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.

Figure 1

Survivin levels in plasma and synovial fluid of patients with rheumatoid arthritis (RA) are significantly increased in the case of erosive joint disease. SEM, standard error of the mean.

Figure 2

Influence of disease-modifying anti-rheumatic drugs on survivin levels of rheumatoid arthritis patients with erosive joint disease. DMARDs, disease modifying anti-rheumatic drugs; MTX, methotrexate; TNF-α inh, tumour necrosis factor alpha inhibitors; SEM, standard error of the mean.

Figure 3

Synovial fluid antibodies of both IgG and IgM isotypes specific for survivin are higher in rheumatoid arthritis patients with the non-erosive course compared with the erosive course of the joint disease. SEM, standard error of the mean.

Figure 4

Expression of survivin in lysates from peripheral blood mononuclear cells of rheumatoid arthritis (RA) patients and from healthy controls following stimulation with various mitogens. Survivin expression was measured following 48 hours of stimulation. TNF-α, tumour necrosis factor alpha; PHA, phytohaemagglutinine; ConA, Concanavalin A; LPS, lipopolysaccharide.

Figure 5

Modulation of (a) survivin expression, (b) proliferation, and (c) IL-6 production following transfection of THP-1 cells with anti-sense oligonucleotides specific for survivin mRNA and non-sense sequences. Data are provided as the percentage of phytohaemagglutinine-stimulated THP-1 cells. The concentration of oligonucleotides throughout was 300 nM.