Using the circulating proteome to assess type I interferon activity in systemic lupus erythematosus
Michael A. Smith, Chia-Chien Chiang, Kamelia Zerrouki, Saifur Rahman, Wendy I. White, Katie Streicher, William A. Rees, Adam Schiffenbauer, Lisa G. Rider, Frederick W. Miller, Zerai Manna, Sarfaraz Hasni, Mariana J. Kaplan, Richard M. Siegel, Dominic Sinibaldi, Miguel A. F. Sanjuán, Kerry A. Casey
Abstract
Abstract Type I interferon (IFN) drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts in blood. Here, we examined whether measurement of circulating proteins, which enter the bloodstream from inflamed tissues, also offers insight into global IFN activity. Using a novel protocol we generated 1,132 aptamer-based protein measurements from anti-dsDNA pos SLE blood samples and derived an IFN protein signature (IFNPS) that approximates the IFN 21-gene signature (IFNGS). Of 82 patients with SLE, IFNPS was elevated for 89% of IFNGS-high patients (49/55) and 26% of IFNGS-low patients (7/27). IFNGS-high/IFNPS-high patients exhibited activated NK, CD4, and CD8 T cells, while IFNPS-high only patients did not. IFNPS correlated with global disease activity in lymphopenic and non-lymphopenic patients and decreased following type I IFN neutralisation with anifrolumab in the SLE phase IIb study, MUSE. In summary, we developed a protein signature that reflects IFNGS and identifies a new subset of patients with SLE who have IFN activity.