scholarly journals miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Martin G. Scherm ◽  
Isabelle Serr ◽  
Adam M. Zahm ◽  
Jonathan Schug ◽  
Saverio Bellusci ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell Activation ◽  
Pancreatic Beta Cells ◽  
Cell Activation ◽  
Clinical Symptoms ◽  
Mechanistic Model ◽  
Treg Cells ◽  
Islet Autoimmunity ◽  
Molecular Approaches

AbstractIn type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.

Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant

2008 ◽  
Vol 31 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Johanna Aarnisalo ◽  
Andras Treszl ◽  
Peter Svec ◽  
Jane Marttila ◽  
Viveka Öling ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell

scholarly journals Sphingosine-1-Phosphate Reduces CD4+ T-Cell Activation in Type 1 Diabetes Through Regulation of Hypoxia-Inducible Factor Short Isoform I.1 and CD69

Diabetes ◽  
2007 ◽  
Vol 57 (2) ◽  
pp. 484-493 ◽  
Author(s):  
S. Srinivasan ◽  
D. T. Bolick ◽  
D. Lukashev ◽  
C. Lappas ◽  
M. Sitkovsky ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Hypoxia Inducible Factor ◽  
Cd4 T Cell ◽  
Sphingosine 1 Phosphate

scholarly journals C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

2017 ◽  
Vol 115 (1) ◽  
pp. 162-167 ◽  
Author(s):  
Yang Wang ◽  
Tomasz Sosinowski ◽  
Andrey Novikov ◽  
Frances Crawford ◽  
David B. Neau ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell Activation ◽  
Posttranslational Modifications ◽  
Cell Activation ◽  
Nod Mice ◽  
Side Chain ◽  
C Terminus

A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

Heparanase prevents the development of type 1 diabetes in non‐obese diabetic mice by regulating T‐cell activation and cytokines production

2008 ◽  
Vol 24 (5) ◽  
pp. 413-421 ◽  
Author(s):  
Menachem Bitan ◽  
Lola Weiss ◽  
Michael Zeira ◽  
Shoshana Reich ◽  
Orit Pappo ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Diabetic Mice

scholarly journals Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity – indications of immune cell activation

2017 ◽  
Author(s):  
M. Laimighofer ◽  
R. Lickert ◽  
R. Fürst ◽  
F. J. Theis ◽  
C. Winkler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
T Lymphocytes ◽  
Cesarean Section ◽  
Cell Activation ◽  
Immune Cell ◽  
Islet Autoimmunity ◽  
Nucleotide Synthesis ◽  
Immune Cell Activation

AbstractBackgroundBirth by Cesarean section increases the risk of developing type 1 diabetes later in life; however, the underlying molecular mechanisms of this effect remain unclear. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system.MethodsWe analyzed gene expression of peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes (n = 109). We investigated effects of Cesarean section on gene expression profiles of children in the first year of life using a generalized additive mixed model to account for the longitudinal data structure. To investigate the effect of islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns of Cesarean section and islet autoimmunity at the gene expression level.ResultsWe identified two differentially expressed pathways in children born by Cesarean section: the pentose phosphate pathway and pyrimidine metabolism, both involved in nucleotide synthesis and cell proliferation. Islet autoantibody analysis revealed multiple differentially expressed pathways generally involved in immune processes, including both of the above-mentioned nucleotide synthesis pathways. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. In addition, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes.ConclusionsWe identified coherent gene expression signatures for Cesarean section, an early risk factor for type 1 diabetes, and islet autoantibodies positivity, an obligatory stage of autoimmune response prior to the development of type 1 diabetes. Both transcriptional signatures were correlated with changes in gene expression during the activation of CD4+ T lymphocytes, reflecting common molecular changes in immune cell activation.

scholarly journals Association of PD-1 and PD-L1 Genetic Polymorphyisms with Type 1 Diabetes Susceptibility

