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302 Serum cytokine analysis and transcriptional blood profiling reveal an association between il-3 and ifn in human sle
  1. S Oon1,
  2. K Monaghan2,
  3. M Ng2,
  4. A Hoi3,
  5. E Morand3,
  6. N Wilson2 and
  7. I Wicks1
  1. 1The Walter and Eliza Hall Institute of Medical Research, Inflammation, Parkville, Australia
  2. 2CSL Limited, Pre clinical biology, Parkville, Australia
  3. 3Monash University, Medicine, Melbourne, Australia

Abstract

Background and aims IFNα, produced by plasmacytoid dendritic cells (pDCs) is a major contributor to SLE pathogenesis. IL-3 promotes pDC survival, but its role in SLE has not been well characterised. This study investigated serum IL-3 and IFNα levels, and a whole blood ‘IL-3 gene signature’ in human SLE.

Methods Serum cytokine levels were measured by ELISA in n=42 SLE donors from The Royal Melbourne Hospital and n=44 healthy donors (HD). IL-3 upregulated genes were determined by RNASeq of HD whole blood (WB) stimulated in vitro with IL-3 for 6 or 24 hours. WB RNASeq analysis was also undertaken in n=31 SLE donors from the Monash Lupus Clinic and n=28 HDs.

Results Serum IL-3 levels correlated with serum IFNα (r=0.612, 95% CI 0.455–0.733, p<0.001). IL-3 stimulation in vitro altered 794 genes (−1≥logFC ≥1, FDR<0.05). Thirty-five of these genes overlapped with differentially expressed genes between SLE and HD. These 35 genes were expressed in 28/31 SLE donors, revealing the presence of an ‘IL-3 gene signature’. There was strong correlation between the IL-3 signature and an IFN signature determined by heirarchical clustering of the five hundred most variable genes in SLE donors (r=0.939, 95% CI 0.898–0.964, p<0.0001).

Conclusions We have previously reported a novel anti-IL-3Rα mAb (CSL362/JNJ-473), which depletes pDCs and reduces IFNα production, as well as neutralising IL-3 signalling (Oon S, JCI Insight, 2016). An association between IL-3 and IFNα was found in this study, raising the possibility that CSL362 may be especially useful for lupus patients with a dual IL-3/IFN gene signature.

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