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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

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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.

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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.

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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]

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

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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

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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.

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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.

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

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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.

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The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets

Project description:Alternative splicing (AS) within the β cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We employed a computational strategy to prioritize pathogenic splicing events in human islets treated with IL-1β + IFN-γ as an ex vivo model of T1D and coupled this analysis with a k-mer based approach to predict RNA binding proteins involved in AS events. In total, 969 AS events were identified in cytokine-treated islets, with the majority (44.8%) involving a skipped exon. AS events occurred with high frequency in MHC Class II-related mRNAs, and targeted qPCR validated reduced inclusion of Exon5 in the MHC Class II gene HLA-DMB, while RNA FISH confirmed HLA-DMB splicing in pancreatic sections from human T1D donors. Together, these data suggest that dynamic control of AS plays a role in the β cell response to inflammatory signals during T1D evolution.

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