Beta cell antigens in type 1 diabetes: triggers in pathogenesis and therapeutic targets.

François-Xavier Mauvais,Julien Diana,Peter Van Endert

doi:10.12688/f1000research.7411.1

Abstract

Research focusing on type 1 diabetes (T1D) autoantigens aims to explore our understanding of these beta cell proteins in order to design assays for monitoring the pathogenic autoimmune response, as well as safe and efficient therapies preventing or stopping it. In this review, we will discuss progress made in the last 5 years with respect to mechanistic understanding, diagnostic monitoring, and therapeutic modulation of the autoantigen-specific cellular immune response in T1D. Some technical progress in monitoring tools has been made; however, the potential of recent technologies for highly multiplexed exploration of human cellular immune responses remains to be exploited in T1D research, as it may be the key to the identification of surrogate markers of disease progression that are still wanting. Detailed analysis of autoantigen recognition by T cells suggests an important role of non-conventional antigen presentation and processing in beta cell-directed autoimmunity, but the impact of this in human T1D has been little explored. Finally, therapeutic administration of autoantigens to T1D patients has produced disappointing results. The application of novel modes of autoantigen administration, careful translation of mechanistic understanding obtained in preclinical studies and in vitro with human cells, and combination therapies including CD3 antibodies may help to make autoantigen-based immunotherapy for T1D a success story in the future.

Highlights

Introduction and contextThe key role in type 1 diabetes (T1D) of T lymphocytes recognizing self-antigens expressed by insulin-producing beta cells in pancreatic islets is amply documented and beyond reasonable doubt
As discussed in detail in many excellent reviews, a large number of such autoantigens, generally recognized by autoantibodies, have been identified and are targeted by CD8+ and CD4+ T cells that may contribute to beta cell destruction but can have a regulatory, protective role. (Pre-)proinsulin ([P]PI), glutamic acid decarboxylase (GAD), the tyrosine phosphatase IA-2, and the zinc transporter ZnT8 play a prominent role and are recognized by autoantibodies detected in routine clinical laboratory assays
We have found that ZnT8 is a major autoantigen for CD8+ T cells in pediatric diabetes[20]; as transfer of ZnT8-specific human CD8+ T cells can induce diabetes in HLAhumanized mice, such cells may play an important role in the human pathology[21]

Summary

Introduction

Introduction and context The key role in type 1 diabetes (T1D) of T lymphocytes recognizing self-antigens expressed by insulin-producing beta cells in pancreatic islets is amply documented and beyond reasonable doubt. Novel insights on frequency and expression signatures of self-reactive T cells While the vast majority of research efforts concerning autoreactive T cells has focused on detecting and enumerating such cells, possibly combined with limited functional analyses, recent studies suggest that exploration of adaptive autoimmunity should go beyond this step and aim to perform in-depth characterization of phenotypic and functional properties.

Results

Conclusion