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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