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Chenyue Qian ◽  
Heming Guo ◽  
Xiaohong Chen ◽  
Aiming Shi ◽  
Sicheng Li ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell Activation ◽  
Genetic Background ◽  
Chinese Population ◽  
Genomic Dna ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Diabetes Susceptibility ◽  
Programmed Death

Aims. The programmed death- (PD-) 1/PD-1 ligand (PD-L) pathway plays an important role in regulating T cell activation and maintaining peripheral tolerance. Accumulated studies showed that PD-1/PD-L1 pathway was involved in the development of type 1 diabetes (T1DM). Since the genetic background of type 1 diabetes differs greatly among the different population, we aim to investigate the association of genetic polymorphisms in PD-1 and PD-L1 with T1DM susceptibility in Chinese population. Methods. In total, 166 T1DM patients and 100 healthy controls were enrolled into the study. Genomic DNA was extracted from 4 mL peripheral blood samples collected from each subject. Genotyping of 8 selected SNPs of PD-1 and PD-L1 was carried out by the pyrosequencing PSQ 24 System using PyroMark Gold reagents (QIAGEN). Results. SNP rs4143815 in PD-L1 was significantly associated with T1DM. People carrying the C allele of rs4143815 suffering less risk of T1DM and T1DM patients with G/G genotype showed higher levels of autoantibody (AAB) positive incidence compared with C allele carriers. No significant associations were found in other SNPs. Conclusions. Our results indicate that rs4143815 of PD-L1 is significantly associated with T1DM and may serve as a new biomarker to predict the T1DM susceptibility.

scholarly journals CD226 Deletion Reduces Type 1 Diabetes in the NOD Mouse by Impairing Thymocyte Development and Peripheral T Cell Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Melanie R. Shapiro ◽  
Wen-I Yeh ◽  
Joshua R. Longfield ◽  
John Gallagher ◽  
Caridad M. Infante ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nod Mouse ◽  
Thymocyte Development

scholarly journals Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2185 ◽  
Author(s):  
Marco Infante ◽  
Camillo Ricordi ◽  
Janine Sanchez ◽  
Michael J. Clare-Salzler ◽  
Nathalia Padilla ◽  
...  
Keyword(s):  
Vitamin D ◽  
Type 1 Diabetes ◽  
Vitamin D Deficiency ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Current Knowledge ◽  
Islet Autoimmunity ◽  
Immunomodulatory Effects

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

scholarly journals CD5 expressing CD8+ T cell subsets differ between children with Type 1 Diabetes and controls

2021 ◽  
Author(s):  
Josefine Wadenpohl ◽  
Julia Seyfarth ◽  
Paul Hehenkamp ◽  
Maximilian Hoffmann ◽  
Sebastian Kummer ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
B Cell ◽  
Quantitative Pcr ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell

Different lymphocyte subsets are involved in autoimmune pathogenesis of Type 1 Diabetes (T1D). Previous studies suggested a role of CD5 expressing T and B cells including rare unconventional lymphocytes with combined T- and B-cell features (DE cells). We performed algorithm-supported multi-parameter flow cytometry and quantitative PCR to investigate immune cell subsets and DE cells in children with T1D (n=20) and matched controls (n=20). Comparisons of conventional immune cells detected increased proportions of CD3+ T cells in T1D patients whereas CD19+ B cell proportions were comparable to controls. Self-organizing maps for flow cytometry analyses (FlowSOM) showed highly similar CD5 expressing B-cell subsets and no differences for DE cells were detected between the study groups by flow cytometry or specific quantitative PCR. Notably, differences in CD8 positive T cells were indicated by FlowSOM and similarity-based tSNE analyses. Study group comparison confirmed significantly reduced CD8+ T-cell proportions with moderate or low CD5 expression in T1D patients. Finally, In vitro experiments showed stable CD5 expression differences of CD8+ T cells after T-cell activation, cytokine stimulation and culture. We observed differences of T-cell co-receptor CD5 expression in T1D patients with potential relevance for immune regulation of CD8+ T-cell activation.

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