title: Balance between survivin, a key member of the apoptosis inhibitor family, and its specific antibodies determines erosivity in rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is a highly heterogeneous disease with respect to its joint destructivity. The reasons underlying this heterogeneity are unknown. Deficient apoptosis in rheumatoid synovial tissue has been recently demonstrated. We have therefore decided to study the synovial expression of survivin, a key member of the apoptosis inhibitor family. The levels of survivin and antibodies against survivin were assessed by an ELISA in matched blood and synovial fluid samples collected from 131 RA patients. Results were related to joint erosivity at the time of sampling. Monocytes were transfected with survivin anti-sense oligonucleotides and were assessed for their ability to produce inflammatory cytokines. Survivin levels were significantly higher in patients with destructive disease as compared with in RA patients displaying a non-erosive disease. High survivin levels were an independent prognostic parameter for erosive RA. In contrast, high levels of antibodies against survivin were found in patients with non-erosive RA, and were negatively related to erosivity. Survivin levels in RA patients were influenced by treatment, being significantly lower among patients treated with disease-modifying anti-rheumatic drugs. Specific suppression of survivin mRNA resulted in downregulation of IL-6 production. We conclude that survivin determines the erosive course of RA, whereas survivin antibodies lead to a less aggressive course of the disease. These findings together with decreased survivin levels upon disease-modifying anti-rheumatic drug treatment, and the downregulation of inflammatory response using survivin anti-sense oligonucleotides, suggest that extracellular survivin expression mediates the erosive course of joint disease whereas autoimmune responses to the same molecule, manifested as survivin targeting antibodies, mediate protection.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborg, Sweden. maria.bokarewa@rheuma.gu.se
authors.forename: Maria
authors.initials: M
authors.lastname: Bokarewa
authors.forename: Sofia
authors.initials: S
authors.lastname: Lindblad
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Bokarew
authors.forename: Andrej
authors.initials: A
authors.lastname: Tarkowski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6 / Q000378:metabolism; D007596:Joints / Q000473:pathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D000077022:Survivin; D013582:Synovial Fluid / Q000378:metabolism*; D013873:Thionucleotides / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D018501:Antirheumatic Agents; D001323:Autoantibodies; D001324:Autoantigens; C107489:BIRC5 protein, human; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D051034:Inhibitor of Apoptosis Proteins; D015850:Interleukin-6; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D000077022:Survivin; D013873:Thionucleotides
references.citation: Biochem J. 1999 Dec 1;344 Pt 2:305-11
references.pmid: 10567210
references.citation: J Pathol. 2003 Mar;199(3):275-88
references.pmid: 12579529
references.citation: Immunol Today. 2000 Feb;21(2):78-82
references.pmid: 10652465
references.citation: Arthritis Rheum. 2000 Mar;43(3):599-607
references.pmid: 10728754
references.citation: Cancer Res. 2000 Jun 1;60(11):2805-9
references.pmid: 10850418
references.citation: J Rheumatol. 2000 Sep;27(9):2283-4
references.pmid: 10990254
references.citation: Curr Biol. 2000 Nov 2;10(21):1319-28
references.pmid: 11084331
references.citation: J Pathol. 2001 Jan;193(1):110-6
references.pmid: 11169523
references.citation: JAMA. 2001 Jan 17;285(3):324-8
references.pmid: 11176843
references.citation: J Rheumatol. 2001 May;28(5):950-5
references.pmid: 11361221
references.citation: Br J Haematol. 2001 Jul;114(1):63-9
references.pmid: 11472346
references.citation: Arthritis Rheum. 2001 Dec;44(12):2899-908
references.pmid: 11762951
references.citation: J Biol Chem. 2002 Feb 1;277(5):3247-57
references.pmid: 11714700
references.citation: Oncogene. 2002 Apr 18;21(17):2613-22
references.pmid: 11965534
references.citation: Arthritis Rheum. 2002 Jun;46(6):1512-8
references.pmid: 12115181
references.citation: Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10025-30
references.pmid: 12119414
references.citation: J Immunol. 2002 Aug 15;169(4):1760-7
references.pmid: 12165497
references.citation: J Rheumatol. 2002 Aug;29(8):1609-14
references.pmid: 12180717
references.citation: J Pharmacol Exp Ther. 2002 Oct;303(1):124-31
references.pmid: 12235242
references.citation: Cancer Chemother Pharmacol. 2002 Nov;50(5):343-52
references.pmid: 12439591
references.citation: Clin Cancer Res. 2003 Mar;9(3):1098-104
references.pmid: 12631613
references.citation: Curr Opin Rheumatol. 2003 May;15(3):274-9
references.pmid: 12707581
references.citation: J Urol. 2003 Jul;170(1):230-4
references.pmid: 12796695
references.citation: Ann Oncol. 2003 Jul;14(7):1045-50
references.pmid: 12853345
references.citation: J Cell Physiol. 2003 Oct;197(1):8-29
references.pmid: 12942537
references.citation: Oncogene. 2003 Nov 24;22(53):8581-9
references.pmid: 14634620
references.citation: Ann Rheum Dis. 2003 Dec;62(12):1139-44
references.pmid: 14644850
references.citation: Rheumatology (Oxford). 2003 Dec;42(12):1433-44
references.pmid: 12832715
references.citation: Arthritis Rheum. 1988 Mar;31(3):315-24
references.pmid: 3358796
references.citation: Eur J Immunol. 1988 Oct;18(10):1535-40
references.pmid: 3263920
references.citation: J Clin Invest. 1995 Sep;96(3):1631-8
references.pmid: 7657832
references.citation: Arthritis Rheum. 1997 Jan;40(1):80-6
references.pmid: 9008603
references.citation: J Clin Invest. 1997 Feb 1;99(3):439-46
references.pmid: 9022077
references.citation: Springer Semin Immunopathol. 1998;20(1-2):247-59
references.pmid: 9836380
references.citation: Arthritis Rheum. 2000 Jan;43(1):14-21
references.pmid: 10643695