Where, How, and When: Positioning Posttranslational Modification Within Type 1 Diabetes Pathogenesis

Abstract

Autoreactive T cells specific for islet autoantigens develop in type 1 diabetes (T1D) by escaping central as well as peripheral tolerance. The current paradigm for development of islet autoimmunity is just beginning to include the contribution of posttranslationally modified (PTM) islet autoantigens, for which the immune system may be ignorant rather than tolerant. As a result, PTM is the latest promising lead in the quest to understand how the break in peripheral tolerance occurs in T1D. However, it is not completely clear how, where, or when these modifications take place. Currently, only a few PTM antigens have been well-thought-out or identified in T1D, and methods for identifying and characterizing new PTM antigens are rapidly improving. This review will address both reported and potential new sources of modified islet autoantigens and discuss how islet neo-autoantigen generation may contribute to the development and progression of T1D.

SUMOylation of Enzymes and Ion Channels in Sensory Neurons Protects against Metabolic Dysfunction, Neuropathy, and Sensory Loss in Diabetes

“…Diabetes-induced nerve damage is highly diffuse, follows a variable course, and is tightly linked to the extent of metabolic dysfunction and generation of reactive oxygen species (ROS) (Feldman et al, 2017). Recent studies suggest that ROS and oxidative stress regulate key cellular processes via post-translational modifications such as ubiquitination, acetylation, nitrosylation, glycation, and linked b--acetlglucosamin ((O-GlcNAcylation), which have been implicated in late complications of diabetes (McLaughlin et al, 2016;Forbes and Cooper 2013).…”

Diagnostic accuracy of the anti‐glutamic acid decarboxylase antibody in type 1 diabetes mellitus: Comparison between radioimmunoassay and enzyme‐linked immunosorbent assay

“…Type 1 diabetes mellitus is caused by an autoimmune mechanism that destroys β‐cells in pancreatic islets, resulting in absolute deficiency in insulin. The detection of auto‐antibodies to islet antigens in serum is one of the key elements in the diagnosis of type 1 diabetes mellitus.…”

Determining T-cell specificity to understand and treat disease

“…This has been shown in e.g. T1D 67,68 , systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) 64,69,70 . Studies have shown that prediabetic NOD mice have antibodies and effector T cells that react against citrullinated GPR78 66 , and additionally, increased T cell reactivity to citrullinated peptides arising from GAD65 was described in T1D subjects 65 .…”