The evolving landscape of autoantigen discovery and characterization in type 1 diabetes

Anthony W. Purcell, Salvatore Sechi, Teresa P. DiLorenzo

Research output: Contribution to journalArticle

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell–mediated destruction of insulin-producing b-cells. High risk for disease, in those with genetic susceptibility, is predicted by the presence of two or more autoantibodies against insulin, the 65-kDa form of glutamic acid decarboxylase (GAD65), insuli-noma-associated protein 2 (IA-2), and zinc transporter 8 (ZnT8). Despite this knowledge, we still do not know what leads to the breakdown of tolerance to these autoantigens, and we have an incomplete understanding of T1D etiology and pathophysiology. Several new autoantibodies have recently been discovered using innovative technologies, but neither their potential utility in monitoring disease development and treatment nor their role in the pathophysiology and etiology of T1D has been explored. Moreover, neoantigen generation (through posttranslational modification, the formation of hybrid peptides containing two distinct regions of an antigen or antigens, alternative open reading frame usage, and translation of RNA splicing variants) has been reported, and autoreactive T cells that target these neoantigens have been identified. Collectively, these new studies provide a conceptual framework to understand the breakdown of self-tolerance, if such modifications occur in a tissue- or disease-specific context. A recent workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together investigators who are using new methods and technologies to identify autoantigens and characterize immune responses toward these proteins. Researchers with diverse expertise shared ideas and identified resources to accelerate antigen discovery and the detection of autoimmune responses in T1D. The application of this knowledge will direct strategies for the identification of improved bio-markers for disease progression and treatment response monitoring and, ultimately, will form the foundation for novel antigen-specific therapeutics. This Perspective highlights the key issues that were addressed at the workshop and identifies areas for future investigation.

Original languageEnglish (US)
Pages (from-to)879-886
Number of pages8
JournalDiabetes
Volume68
Issue number5
DOIs
StatePublished - Jan 1 2019

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Autoantigens
Type 1 Diabetes Mellitus
Antigens
Autoantibodies
National Institute of Diabetes and Digestive and Kidney Diseases (U.S.)
Noma
Research Personnel
Insulin
RNA Splicing
Technology
Self Tolerance
Education
Glutamate Decarboxylase
Post Translational Protein Processing
Genetic Predisposition to Disease
Autoimmunity
Open Reading Frames
Autoimmune Diseases
Disease Progression
Proteins

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

The evolving landscape of autoantigen discovery and characterization in type 1 diabetes. / Purcell, Anthony W.; Sechi, Salvatore; DiLorenzo, Teresa P.

In: Diabetes, Vol. 68, No. 5, 01.01.2019, p. 879-886.

Research output: Contribution to journalArticle

Purcell, Anthony W. ; Sechi, Salvatore ; DiLorenzo, Teresa P. / The evolving landscape of autoantigen discovery and characterization in type 1 diabetes. In: Diabetes. 2019 ; Vol. 68, No. 5. pp. 879-886.
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