Comparison of gene expression signatures in the target tissues of four autoimmune diseases show up-regulation of interferon pathways and indicate potential therapeutic targets
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Autoimmune diseases occur when the immune system cannot differentiate between the host body and a foreign object, and mistakenly attacks the host. Many different types of autoimmune diseases affect approximately 5-8% of the world population (Fugger et al. 2020). Not only are these physically devastating conditions, but most of the therapies being used to treat them are not currently effective in the majority of patients (Fugger et al. 2020). In an effort to better understand this serious health concern and seek out new treatment options, Szymczak et al. studied gene expression levels in the tissues targeted by the immune system for four different diseases (Szymczak et al. 2021). They compared the levels of expression across all four to identify potential therapeutic targets. Their research aimed to identify the similarities and differences between the lists of genes affected by each disease, and use that data to find gene pathways in common that could be targeted for therapy. These gene pathways, if found, could also indicate drugs already in existence to be repurposed for treatment of these autoimmune diseases.
For this study, the authors examined RNA sequencing datasets compiled by other researchers. RNA-seq showed them what genes were being transcribed and expressed in the target tissues of patients with type 1 diabetes (T1D), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA) where the tissues they examined were pancreatic 𝛽 cells, kidney cells, optic chiasm, and joint tissue respectively. Of the autoimmune diseases they could have studied, these four were selected because they shared several common features, such as they all have the same gene variants commonly associated with disease risk (as determined by a genome-wide association study), and they often exhibit intense attacks by the immune system on target tissues followed by periods of decreased inflammation and partial recovery of the tissue. They compared the data from these patients to the RNA-seq data taken from control patients to determine what genes were being expressed differently in each disease. Once they did this, they were able to compare across diseases.
The results of this study successfully showed that the autoimmune diseases examined had several genes that were differentially expressed in all four illnesses, and pointed the researchers towards types of drugs that might be able to treat autoimmune diseases. Furthermore, these results led the authors to conclude that future research would benefit from studying how the immune system communicates with the target tissues. Most of the genes in common between the diseases were up-regulated, while the down-regulated genes tended to be specific to the function of the target tissue in question. Of the up-regulated gene pathways, they found the most common ones were pathways related to antigen presentation, activation of immune cells, or interferon pathways. Interferon pathways were enriched for all four diseases, especially T1D and SLE. Interferons (IFNs) are signals put out by the body that promote inflammation, so their up-regulation indicates the target tissues are triggering inflammatory responses in affected patients significantly more than control patients. They confirmed that the sequencing data reflected gene expression in non-immune cells in the target tissues by examining available single-cell/nucleus-RNA-sequencing data from affected tissues of each disease (in this instance pancreatic 𝛽 cells (T1D), kidney epithelial cells (SLE), brain neurons (MS), and synovial fybroblasts (RA)). They further illustrated the prevalence of IFN gene pathway expression in all four diseases with a type of analysis that allowed them to compare datasets and observe (dis)similarities between all possible pairs of diseases. This showed that interferon signatures were present in all four target tissues.
From these results, the authors identified several classes of drugs that could be used to treat multiple different autoimmune diseases, and of those drugs they were especially interested in JAK inhibitors. JAK inhibitors block activation of kinases JAK1 and JAK2 downstream in the IFN pathway, preventing IFNs from triggering an inflammatory response. Another promising result of the study was the identification of the candidate gene TYK2, which they found across all four diseases. TYK2 is an important piece of the JAK-STAT signaling pathway. Both JAK inhibitors and TYK2 inhibitors are already being investigated as possible treatment options (JAK inhibitors have been approved for RA and have promising clinical trial results for patients with SLE, TYK2 inhibitors are in clinical trials for psoriasis), which means we already know more about them and their pharmacological effects than if we were studying them anew.
These findings have great potential to help develop new therapies for autoimmune diseases. Identificaiton of these pathways gives us more insight into common functionalities among different autoimmune diseases, which will allow us to treat them better in the future. However it is important to remember that these results only identified pathways for the inflammatory response shared by these diseases, and do not address treatment of other symptoms or causes of these diseaes. Furthermore this study only examines four diseases out of the scores of autoimmune sicknesses we have identified. The paper also had some limitations in the scarcity of RNA-seq data for target tissues in affected patients, and the prescence of immune cells in the target tissues which have the potential to skew the data. If future research were to address these limitations, and continue these comparisons with a broader scope of diseases, the inclusion of genetic data in developing therapies could lead to better treatment for these diseases.
References:
Fugger L., L. T. Jensen, and J. Rossjohn, 2020 Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases. Cell 181: 63–80. https://pubmed.ncbi.nlm.nih.gov/32243797/
Szymczak F., M. L. Colli, M. J. Mamula, C. Evans-Molina, and D. L. Eizirik, 2021 Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. Sci Adv 7.https://pubmed.ncbi.nlm.nih.gov/33523973/
Isabelle Wierum is a junior Bioinformatics major at Davidson College. Contact her at iswierum@davidson.edu.
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