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

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...

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Autores principales: Rodriguez-Calvo, Teresa, Johnson, James D., Overbergh, Lut, Dunne, Jessica L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089389/
https://www.ncbi.nlm.nih.gov/pubmed/33953728
http://dx.doi.org/10.3389/fimmu.2021.667989
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author Rodriguez-Calvo, Teresa
Johnson, James D.
Overbergh, Lut
Dunne, Jessica L.
author_facet Rodriguez-Calvo, Teresa
Johnson, James D.
Overbergh, Lut
Dunne, Jessica L.
author_sort Rodriguez-Calvo, Teresa
collection PubMed
description 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.
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spelling pubmed-80893892021-05-04 Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets Rodriguez-Calvo, Teresa Johnson, James D. Overbergh, Lut Dunne, Jessica L. Front Immunol Immunology 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. Frontiers Media S.A. 2021-04-19 /pmc/articles/PMC8089389/ /pubmed/33953728 http://dx.doi.org/10.3389/fimmu.2021.667989 Text en Copyright © 2021 Rodriguez-Calvo, Johnson, Overbergh and Dunne https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Rodriguez-Calvo, Teresa
Johnson, James D.
Overbergh, Lut
Dunne, Jessica L.
Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets
title Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets
title_full Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets
title_fullStr Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets
title_full_unstemmed Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets
title_short Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets
title_sort neoepitopes in type 1 diabetes: etiological insights, biomarkers and therapeutic targets
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089389/
https://www.ncbi.nlm.nih.gov/pubmed/33953728
http://dx.doi.org/10.3389/fimmu.2021.667989
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