Generation and Recognition of Beta Cell Neo-Epitopes

Prior to the onset of type 1 diabetes, there is a progressive loss of self-tolerance. Continued accumulation of auto-antibodies that recognize beta cell derived proteins and the coincident or subsequent activation and activity of auto-reactive T cells lead to the destruction of pancreatic beta cells and loss of insulin secretion.  However, important questions remain regarding events that surround the initial loss of tolerance and the subsequent failure of regulatory mechanisms to arrest autoimmunity and preserve an adequate number of functional beta cells.  It is increasingly evident that various processes can lead to the generation of different classes of neo-epitopes, including enzymatic and non-enzymatic post-translational modification of self-proteins that increase the affinity of epitope presentation and/or recognition by CD4+ T cells. Emerging data suggest that conditions of ER stress promote neo-antigen formation in beta cells, giving rise to an increasing array of neo-epitopes which have the potential to activate pathogenic T cells that may not be effectively eliminated by negative selection. Indeed, such neo-epitope specific T cells are present at elevated frequencies in the peripheral blood of patients with established type 1 diabetes and can also be found among T cells isolated from the pancreatic draining lymph nodes and islet infiltrating T cells of cadaveric organ donors with established diabetes. Together, these observations support a paradigm in which neo-epitope generation leads to succssive waves of immune activation, initiating a feed forward loop that can amplify the antigenic repertoire towards pancreatic beta cell proteins. Our ongoing studies seek to determine the stage of the disease process during which various classes of neo-epitope specific T cell responses appear by examining samples from at-risk individuals and to establish whether neo-epitope responses associate with particular disease endotypes.