Background/Purpose:

Survivin is a proto-oncogene known to regulate cell division and apoptosis. In patients with rheumatoid arthritis, survivin has emerged as an independent predictor of severe disease recognised by the progressive joint damage and resistance to anti-rheumatic treatment.

Objectives: In the present study we assessed if inhibition of survivin is sufficient to reduce arthritis and joint damage in experimental autoimmune models of rheumatoid arthritis. 

Methods: Survivin production was inhibited by a lentiviral construct, which coded for shRNA (shSurv) suppressing survivin gene. shSurv was provided as a single injection (10⁶-10⁷ particles/mouse) on the day of first immunization or on the day of clinical onset of arthritis. Five independent experiments were performed. Each experiment contained the control group received non-targeting transduction particles.

Results: Intra-articular and intra-peritoneal delivery of shSurv resulted in a pronounced inhibition of survivin in spleen and in bone marrow. Inhibition of survivin, early at immunization and later at clinical signs of arthritis, significantly alleviated clinical and histological signs of arthritis and production of antigen-specific antibodies. Also, it reduced cartilage- and bone destruction in the inflamed joints in microCT. Survivin inhibition was inversely correlated to an increase of transcription repressors Bcl-6 and Blimp-1. In consistence with overexpression of Blimp-1, shSurv mice had low levels of IL-2, suppressed proliferation response and increased populations of the effector CD4+ and CD8+ cells, followed by high IL-6 and IL10 production. shSurv mice had increased populations of Tregs (CD4+Foxp3+) and Th2 cells supported by high mRNA of Foxp3 and GATA3, and high release of IL-10 and IL-4. Inhibition of survivin was associated with a sequential impairment of Bcl-6 functions and small follicular T and B cell populations, and poor affinity maturation of antigen-specific antibodies.

Conclusion: We show that survivin is the essential regulator of molecular and cellular events in the pathogenesis of arthritis. It enhances synovial proliferation and aggressive growth and participates in the mounting of antigen-dependent T and B cell responses. Importantly, survivin regulates the Bcl-6 dependent events attracting attention to the important role of this duo in the pathogenesis of rheumatoid arthritis.

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« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/survivin-inhibition-disturbs-bcl-6-and-blimp-1-control-of-lymphocyte-maturation-and-alleviates-antigen-induced-arthritis/