Abstract
Type 1 diabetes (T1D) is an immune-mediated disease in which the insulin-producing beta cells are selectively targeted for destruction. An important component of this immune destruction is mediated through CD4+ and CD8+ T cells that recognize epitopes derived from beta cell proteins. This chapter addresses the increasingly appreciated role that deimination of self-proteins plays in T1D, based on observations in human subjects and insights gained through the NOD model. After addressing the general phenomenon of determinant spreading we present evidence supporting the enhanced presentation of deiminated peptides by T1D susceptible HLA and the in vivo conversion of arginine to citrulline both in model antigens and beta cell associated proteins. Furthermore, we present evidence that enzymatic deimination of arginine to citrulline is promoted by beta cell stress and that peptides derived from established beta cell antigens are preferentially recognized by T cells in their deiminated form. Finally, we discuss prospects for diagnostic detection of anti-citrulline responses in T1D.
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