J Immunol. 2002 Jun 1;168(11):5605-11
pubmed: 12023357
J Immunol. 2017 Jul 15;199(2):449-457
pubmed: 28584006
Immunity. 2019 Mar 19;50(3):763
pubmed: 30893589
Acta Neuropathol Commun. 2017 Nov 25;5(1):88
pubmed: 29178933
Neurol Neuroimmunol Neuroinflamm. 2021 May 21;8(4):
pubmed: 34021057
J Immunol. 2015 Jul 1;195(1):17-22
pubmed: 26092813
Nature. 2012 Feb 29;483(7388):227-31
pubmed: 22388819
J Exp Med. 2012 May 7;209(5):1001-10
pubmed: 22547654
J Clin Invest. 2017 Oct 2;127(10):3577-3587
pubmed: 28872464
Nat Immunol. 2002 Oct;3(10):944-50
pubmed: 12244307
Nat Rev Neurosci. 2019 Dec;20(12):728-745
pubmed: 31712781
J Immunol. 2007 Nov 1;179(9):6343-51
pubmed: 17947712
Biochem Biophys Res Commun. 2013 Feb 1;431(1):41-6
pubmed: 23291167
Nature. 2022 Mar;603(7900):321-327
pubmed: 35073561
Nat Commun. 2017 May 26;8:15327
pubmed: 28548102