Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A humanized mouse model to study type 1 diabetes

ABSTRACT: The clinical management of type 1 diabetes (T1D) faces the lack of fully predictive biomarkers and of antigen-specific therapies to prevent its development. From a therapeutic standpoint, preclinical modls of T1D have fallen short of directly translating into the human. To circumvent this limitation, we developed a new mouse model that is deficient for expression of murine major histocompatibility complex class I, class II and of murine insulin genes and instead expresses HLA-A*02:01, the high susceptibility HLA-DQ8 molecule and human insulin. The metabolic and immune phenotype of these mice is basically identical to that of the parental strains. Upon expression of B7.1 under the control of the rat insulin promoter, these mice develop T1D along with a T-lymphocyte response to human preproinsulin epitopes spanning the whole autoantigen sequence. This new model will allow evaluating peptide-based immunotherapy that may directly apply to human T1D.

ORGANISM(S): Mus musculus

PROVIDER: GSE101551 | GEO | 2017/07/19

SECONDARY ACCESSION(S): PRJNA394820

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A humanized mouse strain that develops spontaneously immune-mediated diabetes.

Project description:The clinical management of type 1 diabetes (T1D) faces the lack of fully predictive biomarkers and of antigen-specific therapies to prevent its development. From a therapeutic standpoint, preclinical modls of T1D have fallen short of directly translating into the human. To circumvent this limitation, we developed a new mouse model that is deficient for expression of murine major histocompatibility complex class I, class II and of murine insulin genes and instead expresses HLA-A*02:01, the high susceptibility HLA-DQ8 molecule and human insulin. The metabolic and immune phenotype of these mice is basically identical to that of the parental strains. Upon expression of B7.1 under the control of the rat insulin promoter, these mice develop T1D along with a T-lymphocyte response to human preproinsulin epitopes spanning the whole autoantigen sequence. This new model will allow evaluating peptide-based immunotherapy that may directly apply to human T1D.

2021-06-02 | GSE151644 | GEO

Genome-wide DNA methylation profiling of CD4+ T cells and CD19+ B cells in autoimmune-disease associated HLA class II genotype carriers (HLA-DR2-DQ6, -DR3-DQ2 and -DR4-DQ8 homozygotes) using Illumina Infinium HumanMethylation EPIC beadchip

Project description:The Human leukocyte antigen (HLA) -region, especially HLA class I and II genes, plays a major role in the predisposition to autoimmune disorders. Particularly three HLA haplotypes, DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2), DRB1*04:01-DQA1*03-DQB1*03:02 (DR4-DQ8) and DRB1*15-DQA1*01-DQB1*06:02 (DR2-DQ6), have an important role in many autoimmune diseases: for example, in type 1 diabetes (T1D) the DR2-DQ6 is associated with a strongly decreased T1D risk and the DR3-DQ2 and DR4-DQ8 are associated with a moderately increased T1D risk. To clarify the mechanisms behind this association, we examined genome-wide DNA methylation in CD4+ T cells and CD19+ B cells of healthy subjects homozygous either for DR3-DQ2 (n = 19), DR4-DQ8 (n = 17) or DR2-DQ6 (n = 14), and compared methylation between the genotypes. For the study, CD4+ T cells and CD19+ B cells were isolated consecutively from PBMC samples using magnetic bead separation. DNA was extracted from the cell lysates with AllPrep DNA/RNA/miRNA Universal Kit (Qiagen, Germany). Then the individual DNA samples were pooled into 11 pooled samples with 4–5 samples per pooled sample. The original 50 samples were designated pools based on age and sex to ensure that the age and sex distributions would be as similar as possible between the pooled samples. The mean age (±SD) in the three HLA-groups (DR2-DQ6, DR3-DQ2 and DR4-DQ8) were 15.0 (±8.3), 11.1 (±5.6) and 11.8 (±7.9) and their male to female ratios were 8/6, 9/10 and 11/6. Similar pooled samples were created for both the CD4+ T cell and the CD19+ B cell samples. Then DNA methylation was examined in the pooled CD4+ T cell and CD19+ B cell samples using Illumina Infinium HumanMethylation EPIC beadchip.

2024-06-20 | E-MTAB-13654 | biostudies-arrayexpress

The Position Beta57 of IAg7 Controls the Early Anti-Insulin Response and Onset of Diabetes in NOD mice to Link MHC and Disease [sequencing]

Project description:Abstract- The class II region of the Major Histocompatibility locus is the main contributor to the genetic susceptibility to type 1 diabetes (T1D). The loss of an aspartic acid at position 57 of diabetogenic HLA-DQ8 chains supports this association; it influences the recognition of peptides in the context of HLA-DQ8, and I-Ag7 using a mechanism termed the P9 switch. Here, we built register-specific insulin MHC tetramers, Ins12-20 and Ins13-21, to examine anti-insulin CD4 T cell responses during the early pre-diabetic phase of disease in mice. A single cell gene expression analysis and single cell T cell receptor (TCR) sequencing of anti-insulin CD4 T cells performed in 6 and 12-week-old NOD mice, revealed tissue-specific gene expression signatures. TCR signaling and clonal expansion were found only in the islets of Langerhans. and produced either classical Th1 differentiation or an unusual Treg phenotype, independent of TCR usage. The early phase of the anti-insulin response was dominated by cells specific for Ins12-20, the register that supports a P9 switch mode of recognition. The presence of the switch was demonstrated by TCR sequencing, re-expression, mutagenesis, and functional testing of alpha/beta TCR pairs in vitro. The genetic correction of the beta57 mutation resulted in the disappearance of D/E residues in the CDR3beta of anti-Ins12-20 T cells, and inability of cells normally activated by a switch to recognize the Ins9-23 peptide. These results provide the first molecular mechanistic explanation that links the unique MHC class II polymorphism of T1D with the recognition of islet antigens and disease onset.

