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.

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

“…Evidence of secretory dysfunction in T1D etiology in the form of neoantigens, identified as hybrid peptides containing fragments of insulin, C-peptide, IAPP, and/or CgA, suggest that alterations to prohormone trafficking and processing contribute to the development of CD4 + autoimmunity early in disease progression [ 135 , 136 , 137 ]. Non-native disulfide bond formation during proinsulin folding in the ER was suggested as a contributing factor to neoantigen formation [ 138 ]. While a definitive link between cytokine exposure, non-native disulfide bond formation, and defects in proinsulin trafficking have yet to be demonstrated in T1D pathogenesis, future studies may consider this common theme of mitochondrial dysfunction and ER redox status as a possible mechanism contributing to T1D etiology.…”

Whole-Slide Image Analysis of Human Pancreas Samples to Elucidate the Immunopathogenesis of Type 1 Diabetes Using the QuPath Software

“…Modern lifestyle and diet have placed an enormous amount of metabolic pressure on beta cells, which are constantly hyperfunctioning to produce and secrete insulin. This metabolic stress could lead to mistakes in the translational and post-translational processing of insulin and other beta cell proteins, which could in turn lead to the generation of neoantigens and to the ultimate recruitment of the immune cells to the pancreas (Rodriguez-Calvo et al, 2021). Insulitis is a hallmark of T1D; CD8+ T cells are the most abundant cell population in an insulitic lesion, followed by CD68+ macrophages, CD20+ B cells, and CD4+ T cells (Willcox et al, 2009).…”

Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes

“…Hence the contribution of HLA should be considered in combination with antigens/peptides that they present. The so far well-established β-cell antigens that are targeted by both B and T cell responses are INS, GAD65, IA2 and Znt8 but the list of target antigens is increasing ( 34 , 35 , 53 ). Of the β-cell proteins targeted as autoantigens, only SNPs in the INS gene are associated with an increased risk for T1D.…”