Objective
Autoimmune diseases often exhibit a puzzling pattern: although harmful immune responses target molecules (autoantigens) found throughout an organ, the resulting inflammation tends to occur in patches rather than affecting the entire organ evenly. For example:
In type 1 diabetes, only about 20% of insulin-producing areas (islets) show inflammation, while surrounding tissue looks normal.
In cutaneous lupus, the rash occurs in clearly defined areas surrounded by normal skin.
We see patchy inflammation in many other autoimmune diseases like psoriasis, ulcerative colitis, giant cell arteritis, and atopic dermatitis. However, the exact mechanisms behind this remain unclear. A key question is what is happening at the boundary between inflamed and unaffected tissue.
The goal of this study is to understand how tissues protect themselves from damage in autoimmune diseases. We would like to examine tissue that surrounds inflamed areas in more detail. We think that in these areas there are mechanisms that dampen down autoimmune responses and would like to understand these in more detail. If we understood them better we may be able to boost them in people at risk of autoimmune disease to avoid tissue damage or make sure that the disease remains settled.
We are taking two approaches to explore this:
Aim 1: We would like to re-examine data that has previously been generated from many different autoimmune diseases, including SLE, rheumatoid arthritis and inflammatory bowel disease. This data is from a technique called “single cell RNA sequencing” where cells are isolated from an inflamed tissue one at the time and we measure what they are producing (RNA). We think that the mechanisms that protect tissue are similar in different organs and different autoimmune diseases. In many of these diseases, datasets has already been generated from inflamed areas, adjacent areas and entirely healthy tissue. We would like to reexamine these datasets, combining them to allow us to computationally define the shared biological mechanisms across organ system that allow different tissues to protect themselves from damages associated with autoimmunity. Our reason for this approach is that as more datasets across a range of autoimmune diseases are generated, we will have a better chance of identifying these mechanisms than if we focused on a single disease or organ at the type to perform these analyses.
Aim 2: We would like to generate new data to look at how tissue protects itself in the pancreas in Type 1 diabetes and in lupus skin rashes. In both conditions there are areas of inflammation surrounded by normal tissue. The position of individual cells - whether they are close to the inflammatory area or more distant - is probably very important but this information is usually lost by single cell RNA sequencing. Using a newer technology called “spatial transcriptomics” we can retain this information by measuring what individual cells produce on slides from affected tissue. We can see how cells change depending on how far they are from the inflammation and focus more closely on cells that immediately border inflamed areas.
The long-term goal of this effort is to uncover universal strategies that tissues use to prevent recurrent and spreading of inflammation. Results from this study could lead to innovative treatments that protect tissue from irreversible damage or restore the immune balance without long-term dependency on medications.
Background Rationale
The goal of this study is to understand how tissues protect themselves from damage in autoimmune diseases. We can see evidence of these defence mechanisms in the patchy distribution of inflammation in many conditions including type 1 diabetes, inflammatory bowel disease and SLE, where areas of active inflammation are surrounded by seemingly normal tissue. We are beginning to understand that these areas are not entirely normal, but have changes that resemble a mild version of the underlying disease. We think that in these areas the tissue is preventing full-blown inflammation to protect itself from damage. In this study we would like to understand how tissue does this in these regions. Understanding this will help us boost those responses to prevent organ damage. Because we see the same pattern in many different conditions we think it is likely that there are commonalities between different autoimmune diseases.
Understanding these patterns is crucial for addressing two major challenges in autoimmune diseases. In conditions like SLE, vasculitis, and rheumatoid arthritis, the goal is to sustain remission, and insights into natural remission mechanisms could aid this. In diseases such as type I diabetes, Sjogren’s syndrome, and Hashimoto’s thyroiditis, where tissue damage drives symptoms, studying how inflammation is contained could help prevent further damage.
Description of Project
Autoimmune diseases often exhibit a puzzling pattern: although harmful immune responses target molecules (autoantigens) found throughout an organ, the resulting inflammation tends to occur in patches rather than affecting the entire organ evenly. For example:
In type 1 diabetes, only about 20% of insulin-producing areas (islets) show inflammation, while surrounding tissue looks normal.
In cutaneous lupus, the rash occurs in clearly defined areas surrounded by normal skin
We see patchy inflammation in many other autoimmune diseases like psoriasis, ulcerative colitis, giant cell arteritis, and atopic dermatitis. However, the exact mechanisms behind this remain unclear. A key question is what is happening at the boundary between inflamed and unaffected tissue.
In response to infections, the immune system carefully balances clearing the threat while preventing excessive inflammation to avoid damaging tissues. We think a similar balance occurs in autoimmune diseases: while some areas show active inflammation, nearby tissues (called perilesional tissue) are partly protected. The mechanisms that protect this perilesional tissue are responsible for the patchy pattern of inflammation we see. In these regions the immune system isn't entirely normal - it shows a milder form of the immune activity seen in the disease. However, these boundary areas seem to strike a balance that suppresses inflammation and protects the tissue from further harm.
