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

Abstract

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.

Keywords: Autoimmune disease; High-risk HLA; Islet antigens; Posttranslational modification; Type 1 diabetes.

Fig. 1

Connecting posttranslational modification of islet proteins with the development of type 1 diabetes. This model begins with an as yet undefined environmental stressor. Lead candidates include metabolic stress, via changes in blood glucose concentration, and inflammatory stress, perhaps through viral infection or the close links between the pancreas and the gut. Stress results in a surge in PTM enzyme activity in islets and APC. This surge creates a larger pool of modified proteins, increasing the opportunity for modified peptides to be presented within the islet immune compartment. The genetic predisposition becomes important, as the HLA molecules in question (DQ2 and DQ8) are exceptionally adept at binding deamidated epitopes. If the modified epitopes are treated as “foreign” by the immune system, then an immune response will ensue. This leads to a break in peripheral tolerance to unmodified islet antigens via promiscuous T cells that are able to recognize both their cognate deamidated epitope and the native sequence. Beta cells readily present unmodified antigens, so the autoreactive response quickly becomes destructive, resulting in overt diabetes