title: CXCL13 is elevated in Sjögren's syndrome in mice and humans and is implicated in disease pathogenesis.
abstract: SS is an autoimmune disease. pSS affects exocrine glands predominantly, whereas sSS occurs with other autoimmune connective tissue disorders. Currently, care for patients with SS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms remain uncertain. B-cell abnormalities have been identified in SS. CXCL13 directs B-cell chemotaxis and is elevated in several autoimmune diseases. In this study, we tested the hypothesis that CXCL13 is elevated in SS in mice and humans and that neutralization of the chemokine ameliorates disease in a murine model. We assayed CXCL13 in mouse models and human subjects with SS to determine whether CXCL13 is elevated both locally and systemically during SS progression and whether CXCL13 may play a role in and be a biomarker for the disease. Cxcl13 expression in salivary tissue increases with disease progression, and its blockade resulted in a modest reduction in glandular inflammation in an SS model. We demonstrate that in humans CXCL13 is elevated in serum and saliva, and an elevated salivary CXCL13 level distinguishes patients with xerostomia. These data suggest a role for CXCL13 as a valuable biomarker in SS, as 74% of patients with SS displayed elevated CXCL13 in sera, saliva, or both. Thus, CXCL13 may be pathogenically involved in SS and may serve as a new marker and a potential therapeutic target.
authors.affiliation: 1.School of Dental Medicine, 211 Foster Hall, 3435 Main Street, Buffalo, NY 14214, USA. jkramer@buffalo.edu.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kramer
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klimatcheva
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D054382:Chemokine CXCL13 / Q000032:analysis / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054380:Receptors, CXCR5 / Q000032:analysis; D012469:Salivary Glands / Q000737:chemistry; D012859:Sjogren's Syndrome / Q000209:etiology / Q000276:immunology*; D014987:Xerostomia / Q000276:immunology
chemical_list: C110663:CXCL13 protein, human; C513179:CXCR5 protein, mouse; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D054380:Receptors, CXCR5
keywords: B-cell; CXCR5; saliva; sialadenitis
references.citation: Curr Opin Rheumatol. 2012 Sep;24(5):451-6
references.pmid: 22871954
references.citation: Blood. 2008 Apr 15;111(8):4029-38
references.pmid: 18263783
references.citation: Arthritis Rheum. 2007 Apr;56(4):1134-44
references.pmid: 17393395
references.citation: Arthritis Res Ther. 2009;11(1):R24
references.pmid: 19222863
references.citation: J Autoimmun. 2012 Aug;39(1-2):4-8
references.pmid: 22326205
references.citation: Am J Physiol. 1987 Sep;253(3 Pt 1):G290-7
references.pmid: 3631266
references.citation: J Immunol. 2001 Jan 1;166(1):650-5
references.pmid: 11123349
references.citation: Immunity. 2000 May;12(5):471-81
references.pmid: 10843380
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Jun;111(6):673-80
references.pmid: 21497524
references.citation: Arthritis Rheum. 2004 Jun;50(6):1897-908
references.pmid: 15188366
references.citation: Ann Rheum Dis. 2010 Jun;69(6):1103-9
references.pmid: 19561361
references.citation: Arthritis Care Res (Hoboken). 2012 Apr;64(4):475-87
references.pmid: 22563590
references.citation: Int Dent J. 2000 Jun;50(3):140-61
references.pmid: 10967766
references.citation: Health Qual Life Outcomes. 2009 May 27;7:46
references.pmid: 19473510
references.citation: Joint Bone Spine. 2008 Jan;75(1):1-2
references.pmid: 17905630
references.citation: J Dent Res. 2011 Apr;90(4):445-9
references.pmid: 21212317
references.citation: Immunity. 2002 Jan;16(1):67-76
