Objective
The goal of this study is to investigate how a person's genetics influences their risk for developing type 1 diabetes. Specifically, our goal is to determine if and how the presence of the immune cell proteins, human leukocyte antigens (HLA), namely HLA-DR3 and HLA-DR4, lead to changes in the structure of the pancreas that confer susceptibility of beta cells to stress and destruction.
Background Rationale
Human leukocyte antigens (HLA) are proteins made by immune cells called macrophages. Macrophages use HLA proteins to inform other immune cells about potentially dangerous molecules that need to be destroyed. For example, macrophages can use HLA proteins to tell other immune cells about a specific molecule made by cancer cells. The other immune cells can then use that information to attack and destroy the cancer cells. However, sometimes the HLA proteins are made differently, which can lead to macrophages informing other immune cells about molecules that are not actually dangerous. In type 1 diabetes, macrophages use HLA proteins to tell other immune cells that insulin, or other beta cell molecules, are very dangerous, causing the other immune cells to destroy the beta cells. This is one way by which a person's genetics can influence their risk for developing type 1 diabetes--if their HLA genes lead to changes in their HLA proteins, specifically their HLA-DR proteins, then it becomes more likely that the macrophages will recognize and present a molecule like insulin as "dangerous." However, this does not appear to be the entire story. In addition to their function in communicating with other immune cells, macrophages play very important roles in regulating the structure and function of organ systems, including the pancreas and the pancreatic islets. For example, if macrophages are removed from the pancreas, then islets do not develop correctly, and beta cells do not make and release insulin like they should. Thus, a second way by which HLA proteins on macrophages could increase the risk of type 1 diabetes is by causing changes to the structure of islets and the pancreas as a whole that could lead to stressful cellular "neighborhood" for the beta cells. Our goal, as noted above, is to investigate whether this is true, and, if so, determine how we can use this information to better predict who will eventually develop type 1 diabetes, as well as how to use this information to prevent the disease from occurring in people who are at high genetic risk.
Description of Project
Type 1 diabetes is a disease that tends to run in families, since certain genes, which can be passed down to children from their parents, are associated with the development of the disease. In particular, people who have genes that cause their bodies to make certain types of “human leukocyte antigen,” or “HLA” proteins, called HLA-DR3 and HLA-DR4, have a much higher risk of developing type 1 diabetes than people who do not have those genes. However, it is unknown how the presence of HLA-DR3 or HLA-DR4 contributes to a person’s risk for type 1 diabetes, and why many people who have these HLA types never become diabetic. In this project, we propose to use a new class of technologies called “spatial omics” on human tissues to study how HLA-DR3 and HLA-DR4 might change the structure and gene expression of the pancreas and immune tissues, like the spleen and lymph nodes. Through this work, we hope to better understand how a person’s genetics contributes to their risk for type 1 diabetes, and to find better ways to predict who will eventually develop the disease.
Anticipated Outcome
We expect that this study will enhance our understanding of how a person's genetics affects their risk for type 1 diabetes. We also anticipate that this study will lead to a better understanding of how islet structure is related to its function.
Relevance to T1D
People who are related to patients with type 1 diabetes are at a higher risk of developing the disease; however, we do not fully understand why, or know how to prevent type 1 diabetes in people who have an increased risk. If we can better understand the relationship between the HLAs, which are inherited from our parents, and factors in our environment, and how they interact to promote beta cell dysfunction, then will can better predict who is at the highest risk, and, hopefully, develop new ways to prevent type 1 diabetes in those people.