In conditions like type 1 diabetes, this protective balance can eventually fail, leading to significant damage to the pancreas and the loss of insulin-producing cells. The same occurs in other autoimmune diseases like Sjogren’s syndrome (causing dry eyes and dry mouth) and Hashimoto’s thyroiditis (causing hypothyroidism).
In other autoimmune conditions like systemic lupus erythematosus, rheumatoid arthritis and vasculitis inflammatory varies in intensity over time. Individuals experience periods of remission interspersed by flare. During periods of remission we think that, rather than tissues returning completely to normal, similar protective mechanisms keep inflammation settled.
We would like to understand these protective mechanisms. This is essential to prevent organ damage and preserve function or to keep disease in remission. If we understood them better we may be able to boost them in people at risk of autoimmune disease to avoid tissue damage or make sure that the disease remains settled.
We propose two different ways to examine this:
Single-cell RNA sequencing (scRNAseq): This is a technique that looks at what individual cells are making (RNA). We can use this to tell us what a cell is and what it is doing. This has been used in many autoimmune diseases before although not to answer this specific question. Much of this data is available for researchers to reuse. We will use this to look at perilesional tissue and healed tissue in multiple diseases and look for common patterns.
Spatial transcriptomics (ST): This technique uses microscope slides from tissue to measure what a cell is making (RNA). The advantage of this approach is that we also know where the cell is in tissue and can see how close it is to areas of inflammation. We aim to use this to identify the mechanisms that maintain the protective balance in tissues. We will initially apply this approach in type 1 diabetes and lupus rashes.
The ultimate goal is to uncover universal strategies that tissues use to prevent recurrent and spreading inflammation. This could lead to innovative treatments that protect tissue from damage or restore the immune balance without long-term dependency on medications.
Anticipated Outcome
This research will help us understand how tissues control autoimmune inflammation. The proposal will define mechanisms that are predicted to underlie remission and prevent damaging immune responses across many diseases. The ultimate goal is to leverage these findings for two significant clinical challenges in autoimmune disease:
(1) Organ damage from many autoimmune diseases is irreversible and results in serious illness in the long-term. This study will help guide the development of clinical trials of tolerogenic therapies that can be initiated early to prevent this process to retain organ function
(2) Many conditions are characterized by unpredictable cycles of flare and remission. Clinicians aim to keep patients in a state of remission but also to avoid over-treating with immunosuppression given its negative effects. This is currently very difficult and there are often no biomarkers to guide these decisions. This study will help (a) characterize remission to help personalize treatment decisions and (b) identify the processes responsible so they can be boosted with treatment.
Relevance to T1D
Type 1 diabetes (T1D) is a chronic autoimmune condition where the body's immune system mistakenly attacks the insulin-producing beta cells in the pancreas. Insulin is a hormone essential for regulating blood sugar levels by allowing glucose to enter cells for energy. Without enough insulin, blood sugar levels rise dangerously high, leading to various complications. In contrast to many other forms of autoimmunity, inflammation in T1D is asymptomatic and the damage to the pancreas is the primary cause of symptoms.
When we have an infection the immune system attacks the bug and removes it rapidly. In contrast, when the immune system attacks the pancreas in T1D, it is generally a slow process that takes place over months or years. Unusually the inflammation in the pancreas tends to be patchy rather than affecting all of the beta cells at once. We think that this is because there are mechanisms that are active in the pancreas that protect it from damage. These mechanisms are eventually overwhelmed but understanding them, and how we can boost them, may be key to developing therapies to prevent loss of beta cells.
It can be difficult to visualize this process in the pancreas but we see a similar pattern of inflammation in other autoimmune diseases. Vitiligo is a skin condition where there is damage to the cells that produce pigment (melanocytes). Vitiligo is associated with type 1 diabetes - individuals who have one condition are more likely to have the other. In vitiligo we can see areas of loss of pigment surrounded by normal skin. We know that the apparently normal skin around the areas of vitiligo are not normal but are actively preventing the spread of inflammation.
In this study we aim to understand how tissue protects itself from autoimmune inflammation. This is particularly important in type 1 diabetes as we want to develop therapies that stop damage to beta cells and prevent the development of diabetes. We think these mechanisms are broadly relevant to other types of autoimmunity but it is interesting to study T1D because individuals are not usually on medication to suppress the immune system so we can get a clearer picture of how inflammation is controlled while knowing that what we see is not the result of treatment.
The hope of this study is that we will be able to describe how the body slows, controls and walls off inflammation in the pancreas in type 1 diabetes. With this knowledge we can work towards identifying individuals at risk and giving them therapies that can boost these processes and prevent the development of diabetes.