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 Siegel; Dominic Sinibaldi; Miguel A Sanjuan; Kerry A Casey

doi:10.1038/s41598-020-60563-9

Using the circulating proteome to assess type I interferon activity in systemic lupus erythematosus

Sci Rep. 2020 Mar 10;10(1):4462. doi: 10.1038/s41598-020-60563-9.

Authors

Michael A Smith¹, Chia-Chien Chiang¹, Kamelia Zerrouki¹, Saifur Rahman¹, Wendy I White¹, Katie Streicher¹, William A Rees¹, Adam Schiffenbauer², Lisa G Rider², Frederick W Miller², Zerai Manna³, Sarfaraz Hasni³, Mariana J Kaplan⁴, Richard Siegel⁵, Dominic Sinibaldi⁶, Miguel A Sanjuan¹, Kerry A Casey⁷

Affiliations

¹ AstraZeneca, Gaithersburg, MD, USA.
² Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA.
³ Lupus Clinical Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
⁴ Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, USA.
⁵ Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
⁶ AstraZeneca, Gaithersburg, MD, USA. dominic.sinibaldi@astrazeneca.com.
⁷ AstraZeneca, Gaithersburg, MD, USA. kerry.casey@bms.com.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal, Humanized / pharmacology*
Autoantibodies / blood*
Biomarkers / blood*
Gene Expression Profiling
Humans
Interferon Type I / metabolism*
Lupus Erythematosus, Systemic / blood*
Lupus Erythematosus, Systemic / drug therapy
Lupus Erythematosus, Systemic / genetics
Proteome / analysis*
Severity of Illness Index

Substances

Antibodies, Monoclonal, Humanized
Autoantibodies
Biomarkers
Interferon Type I
Proteome
anifrolumab