Tu137 - Integrated Analysis of Serum Type I/II Interferons and RNA-Seq Identifies Interferon-mediated Cell Type-specific Effects and Prognostic Markers in SLE

Abstract Text: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease. Although interferon plays a central role in the pathogenesis of SLE, the specific effects of each type of interferon on immune cell types remain poorly understood. To uncover the cell type-specific effects of type I/II interferon, we performed an integrated analysis of RNA-seq and serum interferon measurements. We previously reported a bulk RNA-seq database for various immune cell types across multiple autoimmune diseases, including SLE. Serum levels of IFN-α and IFN-γ were measured using Simoa, an ultrasensitive digital ELISA technology, with stored serum samples from 112 SLE patients in this database. Differential gene expression and gene set enrichment analyses revealed that serum IFN-α levels were associated with oxidative phosphorylation and cell cycle pathways in T cells, particularly in Th1, ThA, and CD8 subsets, as well as in B cells. In contrast, serum IFN-γ levels were linked to antigen presentation pathways in monocytes and neutrophils. Focusing on 63 patients meeting the criteria for Lupus Low Disease Activity Status, those with elevated levels of both IFN-α and IFN-γ had the poorest prognosis (p = 0.002). Among all immune cell subsets, oxidative phosphorylation in ThA cells emerged as the most robust predictor of prognosis. In conclusion, a combined analysis of RNA-seq for various immune cell types and simultaneous measurement of serum IFN-α and IFN-γ uncovered the specific effects of each type of interferon. Gene expression analyses suggested that oxidative phosphorylation in ThA cells may serve as a novel therapeutic target to prevent disease flares.