The role of oxidative post-translational modifications in type 1 diabetes pathogenesis

Abstract

The pathogenesis of type 1 diabetes (T1D) involves a complex interplay of genetic predisposition, immune processes, and environmental factors, leading to the selective destruction of pancreatic beta-cells by the immune system. Emerging evidence suggests that intrinsic beta-cell factors, including oxidative stress and post-translational modifications (PTM) of beta-cell antigens, may also contribute to their immunogenicity, shedding new light on the multifaceted pathogenesis of T1D. Over the past 30 years, neoepitopes generated by PTMs have been hypothesized to play a role in T1D pathogenesis, but their involvement has only been systematically investigated in recent years. In this review, we explored the interplay between oxidative PTMs, neoepitopes, and T1D, highlighting oxidative stress as a pivotal factor in immune system dysfunction, beta-cell vulnerability, and disease onset.

Keywords: autoantibodies; autoimmunity; insulin; neoepitopes; oxidative stress; post-translational modifications; t cell; type 1 diabetes.

Figure 1

Hypothesized mechanism of neoepitope generation by oxidative post-translational modifications of beta-cell antigens in type 1 diabetes. Various factors such as viral infections, toxins, and metabolic overload can induce oxidative stress and a state of beta-cell stress, leading to oxidative post-translational modifications (oxPTMs) and, subsequently, neoepitopes that may trigger autoimmune responses. These responses can amplify reactions against native antigens or involve them through epitope spreading. The beta-cell becomes a victim of external events that lead to an accumulation of oxPTM, transforming it and unfairly marking it as a target for the immune system. The figure was created with the help of bioRender.com.