references.pmid: 11825566
references.citation: Eur J Immunol. 2007 Sep;37(9):2405-10
references.pmid: 17683117
references.citation: J Immunol. 2006 May 1;176(9):5276-83
references.pmid: 16621993
references.citation: Eur J Immunol. 2004 Dec;34(12):3346-58
references.pmid: 15495164
references.citation: Arthritis Res Ther. 2011 May 27;13(3):218
references.pmid: 21635716
references.citation: Arthritis Rheum. 2011 Jul;63(7):2021-30
references.pmid: 21480190
references.citation: Eur J Immunol. 2007 Sep;37(9):2400-4
references.pmid: 17683116
references.citation: Eur J Endocrinol. 2004 Feb;150(2):225-34
references.pmid: 14763921
references.citation: J Immunol. 2008 Feb 1;180(3):1938-47
references.pmid: 18209092
references.citation: Am J Pathol. 2012 Sep;181(3):753-60
references.pmid: 22770665
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2770-5
references.pmid: 16477017
references.citation: Endocr Rev. 2007 Aug;28(5):492-520
references.pmid: 17475924
references.citation: Blood. 2006 Jul 15;108(2):432-40
references.pmid: 16543475
references.citation: Ann Rheum Dis. 2013 May;72(5):728-35
references.pmid: 22736090
references.citation: Arthritis Res Ther. 2011 Jun 13;13(3):217
references.pmid: 21672284
references.citation: J Immunol. 2001 Oct 1;167(7):3610-8
references.pmid: 11564773
references.citation: Ann Rheum Dis. 2009 Sep;68(9):1447-52
references.pmid: 18782791
references.citation: Lab Invest. 2003 Mar;83(3):357-65
references.pmid: 12649336
references.citation: Arthritis Rheum. 2008 Nov;58(11):3377-87
references.pmid: 18975336
references.citation: Nature. 1998 Feb 19;391(6669):799-803
references.pmid: 9486651
references.citation: Arthritis Res Ther. 2011;13(6):R194
references.pmid: 22117835
references.citation: Neurology. 2009 Dec 8;73(23):2003-10
references.pmid: 19996075
references.citation: Arthritis Res Ther. 2007;9(4):218
references.pmid: 17697366
references.citation: Arthritis Rheum. 2008 Aug;58(8):2257-67
references.pmid: 18668547
references.citation: Lancet. 2005 Jul 23-29;366(9482):321-31
references.pmid: 16039337
references.citation: J Autoimmun. 2010 Nov;35(3):225-31
references.pmid: 20674271
references.citation: Arthritis Rheum. 2005 Jul;52(7):2109-19
references.pmid: 15986367
references.citation: Proteomics. 2012 Oct;12(19-20):3113-20
references.pmid: 22888089
references.citation: Immunol Rev. 2000 Aug;176:181-93
references.pmid: 11043777
references.citation: Ann Rheum Dis. 2002 Jun;61(6):554-8
references.pmid: 12006334
references.citation: J Rheumatol. 2010 Jan;37(1):45-52
references.pmid: 19955043
references.citation: J Clin Invest. 2012 Mar;122(3):787-95
references.pmid: 22378047
references.citation: Blood. 2008 Mar 1;111(5):2744-54
references.pmid: 18172003
references.citation: J Clin Invest. 2010 Dec;120(12):4251-72
references.pmid: 21084753
references.citation: J Immunol. 2006 Jun 15;176(12):7676-85
references.pmid: 16751415
references.citation: Arthritis Rheum. 2005 Feb;52(2):620-6
references.pmid: 15692971
references.citation: J Immunol. 2010 Aug 1;185(3):1460-5
references.pmid: 20574003
references.citation: Cell. 1996 Dec 13;87(6):1037-47
references.pmid: 8978608
references.citation: Arthritis Res Ther. 2011;13(6):R182
references.pmid: 22044682
references.citation: J Rheumatol. 2002 Apr;29(4):726-30
references.pmid: 11950013
references.citation: J Autoimmun. 1988 Apr;1(2):185-94
references.pmid: 3075461
references.citation: J Clin Invest. 2002 Jan;109(1):59-68
references.pmid: 11781351
references.citation: Lab Invest. 2006 Dec;86(12):1243-60
references.pmid: 17075579
references.citation: J Exp Med. 1999 Jan 18;189(2):403-12
references.pmid: 9892622
references.citation: Arthritis Rheum. 1990 Mar;33(3):453
references.pmid: 1690544