TY - JOUR
T1 - The evolving landscape of autoantigen discovery and characterization in type 1 diabetes
AU - Purcell, Anthony W.
AU - Sechi, Salvatore
AU - DiLorenzo, Teresa P.
N1 - Funding Information:
Acknowledgments. The authors acknowledge all those who attended the Autoantigens Discovery and Characterization in Type 1 Diabetes workshop whose participation contributed to our views regarding the themes presented here. The authors especially thank Lisa M. Spain of the National Institute of Diabetes and Digestive and Kidney Diseases for discussions, suggestions, and encouragement throughout the workshop. Funding. A.W.P. acknowledges fellowship support from the Australian National Health and Medical Research Council (1044215). Work in the laboratory of T.P.D. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK120420, and P30 DK020541, which supports the Einstein-Mount Sinai Diabetes Research Center), the National Institute of Allergy and Infectious Diseases (R01 AI123730), and the American Diabetes Association (1-16-IBS-069). T.P.D. is the Diane Belfer, Cypres & Endelson Families Faculty Scholar in Diabetes Research. Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Publisher Copyright:
© 2019 by the American Diabetes Association.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.2337/dbi18-0066
DO - 10.2337/dbi18-0066
M3 - Article
C2 - 31010879
AN - SCOPUS:85065116131
VL - 68
SP - 879
EP - 886
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 5
ER -