Where, How, and When: Positioning Posttranslational Modification Within Type 1 Diabetes Pathogenesis

Autoreactive T cells specific for islet autoantigens develop in type 1 diabetes (T1D) by escaping central as well as peripheral tolerance. The current paradigm for development of islet autoimmunity is just beginning to include the contribution of posttranslationally modified (PTM) islet autoantigens, for which the immune system may be ignorant rather than tolerant. As a result, PTM is the latest promising lead in the quest to understand how the break in peripheral tolerance occurs in T1D. However, it is not completely clear how, where, or when these modifications take place. Currently, only a few PTM antigens have been well-thought-out or identified in T1D, and methods for identifying and characterizing new PTM antigens are rapidly improving. This review will address both reported and potential new sources of modified islet autoantigens and discuss how islet neo-autoantigen generation may contribute to the development and progression of T1D.