Type 1 diabetes (T1D) exhibits significant heterogeneity in disease progression, driven in part by variable immune-mediated destruction of insulin-producing β cells. This project focuses on Programmed Death-Ligand 1 (PD-L1), a critical immune checkpoint protein that protects β cells by suppressing autoimmune responses via interaction with PD-1 on immune cells [1]. β cells also release PD-L1 […]
Year: 2025
Oxidized Insulin as a Biomarker for Type 1 Diabetes Pathogenesis
Reactive oxidants are generated during the metabolism of glucose and serve as important signaling messengers to trigger insulin secretion and beta cell expansion in response to elevated levels of glucose. However, chronic exposure to oxidants under hyperglycemic conditions causes chronic oxidative stress which results in cellular damage, impaired glucose-stimulated insulin secretion, and, eventually, cell death. […]
The role of beta cell lysosomal dysfunction in diabetes autoimmunity
As alterations in autophagic flux may contribute to T1D, we are seeking to determine if particular lysosomal components of beta cell autophagy participate in or dysregulate this essential process. The focus of this addendum is on the enzyme cathepsin H as specific genetic variants in this gene have been identified as T1D–associated SNPs. Through these […]
Role of pancreas-associated myeloid cells in homeostasis and T1D
This project aims to uncover how macrophage dysregulation promotes autoimmune β–cell destruction. Our lab has identified distinct pancreatic macrophage subtypes that mediate localized immune control by regulating T cell activity. Aim 1 will use single cell sequencing to comprehensively profile pancreatic macrophage subsets and their communication with T cells during immune homeostasis and in Type […]
Harnessing the local cholinergic anti-inflammatory reflex in the pancreatic islet to delay or prevent type 1 diabetes
Type 1 Diabetes (T1D) is characterized by autoimmune destruction of insulin-producing beta cells within the pancreatic islets. Resident macrophages in the islets play a key role in maintaining tissue homeostasis but can also promote inflammation. The cholinergic anti-inflammatory reflex, known to suppress inflammation, may influence islet macrophages, but direct cholinergic innervation has not been established. […]
Investigation of Myeloid CADM1 during T1D
Type 1 diabetes (T1D) is characterized by the hyperglycemia resulting from the autoimmune destruction of the insulin–expressing β–cells of the pancreas. As the prevalence of the disease continues to increase worldwide, it remains imperative to identify therapeutic strategies that can (1) preserve pancreatic beta–cell mass and function and (2) prevent the immune response that initiates […]
Pancreatic Beta-Cells, Oxidative Stress, and Gestational Diabetes
The late stages of mammalian pregnancy are accompanied by a mild increase in insulin resistance, likely due to enhanced glucose demand for the growing fetus. Therefore, as an adaptive process to maintain normal blood glucose levels during pregnancy, maternal insulin–producing cell (β–cell) mass expands, leading to increased insulin release. Defects in functional β–cell adaptive expansion […]
Proinsulin biosynthesis and (mis)folding in type 1 diabetes
A well–recognized feature of pancreatic ß–cells is their limited expression of endogenous antioxidants. From recent support by nPOD and HIRN/CBDS, my lab made the entirely novel observation, using metabolic labeling in pancreatic slices derived from 5 T1D donors, that disulfide–bond formation (i.e., folding) of newly–synthesized (radiolabeled) proinsulin is dramatically impaired with a surprisingly large fraction […]
Understanding common tissue tolerance mechanisms in autoimmunity
A curious feature of type I diabetes (T1D) is that, while the proteins that the immune system targets are broadly expressed in beta cells, inflammation of insulin-producing cells (insulitis) is patchy and damage develops gradually. In stage 1 or 2 T1D, prior to the onset of clinically evidence disease, the majority of insulin-producing cells are […]
Live human pancreas tissue slices as a platform for investigating the immunopathological processes of type 1 diabetes
Type 1 diabetes (T1D) is characterized by the loss of insulin producing β cells precipitated by infiltration of the pancreas by autoimmune T lymphocytes. We have shown that there is a parallel loss of function in the mass of β cells still remaining when T1D is diagnosed. This project aims to better understand how and […]
Immune receptor repertoires associated with type 1 diabetes progression
Immune receptors, including T cell receptors (TCRs) on T cells and B cell receptors (BCRs) on B cells, are central to immune responses, mediating antigen recognition and tissue specificity. Characterizing the immune receptor repertoires during type 1 diabetes (T1D) progression provides key insights into the T and B cell populations contributing to disease pathogenesis. The […]
Antigen discovery for regulatory T cells in T1D
The Brusko Lab is generally interested in the cellular immune response involved in the disease process leading to type 1 diabetes (T1D). A strong genetic association between T1D and the MHC class II gene region of the adaptive immune system has implicated coordinated T and B cell responses as a central mediator of the disease […]
T cell autoreactivity, phenotype and function directly from islets of donors with recent onset type 1 diabetes (T1D) and from donors with islet-associated autoantibodies, but without clinical disease
The goal of this project is to further our understanding of the CD4 T cells and CD8 T cells that infiltrate the islets in autoantibody+ donors at risk for development of type 1 diabetes (T1D) and from donors with recent onset T1D. We will hand pick islets from digests of live pancreas slices from the […]
Single Islet Functional Heterogeneity from control donors, auto antibody+ donors, and donors with recent onset type 1 diabetes (T1D)
In T1D, pancreatic islets are infiltrated by lymphocytes (so called “insulitis”) and those T cells appear to drive β-cell dysfunction, and death. However, it has been long observed that not all islets within a T1D donor’s pancreas are infiltrated; even those in close proximity such that some islets have many infiltrating T cells while others […]
Functional alpha cell heterogeneity
In type 1 diabetes (T1D), the destruction of insulin-producing beta cells is well known. But another emerging issue— not well understood—is the dysfunction of alpha cells. These cells produce glucagon, a hormone that helps prevent blood sugar from dropping too low. In people with T1D, alpha cells often fail to respond properly when blood sugar […]
Evaluation of the islet-immune interface in Cystic Fibrosis-related Diabetes
Cystic fibrosis (CF)-related diabetes (CFRD) is present in upwards of 20% of adolescents and 40-50% of adults with CF and is associated with significant glycemic variability, poor glycemic control, and unpredictable hypoglycemia. CFRD is increasing in prevalence as new disease-modifying therapies have led to a significant increase in life expectancy in those with CF. While […]
Assessing T1D islet dysfunction: β-β cell connectivity defects, T-cell induced islet dysfunction, and cystic fibrosis-related diabetes (CFRD)
The availability of pancreas slices from nPOD from T1D and normal control donors has provided a huge thrust in the study of T1D islet biology as it requires the inflamed islet to be intact within a pancreas slice for accurate assessment. We have developed capabilities to culture these pancreas slices for ~10 days allowing virus […]
Connection between alpha cell function and T-cell antigen specificity in type 1 diabetes
Given that in Aab+ donors alpha cells become dysfunctional before donor’s blood glucose levels are impaired, it is important to differentiate whether a) alpha cells become dysfunctional first, which attracts and activates immune cells, or b) vice versa. In pre–T1D the first phase insulin secretion is dampened. We and others have shown that this phase […]
Expression of pancreatic Notch1 in type 1 diabetes
Pancreatic tissue is composed of two dominant cell types: small clusters of insulin producing cells called the islets of Langerhans and exocrine cells in the surrounding stroma. The endocrine and exocrine pancreatic tissues are fundamentally different in terms of anatomical organization, basic function and pathological conditions, and they are consequently believed to be largely independent […]