Objective
Autoimmune diseases are polygenic, meaning that many DNA variants across the genome of an individual influence their disease susceptibility. While this is a well accepted feature of MS, T1D, and SLE, most studies have focused on the effects of DNA risk variants individually, which restricts insights gained. Because all the variants collectively present in an individual are most predictive of disease risk, we aim to conduct studies regarding the origins of autoimmunity through the lens of variant combinations. Specifically, we seek to define the signaling pathways disrupted by combinations of disease associated variants and to understand how variant combinations work together to control a specific pathway with known importance to CD4+ T cell behavior and autoimmune disease risk. Through this knowledge, we hope to find therapeutic targets that are specific to the causes of disease and better understand how to prioritize therapies based on specific DNA variants.
Background Rationale
Autoimmune diseases represent a diverse and increasingly prevalent collection of disorders with a strong genetic component. Human genetic studies have defined over 100 regions of DNA associated with risk of each MS, T1D, and SLE. However, because most of these regions are not directly inside DNA that encodes genes, it has been challenging to understand precisely how these variants alter immune function to promote disease. Interestingly, even though MS, T1D and SLE have distinct symptoms and largely affect different tissues in the body, each of these diseases share several genetic risk elements, suggesting that there are conserved underlying molecular changes driving pathology. Importantly, this indicates that treatment strategies designed to target the early drivers of disease may be effective across these contexts. However, there remains limited understanding of mechanics governing disease susceptibility which has restricted the development of therapies specific to the source of dysfunction
Based on functional annotations of the genome, many autoimmune risk variants are predicted to affect a specific subset of immune cells, called CD4+ T cells. These cells recruit and activate other cell types and can illicit chain-reactions across the immune compartment, leading to increased inflammation in certain contexts. CD4+ T cells been demonstrated to exacerbate disease symptoms in MS, T1D, and SLE patients, which confirms their importance to disease progression. However, CD4+ T cell behavior can still vary by indication and their exact role in initiating disease is yet to be fully revealed. By improving our understanding of how disease associated variants influence CD4+ T cell function, we can pinpoint the origins of disease and reveal opportunities to therapeutically target these epicenters. Additionally, autoimmune diseases are polygenic, meaning that many DNA variants drive disease risk as opposed to one variant per person. While this is a well-accepted feature of MS, T1D, and SLE, most studies have focused on the effects of DNA risk variants individually. Ultimately, the combination of variants in a person determines overall disease risk. To understand disease susceptibility, an improved understanding of the convergent and cooperative effects of disease associated variants is required. We seek to integrate what is known about the cell types and genetic variants that contribute to disease risk and perform studies that create a more cohesive picture of autoimmune susceptibility.
Description of Project
Across the human genome, hundreds of DNA variants have been associated with risk of autoimmune disease, many of which are shared risk factors for a combination of multiple sclerosis (MS), type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). However, the majority of these variants lie outside of gene bodies, in regulatory DNA that has subtle effects on gene expression, which has limited our understanding of the root causes of each disease. Despite distinct symptoms, MS, T1D, and SLE have several overlapping DNA risk elements, suggesting shared underlying mechanisms that may inform development of widely applicable therapeutic strategies.
Our objective is to use genetic clues regarding the origins of MS, T1D, and SLE to overcome existing knowledge gaps and identify drug targets relevant to disease causing pathways. Genetic studies have shown that many of these DNA variants are present in regulatory regions active in a specific immune cell subset called CD4+ T cells. This cell type has been demonstrated to promote inflammation in patients and mediates some of the central features of disease progression. Our studies will focus on revealing changes in CD4+ T cell signaling caused by disease risk variants that might precede disease onset. Additionally, autoimmune disease risk is most strongly conferred by the combination of disease associated variants, although most studies have focused on individual regions of DNA in isolation. We aim to understand how combinations of autoimmune associated DNA variants collectively push CD4+ T cells into a harmful state that promotes inflammation. We will use gene editing technology to program combinations of disease associated variants into human CD4+ T cells for in depth analysis of the key features that drive disease risk. Ultimately, we strive to identify regulators which we can therapeutically target to prevent disease onset and progression. We believe that this work will improve our ability to address the source of dysfunction with therapeutic intervention and tailor strategies to fit specific patient needs.
Anticipated Outcome
From the proposed work, we anticipate an improved understanding of the genetic causes of autoimmunity. Specifically, we will aim to distinguish the pathways that are dysfunctional in immune cells with combinations of MS, T1D, or SLE risk DNA variants. From this data, we will gain an understanding of the shared and disease specific changes that increase disease susceptibility. We anticipate that within these pathways, there are druggable targets we can inhibit to treat disease symptoms and potentially even prevent the initiation of disease in high-risk individuals. This proposal will both identify changes that increase disease susceptibility and assess intervention strategies to stop dysfunction from occurring.
Relevance to T1D
In this work, we will specifically create and profile human cells at high genetic risk of MS, T1D, and SLE to understand the features of cell function that likely contribute to disease susceptibility. This work will be done in CD4+ T cells, which have been distinguished as drivers of some of the features of these diseases, using genetic risk variants significantly associated with each of the disorders. By studying the 100s of DNA regions that have been associated with these autoimmune diseases through gene editing and sequencing assays, we will gain an improved mechanistic understanding of the sources of each indication and identify potential therapeutic interventions.