Ab0117 association of Autoantibodies With the Ifn Signature and Netosis in Patients With Systemic Lupus Erythematosus

Abstract

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by a variety of disease symptoms and an unpredictable clinical course. SLE can lead to premature death as the result of disease activity or because of treatment side effects. This underlines the urgency to identify patients at risk for a complicated disease course, and the need to tailor therapy. Stratification based on immunological manifestations such as autoantibodies, upregulation of type I interferon (IFN) regulated genes (IFN signature) and neutrophil extracellular trap (NET) formation via NETosis can help to improve treatment outcome in SLE.ObjectivesHere we study the association between SLE-related autoantibodies, the IFN signature and NET formation in patients with SLE, which could lead to improved tools for patient stratification and more targeted treatment options.MethodsWe studied the association between the IFN signature and plasma induced NET formation with 57 autoantibodies in 25 patients with SLE. The presence of an IFN signature was determined using the sum of standardized mRNA expression of IFI44L, IFITM1, SERPING1, and LY6E in monocytes from SLE patients. Plasma induced NET formation was studied with quantitative live imaging. The threshold for the presence of an IFN signature or NET formation were both set at 2 SD above the mean of a group of healthy controls. With principal component analysis (PCA) and hierarchical clustering we associated autoantibody concentrations with the IFN signature and NET formation. This study was a separate analysis from larger cohorts, of which results have been previously published.[1,2]ResultsWe observed two distinct clusters with the PCA: one cluster contained mostly patients with an IFN signature, and another cluster contained a mix of patients with (IFN) and without (noIFN) an IFN signature. Patients with (NET) and without (noNET) plasma induced NET formation were equally distributed between the clusters. PC1 explains 22.7% of total variability, and is mainly driven by antibodies against histones, RibP2, RibP0, EphB2, RibP1, PCNA, dsDNA, and nucleosome. Hierarchical cluster analysis confirmed the two clusters (Figure 1). In addition, we found a trend towards increased concentrations of autoantibodies against EphB2, RibP1, and RNP70 in patients with an IFN signature. We found a negative correlation of NET formation with anti-FcER and anti-PmScl100.ConclusionWe identified a subgroup of patients with an IFN signature who express increased concentrations of antibodies against DNA and RNA-associated proteins. We did not find positive associations between autoantibodies and plasma induced NET formation. Our study further strengthens the evidence of a correlation between RNA-binding autoantibodies and the IFN signature. As the IFN signature currently is not part of the standard follow-up for patients, partially due to its associated costs, a profile of DNA and RNA-binding autoantibodies might be used for patient stratification, especially related to anti-IFN treatment.References[1]Brunekreef, T., et al. (2021). “Microarray testing in patients with systemic lupus erythematosus identifies a high prevalence of CpG DNA-binding antibodies.” Lupus Sci Med 8(1).[2]van der Linden, M., et al. (2018). “Neutrophil extracellular trap release is associated with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome.” Rheumatology (Oxford) 57(7): 1228-1234.Figure 1.A distinct autoantibody pattern is present in a subgroup of patients with an IFN signature. Footnote: Heatmap of Z-scores for 57 autoantibodies in 25 SLE patients. Vertical axis shows clustering of patients based on IFN signature (blue) or NET formation (orange/brown). Horizontal axis represents clustering based on autoantibody profiles.Acknowledgements:NIL.Disclosure of InterestsNone Declared.