2019-07-25 | GSE134883 | GEO

The Position Beta57 of IAg7 Controls the Early Anti-Insulin Response and Onset of Diabetes in NOD mice to Link MHC and Disease [RT-PCR]

2019-07-18 | GSE134440 | GEO

Transcription Regulatory Networks of CD4 CD8 and CD14 cells in Patients of Type I Mellitus Diabetes

Project description:Insulin-dependent diabetes mellitus (T1D) is an organ-specific auto-immune disease caused by the selective destruction of the pancreatic beta cells by inflammatory cells, especially auto-reactive CD8+ T lymphocytes. In this study we evaluated the differential large scale gene expression profiling using cDNA microarrays of T (CD4+ and CD8+) and monocyte (CD14+) cells. In addition, considering that HLA class II profile may influence the expression of these molecules on the surface of peripheral blood cells, and considering that the mechanisms by which HLA class II susceptibility alleles drive the auto-immune response have not been elucidated, we intend to further stratify T1D patients according to the HLA class II profile. 20 pre-pubertal recently diagnosed T1D patients were selected, HLA-DRB1/DQB1 allele typing and separated in two groups. The group 1(G1) had patients with susceptibility alleles and group 2 (G2) with at least one protection allele. To established relationships between genes, the GeneNetwork 1.2 algorithm was used, 6 networks were obtained, TCD4+ G1 patients X controls, TCD4+ G2 patients X controls, and same situation to TCD8+ and CD14+.

2011-06-15 | E-MEXP-3223 | biostudies-arrayexpress

Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti–PD-1 Immune Checkpoint Inhibitor Cancer Therapy

Project description:Myocarditis has emerged as an immune-related adverse event of immune-checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. Our new NOD-cMHCI/II-/-.DQ8 mouse strain expresses human HLA-DQ8 in the absence of classical murine MHC class I and II. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis development. Using RNA sequencing analyses we performed a thorough characterization of cardiac and skeletal muscle infiltrating T-cells, identifying shared and unique characteristics of both populations.

2024-02-02 | GSE248625 | GEO

Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β-cells [iPSC bulk RNAseq]

Project description:IFNa is a key regulator of the dialogue between pancreatic β-cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human b-cells fostering autoantigen presentation to the immune system. We observed by bulk and single cell RNA sequencing that exposure of human induced pluripotent-derived islet-like cells to IFNa induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulin-producing EndoC-bH1 and human islets cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I expression and related genes and of chemokines. NLRC5 also mediates the effects of IFNa on alternative splicing, a generator of β-cell neoantigens, suggesting that it is a central mediator of the effects of IFNa on β-cells that contribute to trigger and amplify autoimmunity in T1D.

2022-09-14 | GSE203430 | GEO

Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β-cells [RNA-seq]

Project description:IFNa is a key regulator of the dialogue between pancreatic β-cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human β-cells fostering autoantigen presentation to the immune system. We observed by bulk and single cell RNA sequencing that exposure of human induced pluripotent-derived islet-like cells to IFNa induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulin-producing EndoC-βH1 and human islets cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I expression and related genes and of chemokines. NLRC5 also mediates the effects of IFNa on alternative splicing, a generator of β-cell neoantigens, suggesting that it is a central mediator of the effects of IFNa on β-cells that contribute to trigger and amplify autoimmunity in T1D.

2022-09-14 | GSE202852 | GEO

Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β-cells [iPSC scRNAseq]

Project description:IFNa is a key regulator of the dialogue between pancreatic β-cells and the immune system in early type 1 diabetes (T1D). IFNa up-regulates HLA class I expression in human β-cells fostering autoantigen presentation to the immune system. We observed by bulk and single cell RNA sequencing that exposure of human induced pluripotent-derived islet-like cells to IFNa induces expression of HLA class I and of other genes involved in antigen presentation, including the transcriptional activator NLRC5. We next evaluated the global role of NLRC5 in human insulin-producing EndoC-βH1 and human islets cells by RNA sequencing and targeted gene/protein determination. NLRC5 regulates expression of HLA class I expression and related genes and of chemokines. NLRC5 also mediates the effects of IFNa on alternative splicing, a generator of β-cell neoantigens, suggesting that it is a central mediator of the effects of IFNa on β-cells that contribute to trigger and amplify autoimmunity in T1D.

2022-09-14 | GSE203384 | GEO

Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2

Project description:Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic β-cells. Recognition of these autoantigens by CD8¬¬+ T cells results in the destruction of pancreatic β-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of β-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation. These results indicate that insulin-derived peptides, presented by HLA-class I molecules at the cell surface, originate from ER-resident proinsulin that has been dislocated to the cytosol for subsequent degradation. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future therapies that may cure or even prevent T1D.

2024-03-20 | PXD049996 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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