Role of citrullination in the generation of autoantigens in Type 1 Diabetes.

Type 1 diabetes (T1D) is an autoimmune disease resulting in insulin deficiency caused by immune destruction of pancreatic beta-cells. Recently, an active role for the beta-cell in its own destruction has been proposed, for instance by secretion of chemokines attracting immune cells, but also by generation of neo-antigens. As such, stressed beta-cells will alter protein processing resulting in generation of modified proteins that can become antigenic. We have demonstrated that citrullination is such a pathway resulting in generation of autoantigens, e.g. through citrullination of an endoplasmic reticulum chaperone, GRP78. Here, we wish to explore how citrullination contributes to T1D development and whether interfering with citrullination can prevent progression of the disease. More specifically we will investigate how and where citrullination happens in betacells and investigate the contribution of beta-cells as well as infiltrating immune cells in this process. We will use different ways to block citrullination and evaluate its impact on disease progression and we will explore whether inducing tolerance towards citrullinated GRP78 specifically can block development of diabetes in a mouse model of T1D. The data generated will further clarify the role of the beta-cell itself in driving its own destruction and specifically elucidate the role of citrullination of beta-cell proteins induced by inflammatory stress in this process, thus opening potential therapeutic avenues.