The Influence of Anti-N-Acetyl-D-Glucosamine B cells on Type One Diabetes in Mice

University Of Alabama At Birmingham, Birmingham AL

Investigators

Linked publications & trials

Abstract

ABSTRACT Type I diabetes (T1D) is an autoimmune disease in which insulin-producing βcells are destroyed by the immune system resulting in an inability to regulate blood glucose levels, which ultimately leads to vascular and neurological complications. A strong negative correlation with childhood Scarlet Fever, a Group A Streptococcal (GAS) infection, and T1D has been demonstrated in human populations. Additionally, immunization with GAS vaccines leads to diabetes resistance in rodent models. B lymphocytes respond to GAS infection by producing large amounts of antibodies to bacterial cell wall-associated N-acetyl-Dglucosamine (GlcNAc), which also bind O-GlcNacylated proteins that are enriched in pancreatic, βcells. We will examine a role for GlcNAc specific B lymphocytes in modulating T1D in mouse models and test the hypothesis that anti-GlcNAc lymphocytes protect against T1D by generating anti-GlcNAc Abs which clear OGlcNacylated proteins released from dead βcells and dampen the autoimmune response to βcells. However in other developmental contexts, we propose that anti-GlcNAc B lymphocytes have the potential to induce T1D by presenting O-GlcNAcylated βcell autoantigens to diabetogenic T cells. Specific Aim 1 will be to determine the mechanism of anti-GlcNAc antibody mediated prevention of T1D in NOD mice. The protective ability of timed passive anti-GlcNAc antibody administration will be studied in relation to βcell death during neonatal remodeling of NOD pancreas. The alternative part of our hypothesis will be to determine the influence of GlcNAc-specific B cell subsets on the rate and severity of T1D progression. Transgenic mice expressing GlcNAc-specific B lymphocytes will be used to facilitate these studies, which will be analyzed by in situ, and flowcytometric immunofluorescence of pancreas and pancreatic lymph node nodes in addition to monitoring βcell function. The second aim will study the role of B lymphocytes in the development of diabetogenic T cells. It will be determined whether there is a modification of TCR clonal diversity of CD4 and CD8 T cells in islet infiltrates of mice treated as in Aim 1 and how these changes relate to the development of T1D. The knowledge of how a common infectious organism, Group A Streptococcus, alters an individual[unreadable]s propensity to develop type I diabetes (T1D) will be applied to understanding mechanisms involved in T1D induction and progression in the NOD model which simulates many aspects of human T1D. The long-term goal of this project is to identify factors that can influence the progression of T1D in susceptible individuals, which may improve T1D diagnosis and development of immunization strategies for prevention of T1D.