Objective
utoimmune diseases—like type 1 diabetes (T1D), lupus (SLE), and multiple sclerosis (MS)—happen when our immune system mistakenly attacks the body’s own cells. While these diseases appear different, they share a crucial genetic link: certain variations in molecules called human leukocyte antigens (HLA). These HLA proteins normally help the immune system distinguish “self” from “invader” by presenting small bits of proteins (peptides) to immune cells. But in autoimmune conditions, some HLA variants present the body’s own peptides in a way that fuels harmful attacks.
Our project’s main objective is to reveal precisely which peptides are displayed by “risk” HLA variants associated with T1D, SLE, and MS, and how these differ from peptides presented by “protective” HLA variants. By using a large-scale screening process to test millions of possible peptides, advanced computer models to predict which ones spark immunity, and single-cell analyses to find out which tissues produce them, we aim to uncover the critical targets that drive or prevent autoimmunity. Ultimately, this knowledge will guide more effective and targeted treatments—ones that stop destructive immune responses at the source without suppressing the body’s overall ability to fight infections.
Background Rationale
Autoimmune diseases—such as type 1 diabetes (T1D), lupus (SLE), and multiple sclerosis (MS)—occur when the immune system mistakenly targets the body’s own tissues. While these conditions may look very different on the surface, they all share strong genetic ties to specific human leukocyte antigen (HLA) genes. HLA molecules normally serve as “display cases,” presenting small bits of proteins (peptides) to immune cells so the body can distinguish between healthy tissues and potential threats.
In people carrying certain “risk” HLA variants, the immune system seems to misread the signals coming from these displayed peptides. Instead of ignoring proteins that belong in the body, immune cells treat them like foreign invaders and mount sustained, damaging attacks. These attacks can lead to the destruction of insulin-producing cells in T1D, widespread tissue inflammation in SLE, or harmful immune activity in the central nervous system for MS. On the other hand, “protective” HLA variants appear to prevent or minimize such misdirected immune responses, possibly by presenting peptides in a way that promotes tolerance rather than attack.
Despite knowing these HLA connections for decades, scientists still lack a clear picture of exactly which peptides are displayed by risk versus protective HLA variants—or how those differences lead to disease or protect against it. This knowledge gap keeps us from designing treatments that stop the immune system from targeting crucial tissues without suppressing its normal, healthy functions. By uncovering the precise peptides that trigger autoimmune damage, researchers hope to develop more targeted interventions—ones that block or alter problematic peptide displays while preserving the immune system’s vital ability to fight infections and heal injuries.
Description of Project
Autoimmune diseases - such as type 1 diabetes (T1D), systemic lupus erythematosus (SLE), and multiple sclerosis (MS) - affect millions worldwide. Although these diseases manifest differently - attacking distinct tissues like the pancreas in T1D, connective tissues and organs in SLE, or the nervous system in MS - these disorders share a surprising common thread: strong genetic associations within the human leukocyte antigen (HLA) system. HLA class II proteins normally show fragments of proteins (peptides) to immune cells, helping the body distinguish friend from foe. But certain HLA variants appear to present “self-peptides” in harmful ways, triggering chronic immune attacks on the body’s own tissues.
To uncover why some HLA alleles increase risk while others offer protection, we will use a cutting-edge yeast display platform. This approach lets us systematically screen millions of human protein fragments, revealing which ones latch onto “risk” versus “protective” HLA molecules. Next, we will apply advanced computer models—called protein language models—to understand the structural “grammar” of these interactions. By doing so, we can predict which peptides are most likely to incite damaging immune responses or promote tolerance. Finally, we will delve into single-cell RNA sequencing data to pinpoint the tissues and cell types that generate these critical peptides, offering insight into why the immune system might become overactive in T1D, SLE, or MS.
Ultimately, our work aims to move beyond generic immune suppression by spotlighting the precise peptides that drive autoimmunity - or block it. Such knowledge will pave the way for highly targeted therapies that interrupt pathogenic pathways without compromising healthy immune function. In clarifying the role of self-peptides in disease, we will chart a path toward more personalized and effective treatments that benefit patients across a range of autoimmune disorders.
Anticipated Outcome
By systematically identifying which peptides “risk” HLA variants display in autoimmune diseases—and contrasting those with peptides shown by “protective” HLA variants—this research aims to pinpoint the critical triggers of harmful immune responses. With these discoveries, scientists can design more targeted treatments that disrupt only the pathological side of the immune process without weakening the body’s natural defenses. Such approaches might include small-molecule drugs or custom-designed immune therapies that block specific peptide–HLA interactions. Ultimately, this precision strategy could reduce the need for broad, lifelong immunosuppression, which leaves patients vulnerable to infections and other complications. In the long term, understanding the detailed landscape of HLA–peptide presentation will open the door to interventions that restore immune tolerance and improve quality of life for individuals affected by type 1 diabetes, lupus, multiple sclerosis, and potentially other autoimmune disorders.
Relevance to T1D
Type 1 diabetes (T1D) occurs when the immune system destroys the insulin-producing beta cells in the pancreas, leading to serious complications if not properly managed. While people with T1D often rely on insulin injections to control blood sugar, the underlying autoimmune process remains poorly understood. Certain human leukocyte antigen (HLA) “risk” variants appear to present parts of pancreatic proteins in a way that provokes the body’s immune system to attack, whereas “protective” HLA variants seem to avoid these harmful peptide displays. By uncovering exactly which peptides are involved—and how HLA variants influence their presentation—this research could pave the way for more targeted therapies. Such treatments would aim to stop the immune attack against beta cells before they are destroyed, potentially reducing or even eliminating the need for chronic insulin therapy. Ultimately, a better grasp of how these HLA-peptide interactions drive T1D could lead to breakthroughs that significantly improve the lives of individuals at risk or living with the disease.