Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Comparison of gene expression in NOD versus NOD.NOR-Chr4 (NR4) splenic B cells.

ABSTRACT: Type 1 Diabetes (T1D) in humans and the non-obese diabetic (NOD) mouse model results from autoreactive T cell destruction of pancreatic beta cells. A pathogenic role for B lymphocytes (B cells) in T1D first became evident when NOD mice made deficient in this population through introduction of an inactivated Igµ heavy chain gene (NOD.Igµnull) or chronic treatment with anti-IgM antibodies were strongly protected from disease. We produced an NOD background strain developing a greatly decreased T1D incidence due to a NOR-derived 44.31Mb congenic region from rs3674285 to D4Mit127 on distal Chr. 4 (termed NOD.NOR-Chr4 (NR4)) containing disease resistance alleles decreasing the pathogenic activity of autoreactive B cells. Microarrays were conducted on B cells purified from spleens of NOD and NR4 mice to highlight differentially expressed genes within the distal Chr. 4 locus. B cells were either cultured in media alone (unstimulated) or with BCR cross-linking anti-IgM-F(ab’)2 fragments (stimulated) for 2h before RNA was extracted for transcript analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE37294 | GEO | 2012/06/08

SECONDARY ACCESSION(S): PRJNA159413

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Comparison of gene expression in NOD versus NOD.NOR-Chr4 (NR4) splenic B cells.

Project description:Type 1 Diabetes (T1D) in humans and the non-obese diabetic (NOD) mouse model results from autoreactive T cell destruction of pancreatic beta cells. A pathogenic role for B lymphocytes (B cells) in T1D first became evident when NOD mice made deficient in this population through introduction of an inactivated IgM-BM-5 heavy chain gene (NOD.IgM-BM-5null) or chronic treatment with anti-IgM antibodies were strongly protected from disease. We produced an NOD background strain developing a greatly decreased T1D incidence due to a NOR-derived 44.31Mb congenic region from rs3674285 to D4Mit127 on distal Chr. 4 (termed NOD.NOR-Chr4 (NR4)) containing disease resistance alleles decreasing the pathogenic activity of autoreactive B cells. Microarrays were conducted on B cells purified from spleens of NOD and NR4 mice to highlight differentially expressed genes within the distal Chr. 4 locus. B cells were either cultured in media alone (unstimulated) or with BCR cross-linking anti-IgM-F(abM-bM-^@M-^Y)2 fragments (stimulated) for 2h before RNA was extracted for transcript analysis. B cells from three independent lots of pooled spleens (n=7-8) from NOD or NR4 female mice, respectively, were purified using a magnetic-activated cell sorting (MACS) negative depletion strategy. Purified B cells from each lot were resuspended at 1x10<7> cells/ml for 2h in complete RPMI media alone or with 10M-BM-5g/ml AffiniPure goat anti-mouse IgM F(abM-bM-^@M-^Y)2 fragments. RNA was then purified from B cells and subjected to one-cycle linear amplification and biotin labeling. Two BCR-stimulated and three unstimulated NOD B cell samples plus three BCR-stimulated and three unstimulated NR4 B cell samples were hybridized to Mouse Genome 430 2.0 Arrays.

2012-06-07 | E-GEOD-37294 | biostudies-arrayexpress

Proteomic identification of MHC class I-associated peptidome derived from non-obese diabetic mouse thymus and pancreas

Project description:The peptides repertoire presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules, referred to as the MHC I-associated peptidome (MIP), regulates all critical events that occur during the lifetime of CD8+ T cells. The MIP presented by thymic antigen presenting cells (APCs) is crucial for shaping CD8+ T cell repertoire and self-tolerance, while the MIP presented by peripheral tissues and organs is not only involved in maintaining periphery CD8+ T cell survival and homeostasis, but also mediates immune surveillance and autoimmune responses of CD8+ T cells under pathological conditions. Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by the destruction pancreatic β cells, mediated primarily by autoreactive CD8+ T cells. Non-obese diabetic (NOD) mouse is one of important animal models of spontaneous autoimmune diabetes that shares several key features with human T1D. Here, we deeply analyzed the MIP derived from the primary tissues of thymus and pancreas in NOD mice using targeted database searches of mass spectrometry data. We demonstrated that the thymus MIP source proteins accommodated only a small portion of the transcriptome of thymus epithelial cells, and partially shared with the MIP source proteins derived from NOD mice pancreas and β cell line. The global view of the MHC I-associated self-peptides repertoire in the thymus and pancreas of NOD mice may serve as a biological reference to identify potential autoantigens targeted by autoreactive CD8+ T cells in T1D.

