FRI0381 Interferon Dysregulation in an Academic SLE Cohort is Associated with Distinct Signaling Differences in Blood Neutrophils VS. Peripheral Blood Mononuclear Cells
Authors: W. White, D. Drubin, X. Guo, L. Yang, R. Zeng, Y. Wu, M. Roberts, R. Lescarbeau, A. Van Hooser, M. Macoritto, M. Petri
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Interferons (IFNs) have long been implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, the specific consequences of IFN activity have not been well-defined. In this study, the biology associated with an IFN activity signature was assessed in SLE blood neutrophil and PBMC fractions. <h3>Objectives</h3> We assessed the alterations in the transcriptome of isolated SLE blood PBMCs and neutrophils associated with IFN dysregulation (IFN signature high vs. low), and used the data to describe activation differences between the cell types. <h3>Methods</h3> RNA was collected from isolated blood PBMC and neutrophil fractions from a cohort of 46 SLE patients and 23 healthy donors. Study patients fulfilled both ACR and SLICC criteria for SLE and represented a clinical population with SLEDAI scores 0–12 (median 2). In addition, 63% were treated with prednisone, an immunosuppressant, or both. Patients were grouped by high or low IFN activity by assessing 21 IFN-inducible genes in PBMCs, and changes in gene expression were determined by RNA sequencing. Gene expression differences were analyzed further to determine the most likely upstream mechanistic explanations for the data in each comparison. The significance of these mechanisms is based on the evaluation of two metrics: 1) supporting gene change enrichment using a hypergeometric distribution, and 2) demonstrating directional consistency as assessed by a binomial distribution. Differential mechanisms between high and low IFN groups were examined in the context of those with activity assumed to be significantly different for SLE patients vs. healthy donors. <h3>Results</h3> This analysis identified mechanisms active in high vs. low IFN neutrophils (table). High IFN neutrophils exhibited unique mechanisms, including IFNG, mTOR, and CCL5-consistent signaling. TGFB1 and MAPK1 activation were distinct in low IFN neutrophils. Most mechanisms activated in PBMCs were common between the IFN groups, and were activated to similar degrees. <h3>Conclusions</h3> In this study of an academic cohort with active SLE and low SLEDAI scores, IFN signature correlated with biologic differences that predominate in neutrophils. The work permits better understanding of the impact of IFN signaling in SLE, by demonstrating different effects in neutrophil vs. PBMC fractions. <h3>Acknowledgements</h3> Research funded by MedImmune LLC <h3>Disclosure of Interest</h3> W. White Shareholder of: AstraZeneca, Employee of: MedImmune, D. Drubin Grant/research support from: MedImmune, X. Guo Shareholder of: AstraZeneca, Employee of: MedImmune, L. Yang Shareholder of: AstraZeneca, Employee of: MedImmune, R. Zeng Shareholder of: AstraZeneca, Employee of: MedImmune, Y. Wu: None declared, M. Roberts Employee of: MedImmune, R. Lescarbeau Grant/research support from: MedImmune, A. Van Hooser Grant/research support from: MedImmune, M. Macoritto Grant/research support from: MedImmune, M. Petri Grant/research support from: MedImmune