The role of the post-translational modification citrullination in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease in which the immune system destroys insulin-producing pancreatic beta-cells, leading to a lack of insulin. Recently, we and others provided evidence that citrullination plays a role in T1D by identifying citrullinated glucose-regulated protein 78 (GRP78) and glutamic acid decarboxylase 65kDa (GAD65) as autoantigens in murine and human T1D, respectively. Citrullination is a post-translational modification in which an arginine residue is converted into a citrulline, an enzymatic reaction mediated by peptidylarginine deiminases (PADs). Although PAD enzymes are required for physiological processes, a dysregulation in PAD activity is highly correlated with the onset and disease progression of several autoimmune diseases. The general objective of this project was to understand how citrullination contributes to T1D pathogenesis and how this knowledge can be exploited in the clinic. Using in silico tools, human primary islets and peripheral blood mononuclear cells from T1D patients, we have shown that citrullinated GRP78 is also an antigen in human T1D. Moreover, using non-obese diabetic (NOD) mice, a mouse model for T1D, we have demonstrated that systemic inhibition of citrullination can prevent diabetes development through modulation of immune pathways. Lastly, vaccination of NOD mice with a peptide of citrullinated GRP78 decreased diabetes incidence by inducing regulatory T cells. In conclusion, this PhD project confirmed the important role of the post-translational modification citrullination in T1D and pointed to the potential of this modification for T1D treatment.