Project 2: Hygiene Hypothesis

(A) Type One Diabetes

Each year in this country more than 13,000 young people are diagnosed with type 1 diabetes (T1D). In this autoimmune disease, insulin-producing b cells are destroyed by CD4 and CD8 T cells infiltrating the pancreatic islets, causing defects in blood glucose homeostasis and ultimately vascular and neurological complications. T1D is potentially life threatening, and an increasingly significant public health problem worldwide, particularly in western European countries where there is an alarming decrease in the age of onset. The “hygiene hypothesis” links the increase in autoimmune phenomena in humans to excessively sanitary conditions early in life. In retrospective studies that seek to link the relationship of typical childhood infectious diseases to T1D, exposure to Streptococcus pyogenes (GAS) had a significant negative correlation with acquisition of T1D. In rodent models treatment with GAS preparations leads to diabetes resistance. In GAS infections antibodies are made against cell wall-associated N-acetyl-D-glucosamine (GlcNAc). We will test the hypothesis that alternative GlcNAc-specific B lymphocyte activities can influence the development of autoimmune diabetes by contributing to protection or acceleration of disease. Anti-GlcNAc antibodies also bind proteins and insulin-containing secretory granules enriched in pancreatic β cells. 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 antibodies that dampen the autoimmune response to GlcNAcylated molecules associated with β islet cells. In an alternative context, we propose that anti-GlcNAc B-lymphocytes can be involved on presenting GlcNAcylated β cell autoantigens to diabetogenic T cells. In Aim 1 we will determine how early immunization and timed passive anti-GlcNAc antibody influence the rate and severity of T1D progression in NOD mice. Aim 2 will study the effects of antibodies on antigen-presenting cell activation of diabetogenic T cells in vitro. Finally in Aim 3 we will determine the mechanisms of protection against T1D development in intact NOD mice.

The knowledge of how a common infectious organism, GAS, alters an individual’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.