2022-10-14 | PXD031966 | Pride

Nfkbid represents an Idd7 locus gene contributing to impaired thymic deletion of CD8 T-cells in NOD mice

Project description:In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T-cells recognizing pancreatic ß-cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed the common H2-Kd and/or H2-Db class I molecules expressed by this strain acquire an aberrant ability to mediate pathogenic CD8 T-cell responses through interactions with T1D susceptibility (Idd) genes outside the MHC. A gene(s) mapping to the Idd7 locus on proximal Chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T-cells. Using an inducible model of thymic negative selection and mRNA transcript analyses we initially identified an elevated Nfkbid expression variant as a strong candidate for an NOD Idd7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T-cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T-cells. These results indicated allelic variants of Nfkbid represent an Idd7 gene contributing to the efficiency of intrathymic deletion of diabetogenic CD8+ T-cells. However, while enhancing thymic deletion of pathogenic CD8+ T-cells, ablation of Nfkbid expression surprisingly accelerated T1D onset in NOD mice likely by numerically decreasing regulatory T- and B-lymphocytes (Tregs/Bregs), thereby reducing their peripheral immunosuppressive effects. We used microarray analysis to identify differentialy expressed genes in thymus under conditions of induced thymic negative selection. We compare two mice strains, NOD-LCMV vs NOD.Ln82-LCMV (a congenic stock for a C57BL/6 derived segment delimited by markers D7Mit117–D7Mit247).

2018-06-14 | GSE115754 | GEO

Increased β-cell proliferation prior to immune-cell invasion prevents progression of type 1 diabetes

Project description:Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D. Here we report that enhancing β-cell mass in female NOD mice early in life (prior to weaning) results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D. We observed that a model exhibiting β-cell hyperplasia on the NOD background (NOD-LIRKO) displayed altered β-cell antigens, and islet transplantation studies showed prolonged graft survival of NOD-LIRKO islets even upon exposure to diabetogenic splenocytes in vivo. Adoptive transfer of splenocytes from the NOD-LIRKOs prevented diabetes development in pre-diabetic NOD mice, while conversely, similar protective outcomes were obtained when NOD-LIRKO splenocytes were adoptively transferred after mixing them with diabetogenic NOD splenocytes in a dose-dependent manner. A significant increase in the splenic CD4+CD25+FoxP3+ regulatory T-cell (Treg) population in the NOD-LIRKO mice was observed to drive the protected phenotype since Treg depletion rendered NOD-LIRKO mice diabetic. The increase in Tregs coupled with a downregulation of key mediators of cellular function, upregulation of apoptosis and activation of TGF-β/SMAD3 signaling pathway in pathogenic T-cells favored reduced ability to kill β-cells. These data provide novel evidence that initiating β-cell proliferation, alone, prior to islet infiltration by immune cells alters the identity of β-cells, decreases pathologic self-reactivity of effector cells and increases Tregs to prevent progression of T1D.

2019-03-29 | GSE128315 | GEO

microRNAs of thymocytes and of peripheral and pancreas-infiltrating T lymphocytes

Project description:As early as one month of age, nonobese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, producing autoimmune diabetes mellitus (T1D) within eightmonths. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes may occur as thymocytes mature into peripheral T lymphocytes. The transcriptome of thymocytes and peripheral CD3+ T lymphocytes from prediabetic or diabetic mice analyzed through microarray hybridizations identified the differentially expressed genes.

2012-07-31 | E-MEXP-3572 | biostudies-arrayexpress

mRNAs of thymocytes and of peripheral and pancreas-infiltrating T lymphocytes

Project description:As early as one month of age, nonobese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, producing autoimmune diabetesmellitus (T1D) within eight months. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes may occur as thymocytes mature into peripheral T lymphocytes. The transcriptome of thymocytes and peripheral CD3+ T lymphocytes from prediabetic or diabetic mice analyzed through microarray hybridizations identified the differentially expressed genes.

