title: Nonstereotyped lymphoma B cell receptors recognize vimentin as a shared autoantigen.
abstract: Ag activation of the BCR may play a role in the pathogenesis of human follicular lymphoma (FL) and other B cell malignancies. However, the nature of the Ag(s) recognized by tumor BCRs has not been well studied. In this study, we used unbiased approaches to demonstrate that 42 (19.35%) of 217 tested FL Igs recognized vimentin as a shared autoantigen. The epitope was localized to the N-terminal region of vimentin for all vimentin-reactive tumor Igs. We confirmed specific binding to vimentin by using recombinant vimentin and by performing competitive inhibition studies. Furthermore, using indirect immunofluorescence staining, we showed that the vimentin-reactive tumor Igs colocalized with an anti-vimentin mAb in HEp-2 cells. The reactivity to N-terminal vimentin of IgG FL Igs was significantly higher than that of IgM FL Igs (30.4 versus 10%; p = 0.0022). However, vimentin-reactive FL Igs did not share CDR3 motifs and were not homologous. Vimentin was expressed in the T cell-rich regions of FL, suggesting that vimentin is available for binding with tumor BCRs within the tumor microenvironment. Vimentin was also frequently recognized by mantle cell lymphoma and multiple myeloma Igs. Our results demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped FL BCRs and by the Igs of mantle cell lymphoma and multiple myeloma and suggest that vimentin may play a role in the pathogenesis of multiple B cell malignancies. These findings may lead to a better understanding of the biology and natural history of FL and other B cell malignancies.
authors.affiliation: Division of Cancer Medicine, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Soung-Chul
authors.initials: SC
authors.lastname: Cha
authors.forename: Hong
authors.initials: H
authors.lastname: Qin
authors.forename: Shibichakravarthy
authors.initials: S
authors.lastname: Kannan
authors.forename: Seema
authors.initials: S
authors.lastname: Rawal
authors.forename: Leticia S
authors.initials: LS
authors.lastname: Watkins
authors.forename: Flavio E
authors.initials: FE
authors.lastname: Baio
authors.forename: Weiguo
authors.initials: W
authors.lastname: Wu
authors.forename: Juliana
authors.initials: J
authors.lastname: Ong
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wei
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kwak
authors.forename: Sang
authors.initials: S
authors.lastname: Kim
authors.forename: Michael S
authors.initials: MS
authors.lastname: Popescu
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Paick
authors.forename: Kunhwa
authors.initials: K
authors.lastname: Kim
authors.forename: Amber
authors.initials: A
authors.lastname: Luong
authors.forename: Richard E
authors.initials: RE
authors.lastname: Davis
authors.forename: Harry W
authors.initials: HW
authors.lastname: Schroeder
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014746:Vimentin / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D014746:Vimentin
references.citation: Blood. 1994 Sep 1;84(5):1361-92
references.pmid: 8068936
references.citation: J Mol Biol. 2003 Dec 5;334(4):733-49
references.pmid: 14636599
references.citation: J Clin Invest. 2004 Apr;113(7):1008-16
references.pmid: 15057307
references.citation: Blood. 2008 Dec 15;112(13):5122-9
references.pmid: 18812466
references.citation: J Exp Med. 2006 Feb 20;203(2):393-400
references.pmid: 16446381
references.citation: Nat Med. 2005 Sep;11(9):986-91
references.pmid: 16116429
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6770-4
references.pmid: 1495966
references.citation: J Clin Oncol. 2009 Jun 20;27(18):3036-43
references.pmid: 19414675
references.citation: Annu Rev Biochem. 1984;53:595-623
references.pmid: 6383201
references.citation: Blood. 1995 May 1;85(9):2528-36
references.pmid: 7727781
references.citation: Clin Chim Acta. 2004 Dec;350(1-2):17-34
references.pmid: 15530456
references.citation: Clin Cancer Res. 2004 Dec 15;10(24):8309-17
references.pmid: 15623607
references.citation: J Immunol Methods. 1986 May 1;89(1):61-72
references.pmid: 3084658
references.citation: Nat Cell Biol. 2003 Jan;5(1):59-63
references.pmid: 12483219
references.citation: Blood. 2008 Apr 1;111(7):3838-48
references.pmid: 18223168
references.citation: J Immunol. 2006 Jan 1;176(1):652-9
references.pmid: 16365461
references.citation: J Exp Med. 2006 Oct 30;203(11):2425-31
references.pmid: 17043145
references.citation: Immunity. 2007 Feb;26(2):205-13
references.pmid: 17306569
references.citation: J Infect Dis. 2006 Jun 15;193(12):1685-92
references.pmid: 16703512
references.citation: J Immunol. 2006 Nov 1;177(9):6192-8
references.pmid: 17056548
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W435-40
references.pmid: 15215425
references.citation: Science. 1985 Jun 21;228(4706):1440-3
references.pmid: 3874430
references.citation: J Clin Oncol. 2006 Jul 1;24(19):3107-12
references.pmid: 16754937
references.citation: Nature. 1991 Jan 17;349(6306):254-6
references.pmid: 1987477
references.citation: Blood. 2012 Nov 15;120(20):4182-90
references.pmid: 23024238
references.citation: Blood. 1991 Aug 1;78(3):581-5
references.pmid: 1859876
references.citation: Nat Rev Cancer. 2005 Apr;5(4):251-62
references.pmid: 15803153
references.citation: J Immunol. 2005 Jun 15;174(12):7773-80
references.pmid: 15944280
references.citation: J Mol Biol. 1982 May 5;157(1):105-32
references.pmid: 7108955
references.citation: Exp Cell Res. 2007 Jun 10;313(10):2265-81
references.pmid: 17498695
references.citation: Blood. 2004 Mar 15;103(6):2332-6
references.pmid: 14630803
references.citation: Science. 2003 Sep 5;301(5638):1374-7
references.pmid: 12920303
references.citation: Leukemia. 2007 Jan;21(1):18-29
references.pmid: 17039231
references.citation: Mol Cell Biol. 2004 Oct;24(20):9198-206
references.pmid: 15456890
references.citation: Blood. 2002 Apr 1;99(7):2562-8
references.pmid: 11895794
references.citation: J Exp Med. 2005 Apr 18;201(8):1229-41
references.pmid: 15837810
references.citation: J Leukoc Biol. 2006 Mar;79(3):489-98
references.pmid: 16365157
references.citation: Science. 1985 Sep 27;229(4720):1390-3
references.pmid: 3929382
references.citation: Bone Marrow Transplant. 2005 Aug;36(4):315-23
references.pmid: 15968284
references.citation: Blood. 2010 Oct 21;116(16):2960-7
references.pmid: 20634382
references.citation: Nat Med. 1999 Oct;5(10):1171-7
references.pmid: 10502821
references.citation: J Natl Cancer Inst Monogr. 2008;(39):44-7
references.pmid: 18648002
references.citation: Blood. 2000 May 1;95(9):2922-9
references.pmid: 10779440
references.citation: Blood. 2006 Nov 1;108(9):3135-42
references.pmid: 16835385
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12747-54
references.pmid: 20543139
references.citation: J Leukoc Biol. 2008 Feb;83(2):263-71
references.pmid: 17974709
references.citation: J Clin Invest. 2005 Jun;115(6):1636-43
references.pmid: 15902303
references.citation: Ann Rheum Dis. 1988 Sep;47(9):708-16
references.pmid: 3052321