A novel subnetwork based analysis reveals shared pathways in T-cell mediated autoimmunity

Abstract

Thymocyte auto-reactivity is an underlying theme of several autoimmune disorders. The precise role of auto-reactive T cells in the initiation and subsequent progression of autoimmune disorders has been studied extensively. However, these disease specific studies ignore pathways that may be in common to several T cell mediated autoimmune pathologies. This can be attributed in part to the shortcomings of traditional gene list based gene expression studies. Here we report a novel method to identify unifying gene expression changes in several autoimmune diseases. In order to uncover pathologically important pathways common to T-cell mediated autoimmune disorders, we used human gene expression data from Multiple Sclerosis, Rheumatoid Arthritis, Juvenile Idiopathic Arthritis and Sjögren’s syndrome. Unlike traditional gene expression analysis, we used jointly active connected subnetwork enrichment to identify subnetworks for each disorder, followed by topological network alignment, which led to identification of shared pathways. We report four pathways shared in these disorders, which include DNA damage response, gonadotropin, innate and adaptive immunity pathways. Importantly, our method did not reveal any common pathways in unrelated diseases. In order to experimentally validate our findings, RNA sequencing of mRNA isolated from salivary glands excised from a murine model of Sjögren’s syndrome was performed. High similarities were observed between Human T-cell mediated autoimmune disorders and Sjögren’s murine model. Collectively, these studies have identified a shared landscape of pathologically significant pathways, including DNA damage response, gonadotropin, innate and adaptive immunity in autoimmune disorders and provide a new methodology to identify common alterations in diseases with similar underlying etiologies.