Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets

Abstract

The mechanisms underlying type 1 diabetes (T1D) pathogenesis remain largely unknown. While autoantibodies to pancreatic beta-cell antigens are often the first biological response and thereby a useful biomarker for identifying individuals in early stages of T1D, their role in T1D pathogenesis is not well understood. Recognition of these antigenic targets by autoreactive T-cells plays a pathological role in T1D development. Recently, several beta-cell neoantigens have been described, indicating that both neoantigens and known T1D antigens escape central or peripheral tolerance. Several questions regarding the mechanisms by which tolerance is broken in T1D remain unanswered. Further delineating the timing and nature of antigenic responses could allow their use as biomarkers to improve staging, as targets for therapeutic intervention, and lead to a better understanding of the mechanisms leading to loss of tolerance. Multiple factors that contribute to cellular stress may result in the generation of beta-cell derived neoepitopes and contribute to autoimmunity. Understanding the cellular mechanisms that induce beta-cells to produce neoantigens has direct implications on development of therapies to intercept T1D disease progression. In this perspective, we will discuss evidence for the role of neoantigens in the pathogenesis of T1D, including antigenic responses and cellular mechanisms. We will additionally discuss the pathways leading to neoepitope formation and the cross talk between the immune system and the beta-cells in this regard. Ultimately, delineating the timing of neoepitope generation in T1D pathogenesis will determine their role as biomarkers as well as therapeutic targets.

Keywords: autoantigens; beta-cell; biomarker; neoepitopes; pathogenesis; type 1 diabetes.

Figure 1

A catalogue of neoepitopes and their production sites/mechanisms in beta-cells. (A) Referenced list of known neoepitopes in type 1 diabetes where the type of PTM, the potential mediator, the antigen and how it is recognized and identified, the species in which it was identified and the reference to the original publication are shown. Cat-L, cathepsin L; ROS, reactive oxygen species; AutoAbs, autoantibodies; TGM, tissue transglutaminase; ChgA, chromogranin A; ER, endoplasmic reticulum; PAD, peptidylarginine deiminase; GAD: glutamate decarboxylase; IA-2: insulinoma-associated antigen 2; ZnT8, zinc-transporter 8; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; GRP78, glucose-regulated protein 78; IAPP, islet amyloid polypeptide; SCG5, secretogranin 5. (B) Schematic representation of a beta-cell showing the current view on sub-cellular origin of specific classes of neoepitopes, as well as the types of products produced.

Figure 2

Proposed model of neoepitope generation and roadmap to their identification and utility in T1D. (A) Schematic representation of how neoepitope generation could lead to autoimmunity and beta-cell killing in T1D. Genetic predisposition, metabolism, environmental insults and immune inflammation are some of the factors that may lead to the formation of a first wave of non-conventional proteins. Impaired clearance of such stressed or dying beta-cells expressing modified proteins will cause activation of APCs and presentation of neoepitopes to T-cells, which can trigger several immune responses. This first cascade of immune activation may cause further beta-cell stress or death, generating an autoreactive loop, with further modification of beta-cell proteins and disease exacerbation. This proposed model could provide evidence for a role of neoepitopes both in initiation and exacerbation of disease. It may indeed be that different ways of stress are needed to activate specific types of PTMs, at different times and with unknown duration, during the disease course. (B) Proposed roadmap to identification and utility of neoepitopes in T1D. Multiple neoepitopes have been identified in T1D and yet their precise role in the disease remains ambiguous. We envision two major areas of research: 1) to improve the identification of neoepitopes and to better delineate their role in disease pathogenesis; 2) to evaluate their use as biomarkers and their therapeutic utility.