Endocrine Abstracts

Objectives: Autoimmune diseases are typically studied with a focus on the immune system, and less attention is paid to responses of target tissues exposed to the immune assault. We aimed to evaluate, based on available bulk RNA sequencing data, whether inflammation induces similar molecular signatures in the target tissues of five autoimmune diseases, namely type 1 diabetes (T1D), Hashimoto’s thyroiditis (HT), rheumatoid arthritis (RA), multiple sclerosis (MS) and systemic lupus erythematosus (SLE). Part of these data, related to T1D, RA, MS and SLE, but not HT, have been recently published (Szymczak et al, Sci Adv 2021). We next mined the datasets to discover similar and disease-specific gene signatures that could be targeted for therapy, including by repurposing drugs already in clinical use for other diseases.

Methods: We quantified the transcriptome from the target tissues of patients and healthy donors for each disease using our bioinformatics pipeline and performed differential gene expression analysis to capture their molecular footprints. Next, we compared the differential expression results of each tissue by Rank-Rank Hypergeometric Overlap (RRHO) to study commonly regulated genes and evaluated shared metabolic pathways. These pathways were then used to identify drugs that could be repurposed. We also performed bulk and single- cell RNA sequencing of induced pluripotent stem cell (iPSC) derived §-cells exposed to lFNo as biological confirmation to evaluate its impact in the different cell (sub)populations.

Results: There are important similarities among up-regulated, but not down-regulated genes, in the target tissues of the five autoimmune diseases studied; common findings include antigen presentation and interferon signatures. The two closest gene expression signatures were observed between T1D and HT. We selected type I lFNs for biological confirmation in human §-cells. Enrichment analysis of commonly up-regulated pathways between target tissues of T1D and HT identified neutrophil degranulation, signaling downstream of type I and type II lFNs, cytokine-cytokine receptor interactions, and cell adhesion molecules, among others. iPSC-derived §- cells exposed to IFNo showed enrichment of pathways related to interferon signaling and antigen presentation but also depletion of pathways related to citric acid cycle and electron transport chain. The effects of IFNo seem to be more marked in specific cell subpopulations. in silico comparison of the top 150 up-regulated genes overlapping between T1D and HT (from the RRHO) against drug-modified datasets highlighted bile acid-derived molecules (which may protect against ER stress) and dihydrofolate-reductase inhibitors as potential candidates to be repurposed.

Conclusions: These novel observations emphasize the role for lFNs in autoimmune diseases and point to novel therapeutic approaches to protect the target tissues of these diseases. Furthermore, our approach offers a method to screen and identify new drugs to be repurposed in a reduced bench-to-bedside timeframe.