Survivin Co-Ordinates Formation of Follicular T-Cells in Rheumatoid Arthritis

Maria Bokarewa¹, Karin Andersson², Malin Erlandsson², Mattias Svensson², Nicola Cavallini³ and Mikael Brisslert², ¹Guldhedsgatan 10, University of Goteborg, Goteborg, Sweden, ²Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden, ³Rheumatology and Inflammation Research, University of Göteborg, Göteborg, Sweden

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: autoantibodies and rheumatoid arthritis, pathogenesis, T cells

Session Information

Title: T cell Biology and Targets in Autoimmune Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose

Survivin is a proto-oncogene that regulates cell division and apoptosis. Recently, survivin has emerged as a biomarker of persistently active and joint destructive rheumatoid arthritis (RA). High serum levels of survivin are frequently associated with antibodies against cyclic citrullinated epitopes (ACPA).

Here we study the role of survivin in the formation of follicular T-cells and in the antibody production in RA.

Methods

The intracellular expression of survivin and Bcl-6 was studied in RA patients (age 21-71 years, disease duration 1-49 years) by flow cytometry and qPCR. DNA binding of survivin and Bcl-6 was studied in stimulated PBMC by chromatin immunoprecipitation.

The effect of survivin modulation on the follicular T-cells and on production of antigen-specific and autoantibodies was studied in collagen-immunized arthritis (CIA) mice, where Survivin transcription was inhibited by shRNA–lentiviral construct (shSurv, 10⁶-10⁷ particles/mouse). In separate experiments, CIA mice were vaccinated with survivin-peptides before the CII immunization. Control CIA mice received non-targeting transduction particles or were vaccinated with irrelevant peptides.

Results

The sSurv+RA group (n=76) was characterized by higher frequency of RF+ and ACPA+ patients, as well as by higher levels of ACPA compared to sSurv-RA (n=68). Intracellular survivin was present in the effector (CD45RA+CD27-) CD4+ T cells. Survivin co-expressed with Bcl-6 on lymphocytes of arthritic mice and in RA patients. Bcl-6+ subset comprised 7-38% of surv+CD4+ T-cells and was also CXCR5+. Bcl6+Surv+ subset of CD4 T cells and mRNA levels of Bcl-6 were lower in blood of sSurv⁺patients.

Follicular (CXCR5+PD-1+) CD4 population in spleen and lymph nodes of arthritic DBA1 mice were mostly surv+Bcl6+. Mice vaccinated with survivin-derived peptides developed the phenotype similar to sSurv+RA patients and had high serum levels of survivin and higher levels of aCII and RF antibodies. Surv-vaccinated mice had significantly increased survivin expression and the subset of surv+Bcl-6+ within CXCR5+CD4+ cells in LN. shSurv-treated mice had reduced CD4+surv+ and CD19+surv+ populations in spleens, and smaller CXCR5+CD4+ and CXCR5+B220+ populations, while Bcl-6 gene transcription was increased. Inhibiting survivin led to lower levels of anti-CII antibodies and lower RF, suggesting insufficient Bcl-6 and poor Tfh development. Chromatin immunoprecipitation showed that survivin binds within Bcl-6 responsive element of Blipm-1 promoter potentially controlling transcriptional activity of Bcl-6.

Conclusion

In this study we demonstrate that RA patients have co-expression of survivin and Bcl-6 in the follicular T helper cells. Changes in survivin transcription modulate formation and function of the follicular T cells by regulating transcriptional activity of Bcl-6, essential factor of germinal center formation and autoantibody production.

Disclosure:

M. Bokarewa,
None;

K. Andersson,
None;

M. Erlandsson,
None;

M. Svensson,
None;

N. Cavallini,
None;

M. Brisslert,
None.

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