title: Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis.
abstract: In multiple sclerosis (MS), lymphocyte--in particular B cell--transit between the central nervous system (CNS) and periphery may contribute to the maintenance of active disease. Clonally related B cells exist in the cerebrospinal fluid (CSF) and peripheral blood (PB) of MS patients; however, it remains unclear which subpopulations of the highly diverse peripheral B cell compartment share antigen specificity with intrathecal B cell repertoires and whether their antigen stimulation occurs on both sides of the blood-brain barrier. To address these questions, we combined flow cytometric sorting of PB B cell subsets with deep immune repertoire sequencing of CSF and PB B cells. Immunoglobulin (IgM and IgG) heavy chain variable (VH) region repertoires of five PB B cell subsets from MS patients were compared with their CSF Ig-VH transcriptomes. In six of eight patients, we identified peripheral CD27(+)IgD(-) memory B cells, CD27(hi)CD38(hi) plasma cells/plasmablasts, or CD27(-)IgD(-) B cells that had an immune connection to the CNS compartment. Pinpointing Ig class-switched B cells as key component of the immune axis thought to contribute to ongoing MS disease activity strengthens the rationale of current B cell-targeting therapeutic strategies and may lead to more targeted approaches.
authors.affiliation: Department of Neurology, UCSF, San Francisco, CA 94148 USA.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Palanichamy
authors.affiliation: Department of Neurology, UCSF, San Francisco, CA 94148 USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Apeltsin
authors.affiliation: Rinat-Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Kuo
authors.affiliation: Rinat-Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Sirota
authors.affiliation: Department of Neurology, UCSF, San Francisco, CA 94148 USA.
authors.forename: Shengzhi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Rinat-Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Pitts
authors.affiliation: Rinat-Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Purnima D
authors.initials: PD
authors.lastname: Sundar
authors.affiliation: Rinat-Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Dilduz
authors.initials: D
authors.lastname: Telman
authors.affiliation: Rinat-Pfizer Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Lora Z
authors.initials: LZ
authors.lastname: Zhao
authors.affiliation: Department of Neurology, UCSF, San Francisco, CA 94148 USA.
authors.forename: Mia
authors.initials: M
authors.lastname: Derstine
authors.affiliation: Department of Neurology, UCSF, San Francisco, CA 94148 USA.
authors.forename: Aya
authors.initials: A
authors.lastname: Abounasr
authors.affiliation: Department of Neurology, UCSF, San Francisco, CA 94148 USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: Department of Neurology, UCSF, San Francisco, CA 94148 USA.
authors.forename: H-Christian
authors.initials: HC
authors.lastname: von Büdingen
mesh_terms: D000328:Adult; D000915:Antibody Affinity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002449:Cell Aggregation; D002490:Central Nervous System / Q000473:pathology*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D020539:Sequence Analysis, Protein; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D055815:Young Adult
chemical_list: D007135:Immunoglobulin Variable Region
references.citation: J Immunol. 2001 Nov 15;167(10):5669-77
references.pmid: 11698439
references.citation: J Immunol. 2007 May 15;178(10):6092-9
references.pmid: 17475834
references.citation: J Exp Med. 2007 Mar 19;204(3):645-55
references.pmid: 17312005
references.citation: BMC Res Notes. 2011 Oct 12;4:404
references.pmid: 21992227
references.citation: Sci Transl Med. 2009 Dec 23;1(12):12ra23
references.pmid: 20161664
references.citation: J Clin Invest. 2012 Dec;122(12):4533-43
references.pmid: 23160197
references.citation: J Clin Bioinforma. 2013 Aug 27;3(1):15