2012-07-31 | E-MEXP-3573 | biostudies-arrayexpress

Assessing the role of microRNAs in post-transcriptional control of thymocytes and peripheral lymphocytes in NOD mice

Project description:As early as one month of age, non-obese diabetic (NOD) mice feature pancreatic infiltration of autoreactive T lymphocytes, which destruct insulin-producing beta cells, leading to autoimmune diabetes mellitus (T1D) within eight months. Thus, we hypothesized that during the development of T1D, the transcriptional modulation of immune reactivity genes, as well as, modulation of microRNAs (miRNAs) may occur during thymocytes mature into peripheral CD3+ T lymphocytes. Our aim is to analyze the transcriptional modulation of mRNA and microRNAs during development of thymocytes into peripheral CD3+ T lymphocytes in the context of the emergence of T1D.

2011-07-01 | E-MEXP-3235 | biostudies-arrayexpress

NOD Mouse Islet Peptide Content Identification

Project description:Beta-cells produce hybrid insulin peptides (HIPs) by linking insulin fragments to other peptides through peptide bonds. HIPs have unique amino acid sequences and are targeted by autoreactive T cells in type 1 diabetes (T1D). Individuals with recent-onset T1D have significantly higher levels of HIP-reactive T cells in their blood compared to non-diabetic control subjects. HIP-reactive T cells have also been found in the residual pancreatic islets of deceased T1D organ donors. In non-obese diabetic (NOD) mice, a major T1D animal model, several CD4 T cell clones that trigger diabetes have been shown to target HIPs. Through mass spectrometry, a subgroup of HIPs containing N-terminal amine groups of various peptides linked to aspartic acid residues of insulin C-peptide has been detected in NOD islets. Our research reveals that these HIPs form spontaneously in beta-cells via an aspartic anhydride intermediate mechanism. This process leads to the creation of a regular HIP with a standard peptide bond and a HIP-isomer (isoHIP) with an isopeptide bond linked to the carboxylic acid side-chain of the aspartic acid residue. Our mass spectrometric analyses confirmed the presence of both HIP isomers in murine islets, thereby validating the occurrence of this new reaction mechanism in beta-cells. The spontaneous formation of neoepitopes through the development of new peptide bonds within cells may contribute to the pathogenesis of T1D and other autoimmune diseases.

2023-11-16 | PXD041616 | Pride

Genome-Wide Gene Expression Profiles in the Pancreatic Lymph Nodes of non-obese diabetic (NOD) mice

Project description:Type 1 diabetes (T1D) is a polygenic autoimmune disorder caused by autoreactive T cells that recognize pancreatic islet antigens and subsequently destroy insulin-producing β-cells. Pancreatic lymph nodes (PLN) are an essential site for the development of T1D, where tolerance to pancreatic self-antigens is first broken and the autoimmune responses are amplified. The purpose of this study was to identify candidate genes and pathways in the PLN that may contribute to the pathogenesis of T1D using a mouse model of T1D. Genome-wide gene expression was measured in individual NOD PLN at 10 days (n=6), 4 weeks (n=6) or 12 weeks of age (n=5), against a pooled sample of age-matched NOD.B10 PLN as the control (n≥6), using Agilent Whole Mouse Genome Microarrays.

2015-03-09 | E-GEOD-66658 | biostudies-arrayexpress

Citrullination of glucokinase is linked to autoimmune diabetes

Project description:Inflammation, including reactive oxygen species and inflammatory cytokines in tissues amplify various post-translational modifications (PTMs) of self-proteins. A number of PTMs have been identified as autoimmune biomarkers in the initiation and progression of Type 1 diabetes (T1D). In this study, we have identified the citrullination of pancreatic glucokinase (GK) as a result of inflammation, triggering autoimmunity and affecting GK biological functions. Glucokinase is expressed in hepatocytes to regulate glycogen synthesis, and in pancreatic beta cells as a glucose sensor to initiate glycolysis and insulin signaling. We identify autoantibodies and autoreactive CD4+ T cells to glucokinase epitopes in the circulation of T1D patients and NOD mice. Finally, citrullination alters GK biologic activity (Km) and suppresses glucose-stimulated insulin secretion. Our studies define glucokinase as a T1D biomarker, providing new insights of how inflammation drives PTMs to create both neoautoantigens and affect beta cell metabolism.

2022-03-17 | PXD028825 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data