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-dsDNApos 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.
Highlights
Type I interferon (IFN) drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts in blood
High-dimensional flow cytometry revealed lower proportions of activated NK, CD4, and CD8 T cells in IFN protein signature (IFNPS)-high/IFN 21-gene signature (IFNGS)-low patients compared with IFNGS-high patients, suggesting that IFNPS can detect IFN activity even when activated cell populations are absent from the blood
Anti-dsDNA IgG was quantitated by autoantibody array and these continuous measurements were associated with the increased DNA-binding SLE Disease Activity Index (SLEDAI) component (Supplementary Fig. S1)
Summary
Type I interferon (IFN) drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts in blood. 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. IFN-inducible gene signatures have great utility in monitoring IFN activity in humans, revealing links between type I IFN and disease pathology. These methods have been inaccessible in autoimmune diseases that feature high titres of anti-DNA autoantibodies (eg, anti-dsDNA, anti-ssDNA, and anti-nucleosome antibodies) owing to assay interference To this end, we evaluated a novel protocol designed to mitigate interference from anti-DNA autoantibodies and, for the first time, we report aptamer-based protein measurements with strong reproducibility and accuracy from sera of patients with SLE. We observed suppression of the type I IFNPS following IFN alpha receptor (IFNAR) neutralisation in MUSE (NCT01438489), a phase IIb study of anifrolumab in moderate to severe SLE, demonstrating specificity of IFNPS for the type I IFN pathway[6]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.