Survivin Essential for the Maturation of Antigen Presenting Cells in Rheumatoid Arthritis Patients

Patients with rheumatoid arthritis (RA) have high levels of survivin and Flt3 ligand (Flt3L) in their blood and synovial fluid. Survivin has been shown to be an early and independent biomarker for patients with severe, joint-destructive RA as well as for patients with therapy-resistant RA. New research by investigators in this subject area suggests that, in patients with RA, survivin is essential for the survival of leukocytes as they differentiate and mature into dendritic cells, thereby raising it as a potential therapeutic target.

Previous studies have shown that Flt3/Flt3L signaling is important for hematopoietic maturation. Studies also have demonstrated that peripheral dendritic cells mature in the spleen and do so in a process that is dependent on Flt3 expression. When Flt3L-induced expression was evaluated for its effect on different survivin transcripts, it was found that the short survivin40 transcript is modulated by Flt3 in the bone marrow.

Sofia E. M. Andersson and colleagues worked in the laboratory of Maria I. Bokarewa, MD, PhD, in the University of Goteberg in Sweden and evaluated the requirement of Flt3/Flt3L signaling for expression of survivin.¹ They measured survivin levels in the blood of 104 healthy controls and calculated that a level of survivin greater than 450 pg/ml was present in fewer than 5% of healthy individuals. The investigators then sought to better understand the relationship between survivin and Flt3L levels in RA patients. They used arthritic mice and found that survivin gene expression was four times higher in the bone marrow than in the spleen. Moreover, when mice were treated with Flt3L, transcription of survivin was higher in the bone marrow than in the spleen.

The team then hypothesized that blocking the Flt3 receptor would affect survivin production in the bone marrow. The Flt3 inhibitor sunitinib reduced survivin expression in the MHCII+CD11-chi dendritic cell population in the spleen. They also found that Flt3/Flt3L system was downregulated when BALB/c mice were treated with survivin shRNA.

Thus, in the current study, the authors were able to treat mice with an Flt3 inhibitor and thereby decrease survivin expression in the bone marrow and in the dendritic cell population in the spleen. When survivin transcription was inhibited by shRNA lentiviral constructs, there was a corresponding reduction in the gene expression of Flt3L. The authors concluded that survivin expression is a downstream event of Flt3L signaling and that it serves as an essential mechanism of survival for bone marrow and spleen hematopoietic cells as they mature and differentiate into antigen presenting cells.