title: Suppressed diversity of survivin splicing in active rheumatoid arthritis.
abstract: BACKGROUND
  Alternative splicing distinguishes normal and pathologic cells. High levels of oncoprotein survivin recognise patients with severe rheumatoid arthritis (RA). Here, we assess clinical relevance of alternative splicing of survivin in leukocytes of peripheral blood (PBMC) and bone marrow (BM) in RA patients.
  
  
  METHODS
  Transcription of survivin wild-type (survivin-WT), survivin-2B and survivin-ΔEx3 was measured in 67 randomly selected RA patients and in 23 patients before and after B cell depletion with rituximab. Analysis was done in relation to disease activity, anti-rheumatic treatment and serum levels of rheumatoid factor (RF) and survivin.
  
  
  RESULTS
  Survivin-WT was the dominant splice variant equally expressed in T and B cells, while survivin-2B and survivin-ΔEx3 were higher in B cells. High disease activity (DAS28>5.1) was associated with an excess of survivin-WT and low ratios between survivin-2B/WT (p=0.035) and survivin-ΔEx3/WT in PBMC. Depletion of B cells by rituximab caused a decrease in survivin-WT (p=0.005) in PBMC, increasing the ratio between survivin-2B/WT (p=0.009) and survivin-ΔEx3/WT (p=0.001) in BM. This increase in survivin-2B/WT was associated with reduction in CD19+ BM cells (r=0.929, p=0.007), RF (IgM, r=0.857, p=0.024; IgA, r=0.739, p=0.021), and DAS28 (0.636, p=0.054). The increase in survivin-ΔEx3 in BM was associated with a reduction of CD19+ BM cells (r=0.714, p=0.058) and DAS28 (r=0.648, p=0.049), while survivin-ΔEx3/WT was associated with RF (IgG, r=0.882, p=0.016).
  
  
  CONCLUSIONS
  This study demonstrates that the suppressed diversity of survivin splicing in leukocytes may attribute to adverse self-recognition in RA. Depletion of autoantibody producing B cells improves the balance of survivin splicing.
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, BOX 480, SE-40530, Gothenburg, Sweden. minnaturkkila@outlook.com.
authors.forename: Minna
authors.initials: M
authors.lastname: Turkkila
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, BOX 480, SE-40530, Gothenburg, Sweden. karin.andersson@rheuma.gu.se.
authors.forename: Karin M E
authors.initials: KM
authors.lastname: Andersson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16 FE280, 171 77, Stockholm, Sweden. sylvie.amu@ki.se.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Amu
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, BOX 480, SE-40530, Gothenburg, Sweden. mikael.brisslert@rheuma.gu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, BOX 480, SE-40530, Gothenburg, Sweden. malin.erlandsson@rheuma.gu.se.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Erlandsson
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, BOX 480, SE-40530, Gothenburg, Sweden. sofia.silfversward@rheuma.gu.se.
authors.forename: Sofia
authors.initials: S
authors.lastname: Silfverswärd
authors.affiliation: Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Gothenburg University, BOX 480, SE-40530, Gothenburg, Sweden. maria.bokarewa@rheuma.gu.se.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Bokarewa
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D001323:Autoantibodies / Q000097:blood / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000097:blood* / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077022:Survivin
chemical_list: D001323:Autoantibodies; C107489:BIRC5 protein, human; D015415:Biomarkers; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin