The role of the cofilin-actin rod stress response in neurodegenerative diseases uncovers potential new drug targets.

OBJECTIVES

Increased expression of type I interferon-induced genes is a hallmark of systemic lupus erythematosus (SLE). Measurement of interferon proteins in plasma has been challenging due to their low abundance. Here we utilise a new high sensitivity assay to evaluate levels of interferon proteins in SLE patients.

METHODS

Seven interferon proteins (type I: IFNα1:IFNα13, IFNα2, IFNβ, IFNω; type II: IFNγ; type III: IFNλ1, IFNλ2:IFNλ3) were measured in 266 SLE patients using the NULISAseq Inflammation Panel 250 (Alamar Biosciences). IFN profiles (normal or high) were determined using the 95th percentile threshold in healthy controls for each IFN protein. Their relationship to disease activity and type I interferon-stimulated gene (ISG) scores was assessed.

RESULTS

All seven IFN proteins were significantly increased in SLE patients compared to healthy controls and were higher in patients with anti-Sm, anti-Ro and anti-RNP antibodies. IFNα1:IFNα13, IFNα2 and IFNω strongly correlated with the ISG score whereas IFNβ did not. The median levels of IFNα1:IFNα13, IFNα2, IFNω, IFNλ1 and IFNλ2:IFNλ3 progressively increased with disease activity whereas this was not the case for either IFNβ or IFNγ. The most frequent IFN profiles were high type I+III (35%, n=93); normal levels of all IFN proteins (25%, n=67); high type I only (21%, n=56); and high type I+II+III (13%, n=34). The latter associated with serological activity (low complement and high dsDNA antibody titres) and nephritis.

CONCLUSIONS

Plasma levels of type I IFN proteins (IFNα1: IFNα13, IFNα2 and IFNω but not IFNβ) and type III IFN proteins (IFNλ1, IFNλ2:IFNλ3) were increased in active disease groups and ISG scores recapitulated this. Longitudinal intra-individual measures of these proteins are needed to explore their utility as biomarkers for SLE disease activity.