Using the Circulating Proteome to Assess Type I Interferon Activity in Systemic Lupus Erythematosus

Abstract Type I interferon (IFN) signaling drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts present in whole blood as described by several IFN gene signatures. As SLE is a complex disease affecting diverse organ systems, we examined whether measurement of circulating proteins, which can infiltrate the bloodstream from afflicted tissues, might also offer insight into global IFN activity. The presence of anti-DNA autoantibodies in patient serum has prevented effective use of SOMAmers for the evaluation of circulating proteins in SLE. Here, we adapted protocols to mitigate for those autoantibodies and report high reproducibility and accuracy with 100% QC pass rate and improved correlation with previously validated multi-analyte platform results. Using SOMAmers together with the IFN 21-gene signature1 (IFNGS), we derived an IFN protein signature that can approximate the IFNGS score. In a cohort of 82 SLE patients and 48 healthy donors, the protein signature was found elevated above healthy donors for most of IFNGS-high patients (49/55, 89%) and also for a subgroup of IFNGS-low patients (7/27, 26%). The protein signature correlated with global disease activity (median SLEDAI score of 4 for the cohort) in both lymphopenic and non-lymphopenic patients. Significant associations with skin involvement, low complement, anti DNA auto-antibodies, and thrombocytopenia were also observed. In sum, our results suggest blood derived protein measurements may complement validated gene signatures to monitor IFN activity.