Abstract
The important role of microRNAs as major modulators of various physiological processes, including immune regulation and homeostasis, has been increasingly recognized. Consequently, aberrant miRNA expression contributes to the defective regulation of T cell development, differentiation, and function. This can result in immune activation and impaired tolerance mechanisms, which exert a cardinal function for the onset of islet autoimmunity and the progression to T1D. The specific impact of miRNAs for immune regulation and how miRNAs and their downstream targets are involved in the pathogenesis of islet autoimmunity and T1D has been investigated recently. These studies revealed that increased expression of individual miRNAs is involved in several layers of tolerance impairments, such as inefficient Treg induction and Treg instability. The targeted modulation of miRNAs using specific inhibitors, resulting in improved immune homeostasis, as well as improved methods for the targeting of miRNAs, suggest that miRNAs, especially in T cells, are a promising target for the reestablishment of immune tolerance.
Highlights
In type 1 diabetes (T1D), the loss of immune tolerance to beta cells in the pancreatic islets of Langerhans leads to an immune cell-mediated destruction of these insulin-producing cells
A multitude of recent studies focused on drivers of T1D pathogenesis; the precise cellular and molecular mechanisms underlying the loss of immune tolerance and their contribution to the highly heterogeneous progression from islet autoimmunity to symptomatic diabetes remain insufficiently investigated
The first study investigated the role of miR92a-3p in humans and mice, revealing that the T cell-specific increased expression of this miRNA during islet autoimmunity favors the development of T follicular helper (TFH) cell precursors and simultaneously impairs the efficient Treg induction, two mechanisms that can critically contribute to the onset and progression of islet autoimmunity (Figure 1) [45]
Summary
In type 1 diabetes (T1D), the loss of immune tolerance to beta cells in the pancreatic islets of Langerhans leads to an immune cell-mediated destruction of these insulin-producing cells. A multitude of recent studies focused on drivers of T1D pathogenesis; the precise cellular and molecular mechanisms underlying the loss of immune tolerance and their contribution to the highly heterogeneous progression from islet autoimmunity to symptomatic diabetes remain insufficiently investigated. Based on the high numbers of miRNAs and their involvement in virtually all biological processes, including immune regulation, multiple studies investigated their biomarker potential in the context of islet autoimmunity and T1D [42, 56, 66, 85,86,87,88,89,90,91]. Another study investigated signatures of circulating miRNAs in the serum of autoantibody-positive children vs their autoantibody-negative siblings In this dataset, several miRNAs, in particular miR21-3p, miR29a-3p, and miR424-5p, correlated with islet autoimmunity and the progression to T1D [36]. Additional evidence is needed to support the concept that circulating miRNAs are a valuable tool for human T1D risk assessment
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