Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which immune-mediated targeting and destruction of insulin-producing pancreatic islet β cells leads to chronic hyperglycemia. There are many β cell proteins that are targeted by autoreactive T cells in their native state. However, recent studies have demonstrated that many β cell proteins are recognized as neo-antigens following posttranslational modification (PTM). Although modified neo-antigens are well-established targets of pathology in other autoimmune diseases, the effects of neo-antigens in T1D progression and the mechanisms by which they are generated are not well understood. We have demonstrated that PTM occurs during endoplasmic reticulum (ER) stress, a process to which β cells are uniquely susceptible due to the high rate of insulin production in response to dynamic glucose sensing. In the context of genetic susceptibility to autoimmunity, presentation of these modified neo-antigens may activate autoreactive T cells and cause pathology. However, inherent β cell ER stress and protein PTM do not cause T1D in every genetically susceptible individual, suggesting the contribution of additional factors. Indeed, many environmental factors, such as viral infection, chemicals, or inflammatory cytokines, are associated with T1D onset, but the mechanisms by which these factors lead to disease onset remain unknown. Since these environmental factors also cause ER stress, exposure to these factors may enhance production of neo-antigens, therefore boosting β cell recognition by autoreactive T cells and exacerbating T1D pathogenesis. Therefore, the combined effects of physiological ER stress and the stress that is induced by environmental factors may lead to breaks in peripheral tolerance, contribute to antigen spread, and hasten disease onset. This Hypothesis and Theory article summarizes what is currently known about ER stress and protein PTM in autoimmune diseases including T1D and proposes a role for environmental factors in breaking immune tolerance to β cell antigens through neo-antigen formation.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease in which insulin-producing pancreatic islet β cells are targeted and destroyed by autoreactive immune cells
Type 1 diabetes is strongly associated with a genetic predisposition to autoimmunity that is conferred by single-nucleotide polymorphisms (SNPs) and gene variants found at many genetic loci
The mechanisms by which tolerance fails are still being elucidated, but a growing body of literature demonstrates that β cell peptides modified by Ca2+-dependent posttranslational modification (PTM) elicit stronger responses from autoreactive T cells than their native counterparts [16, 19, 23, 28,29,30,31, 143, 145]
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease in which insulin-producing pancreatic islet β cells are targeted and destroyed by autoreactive immune cells. This failure in central tolerance mechanisms may be explained by the growing body of literature that abnormal PTM increases the immunogenicity of β cell peptides in both murine and human models of T1D (Table 2) These studies have demonstrated that some β cell proteins undergo various modifications including oxidation [28, 143], Tgase2mediated crosslinking by isopeptide bond [19, 29], Tgase2mediated deamidation [30,31,32], PAD2-mediated citrullination [16, 23, 31], the formation of hybrid peptides [144, 145], and the formation of a defective ribosomal insulin gene product [146]. ER stress-mediated neo-antigen formation may be a common mechanism by which these environmental factors augment autoimmune targeting of β cells and hasten T1D onset
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