The Evolving Landscape of Autoantigen Discovery and Characterization in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell–mediated destruction of insulin-producing β-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), insulinoma-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 biomarkers 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.

Mechanisms of skin autoimmunity: Cellular and soluble immune components of the skin

“…Increasing evidence exists that neoantigens constantly develop through various alternative translation or posttranslational modification and these neoantigens are recognized by T cells, as demonstrated, for example, in type I diabetes. 104 Also, in cancer immunotherapy, T cells have been shown to recognize mutations/neoantigens primarily, which is why response rates to immune checkpoint inhibitors correlate with the number of mutations within a tumor. 105,106 Thus, neoantigen formation might well be one reason for developing skin autoimmunity, in particular in chronic inflammation.…”

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

“…One problem in the autoantigen treatment of T1D is to choose the most relevant autoantigen/s to use as there are so many beta-cell-related autoantigens (Table 1) [54]. There are autoantibodies and T-cell reactivity against insulin, glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2/tyrosine phosphatase (IA-2), zinc transporter 8 (ZnT8), and also against proinsulin, the B-chain of insulin and proinsulin peptides.…”

“…There are autoantibodies and T-cell reactivity against insulin, glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2/tyrosine phosphatase (IA-2), zinc transporter 8 (ZnT8), and also against proinsulin, the B-chain of insulin and proinsulin peptides. Furthermore, many more autoantigens have been described in recent years [54,55]. Hybrid insulin peptides consist of peptide fragments derived from both insulin and other insulin-secretory granule proteins which are fused together to form a hybrid peptide [56].…”

Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome—Review of Classical and New Compounds: Part-I

“…β-Cell dysfunction results from the (i) decreased β-cell mass, increased β-cell apoptosis or decreased regeneration, (ii) long-standing insulin resistance leading to β-cell exhaustion, (iii) glucotoxicity-inductor chronic hyperglycemia, and (iv) chronic elevation of FFA, inducing lipotoxicity and amyloid deposition in β-cells [1]. Relative insulin deficiency can also be caused by autoantibodies against insulin receptors or insulin itself, or by rare defects in the biosynthesis of insulin, insulin receptors, or intracellular transmission [11][12][13]. The following etiological factors should also be considered: (i) pancreatitis, which destroys pancreatic β-cells and leads to pancreatectomy, (ii) increased release of insulin antagonistic hormones, such as somatotropin, glucocorticoids, epinephrine, progestogens, choriomammotropin, ACTH, thyroid hormone and glucagon, and (iii) mitochondrial dysfunction (mitochondrial loss and increased production of oxidants that promote insulin resistance), since this organelle is the main source of energy to cells and thus crucial to many cellular functions, including ATP production, biosynthesis of amino-acids and lipids, cytosolic calcium transport and apoptotic stimuli control.…”