Balance between survivin, a key member of the apoptosis inhibitor family, and its specific antibodies determines erosivity in rheumatoid arthritis.
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.
Bokarewa
Maria
M
Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Göteborg, Sweden. maria.bokarewa@rheuma.gu.se
Lindblad
Sofia
S
Bokarew
Dmitriy
D
Tarkowski
Andrej
A
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
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
Biochem J. 1999 Dec 1;344 Pt 2:305-11
10567210
J Pathol. 2003 Mar;199(3):275-88
12579529
Immunol Today. 2000 Feb;21(2):78-82
10652465
Arthritis Rheum. 2000 Mar;43(3):599-607
10728754
Cancer Res. 2000 Jun 1;60(11):2805-9
10850418
J Rheumatol. 2000 Sep;27(9):2283-4
10990254
Curr Biol. 2000 Nov 2;10(21):1319-28
11084331
J Pathol. 2001 Jan;193(1):110-6
11169523
JAMA. 2001 Jan 17;285(3):324-8
11176843
J Rheumatol. 2001 May;28(5):950-5
11361221
Br J Haematol. 2001 Jul;114(1):63-9
11472346
Arthritis Rheum. 2001 Dec;44(12):2899-908
11762951
J Biol Chem. 2002 Feb 1;277(5):3247-57
11714700
Oncogene. 2002 Apr 18;21(17):2613-22
11965534
Arthritis Rheum. 2002 Jun;46(6):1512-8
12115181
Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10025-30
12119414
J Immunol. 2002 Aug 15;169(4):1760-7
12165497
J Rheumatol. 2002 Aug;29(8):1609-14
12180717
J Pharmacol Exp Ther. 2002 Oct;303(1):124-31
12235242
Cancer Chemother Pharmacol. 2002 Nov;50(5):343-52
12439591
Clin Cancer Res. 2003 Mar;9(3):1098-104
12631613
Curr Opin Rheumatol. 2003 May;15(3):274-9
12707581
J Urol. 2003 Jul;170(1):230-4
12796695
Ann Oncol. 2003 Jul;14(7):1045-50
12853345
J Cell Physiol. 2003 Oct;197(1):8-29
12942537
Oncogene. 2003 Nov 24;22(53):8581-9
14634620
Ann Rheum Dis. 2003 Dec;62(12):1139-44
14644850
Rheumatology (Oxford). 2003 Dec;42(12):1433-44
12832715
Arthritis Rheum. 1988 Mar;31(3):315-24
3358796
Eur J Immunol. 1988 Oct;18(10):1535-40
3263920
J Clin Invest. 1995 Sep;96(3):1631-8
7657832
Arthritis Rheum. 1997 Jan;40(1):80-6
9008603
J Clin Invest. 1997 Feb 1;99(3):439-46
9022077
Springer Semin Immunopathol. 1998;20(1-2):247-59
9836380
Arthritis Rheum. 2000 Jan;43(1):14-21
10643695