Abnormal T-Cell Development in the Thymus of Non-obese Diabetic Mice: Possible Relationship With the Pathogenesis of Type 1 Autoimmune Diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing cells in the pancreas, by direct interactions with autoreactive pancreas infiltrating T lymphocytes (PILs). One of the most important animal models for this disease is the non-obese diabetic (NOD) mouse. Alterations in the NOD mouse thymus during the pathogenesis of the disease have been reported. From the initial migratory disturbances to the accumulation of mature thymocytes, including regulatory Foxp3+ T cells, important mechanisms seem to regulate the repertoire of T cells that leave the thymus to settle in peripheral lymphoid organs. A significant modulation of the expression of extracellular matrix and soluble chemoattractant molecules, in addition to integrins and chemokine receptors, may contribute to the progressive accumulation of mature thymocytes and consequent formation of giant perivascular spaces (PVS) that are observed in the NOD mouse thymus. Comparative large-scale transcriptional expression and network analyses involving mRNAs and miRNAs of thymocytes, peripheral T CD3+ cells and PILs provided evidence that in PILs chemokine receptors and mRNAs are post-transcriptionally regulated by miR-202-3p resulting in decreased activity of these molecules during the onset of T1D in NOD mice. In this review, we discuss the abnormal T-cell development in NOD mice in the context of intrathymic expression of different migration-related molecules, peptides belonging to the family of insulin and insulin-like growth factors as well as the participation of miRNAs as post-transcriptional regulators and their possible influence on the onset of aggressive autoimmunity during the pathogenesis of T1D.

When the Damage Is Done: Injury and Repair in Thymus Function

“…Metabolic distress due to lack of nutrients, primarily glucose, leads to an attenuation of thymic function, with perturbed thymopoiesis in non-obese diabetic (NOD) mice ( 37 ), and reduced thymic atrophy with glucose supplementation in models of mitochondrial dysfunction ( 38 ).…”

Immunohistochemical Characterization of Proliferative Lesions in the Thymus of Aging CD-1 Mice From Two Studies on the RITA Database, With Special Reference to the Perivascular Space

“…15 Likewise, nonobese diabetic mouse models of autoimmune type I diabetes have been associated with a giant perivascular space containing T cells, clusters of B cells, and upregulation of cell migration–related molecules in the perivascular space. 16,17 In the CD-1 mouse, thymic lymphoid hyperplasia, however, has not been associated with any immune-related disease. There is some evidence that immune cell subpopulations of natural killer cells, T-helper cells and cytotoxic T cells in female CD-1 mice undergo significant changes when comparing 2- to 6-month-old animals to animals at 7 to 8 months of age in immunophenotyping investigations.…”

Human Leukocyte Antigen (HLA) Subtype-Dependent Development of Myasthenia Gravis, Type-1 Diabetes Mellitus, and Hashimoto Disease: A Case Report of Autoimmune Polyendocrine Syndrome Type 3

“…T1DM has recently been reported to be associated with failure of peripheral immunologic tolerance as a result of dysfunction of the regulatory T-cells [19], but the mechanism remains to be clarified. However, there is relatively little information available on the association of T1DM with central immunologic tolerance failure, and research on the association between immunologic tolerance and T1DM has been based on animal studies in which non-obese diabetic mice were used [20,21].…”