references.pmid: 23977981
references.citation: Bioinformatics. 2011 Feb 1;27(3):431-2
references.pmid: 21149340
references.citation: J Clin Invest. 2005 May;115(5):1352-60
references.pmid: 15841210
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1347-52
references.pmid: 22232676
references.citation: J Immunol. 1999 Nov 1;163(9):5133-44
references.pmid: 10528220
references.citation: J Neuroimmunol. 2006 Nov;180(1-2):63-70
references.pmid: 16904756
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: Ann Neurol. 2008 Mar;63(3):395-400
references.pmid: 18383069
references.citation: Ann Neurol. 2009 Jun;65(6):639-49
references.pmid: 19557869
references.citation: J Neuroimmunol. 1991 Feb;31(2):91-6
references.pmid: 1991822
references.citation: Cell. 2013 Nov 21;155(5):1178-87
references.pmid: 24267896
references.citation: Nat Med. 2008 Jun;14(6):688-93
references.pmid: 18488038
references.citation: Ann Neurol. 2006 May;59(5):743-7
references.pmid: 16634029
references.citation: Brain Pathol. 2004 Apr;14(2):164-74
references.pmid: 15193029
references.citation: J Neuroimmunol. 2007 Dec;192(1-2):226-34
references.pmid: 17997491
references.citation: Mult Scler. 2013 Aug;19(9):1209-12
references.pmid: 23093485
references.citation: Ann Neurol. 2014 Feb;75(2):266-76
references.pmid: 24375699
references.citation: N Engl J Med. 2008 Feb 14;358(7):676-88
references.pmid: 18272891
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11064-9
references.pmid: 15263096
references.citation: Ann Neurol. 2011 Feb;69(2):292-302
references.pmid: 21387374
references.citation: Cell. 1995 Mar 10;80(5):695-705
references.pmid: 7534214
references.citation: Science. 2002 Sep 20;297(5589):2066-70
references.pmid: 12242446
references.citation: Anal Chem. 2013 Aug 20;85(16):8016-21
references.pmid: 23885761
references.citation: Blood. 2010 Aug 19;116(7):1070-8
references.pmid: 20457872
references.citation: Neurology. 1983 Nov;33(11):1444-52
references.pmid: 6685237
references.citation: Front Microbiol. 2012 Sep 11;3:315
references.pmid: 23024643
references.citation: J Autoimmun. 2011 Dec;37(4):289-99
references.pmid: 21924866
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20066-71
references.pmid: 22123975
references.citation: J Neuroimmunol. 2004 Mar;148(1-2):11-23
references.pmid: 14975582
references.citation: Curr Protoc Hum Genet. 2010 Apr;Chapter 11:Unit 11.11.1-36
references.pmid: 20373513
references.citation: Eur J Immunol. 2008 Jul;38(7):2014-23
references.pmid: 18521957
references.citation: Eur J Immunol. 2010 Oct;40(10):2942-56
references.pmid: 20812237
references.citation: Arch Neurol. 2012 Feb;69(2):191-7
references.pmid: 22332187
references.citation: Brain. 2011 Feb;134(Pt 2):534-41
references.pmid: 21216828
references.citation: J Neurol Sci. 2003 Jul 15;211(1-2):67-73
references.pmid: 12767500
references.citation: Bioinformatics. 2009 May 1;25(9):1189-91
references.pmid: 19151095
references.citation: J Immunol Methods. 2008 Sep 30;338(1-2):67-74
references.pmid: 18706908
references.citation: Ann Neurol. 1998 Feb;43(2):236-43
references.pmid: 9485065
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20216-21
references.pmid: 19875695
references.citation: Lancet. 2011 Nov 19;378(9805):1779-87
references.pmid: 22047971
references.citation: J Neuroimmunol. 2010 Jan 25;218(1-2):134-9
references.pmid: 19900722
references.citation: J Immunol. 2000 Mar 1;164(5):2782-9
references.pmid: 10679121
references.citation: J Neuroimmunol. 2011 Apr;233(1-2):245-8
references.pmid: 21353315
references.citation: J Immunol. 2006 Sep 15;177(6):3728-36
references.pmid: 16951333
references.citation: J Immunol. 2007 Nov 1;179(9):6343-51
references.pmid: 17947712
references.citation: Front Immunol. 2011 Dec 26;2:81
references.pmid: 22566870
references.citation: J Immunol. 2007 May 15;178(10):6624-33
references.pmid: 17475894
references.citation: Brief Bioinform. 2008 Jul;9(4):286-98
references.pmid: 18372315