Grant: Project Grant

Type 1 diabetes (T1D) is an autoimmune disease, resulting from the destruction of the insulin-producing beta- cells in the pancreas by the T-cells of the immune system. In recent years we have discovered over forty places in the genome, where genetic variants inherited from the individual's parents determine the probability that the individual will develop T1D. Normally, T-cells whose receptor recognizes parts of self either die or become inactive thanks to a variety of successive roadblocks, collectively assuring immune self-tolerance. Autoimmunity happens when a small number of T-cells evade these roadblocks and multiply to reach numbers sufficient to do the autoimmune damage. In the past few years, we have discovered a large number of places in the human genome that contain genetic variants, inherited from an individual's parents that can weaken self-tolerance. Self-tolerance is assured by the regulatory T-cells, a subset of the immune system that protect normal tissues while the rest of the T-cells attack bacteria and viruses. The delicate balance between defense from microbes and "collateral damage" to one's own body parts is occasionally broken by rogue T-cells or by a weakening of the regulatory cells. Until recently, distinguishing between these two categories of cells was difficult. Thanks to the discovery of novel markers by Dr. Piccirillo, this distinction can now be made and the cells can be separated and studied. We now wish to use this breakthrough to study whether the progression from antibody positivity to T1D is due to an overactive immune system or to weakening of the regulatory component. Moreover, we have also the technology to separate T-cells that are directed against insulin, from other cells that do their normal job in fighting infection. This powerful combination of methodologies will allow us to isolate the cells directly involved in the development of T1D and study them with the powerful genome-wide methodologies of the CAG.