The Idd4 Locus Displays Sex-Specific Epistatic Effects on Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice

Ivakine, Evgueni A.; Mortin-Toth, Steven M.; Gulban, Omid M.; Valova, Aneta; Canty, Angelo J.; Danska, Jayne S.

doi:10.2337/db06-0758

Cited by 15 publications

(16 citation statements)

References 52 publications

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“…They identified Alox15 as a candidate gene for modifying diabetes susceptibility in NOD mice because it lies within an ϳ20-Mb genetic interval containing the NOD diabetes susceptibility locus Idd4.1 (6). The lipoxygenase encoded by Alox15 is highly expressed in both macrophages and ␤-cells, and it oxidizes the polyunsaturated fatty acids arachidonic acid and linoleic acid, creating unstable lipids with potent cytotoxic and proinflammatory activity.…”

Section: 2 Pmentioning

confidence: 99%

An Apparent Role for Alox15 in the Pathogenesis of Diabetes in the NOD Mouse

Weisberg

Leibel

2008

Diabetes

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Section: 2 Pmentioning

confidence: 99%

An Apparent Role for Alox15 in the Pathogenesis of Diabetes in the NOD Mouse

Weisberg

Leibel

2008

Diabetes

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“…Thus, the D11Gul2850-D11Gul5 interval might include genes that confer additional effects on diabetes. This interval displayed partial overlap with our previous defined Idd4.2 region (14). In contrast, strain D4R6 was not protected from T1D relative to parental NOD mice (p = 0.975, Fig.…”

Section: Fine Mapping Of the T1d Risk Genes On Chromosome 11mentioning

confidence: 82%

“…Previous work from our laboratory and others demonstrated that NOD-background congenic mice harboring NOR-derived Idd4 alleles (Idd4) are protected from T1D (13), and that Idd4 controls the expression of several genes involved in the type 1 IFN (T1IFN) response (15). We also reported that genes within Idd4 act late in the diabetogenic process, controlling the progression from mild to severe insulitis (a crucial checkpoint in T1D pathogenesis) in a sex-specific manner (14). We now report extremely high-resolution mapping of the Idd4 locus using novel NOD-background subcongenic strains, identification of the minimal region, Idd4.1, mediating protection from spontaneous T1D, and molecular genetic analysis of its principle candidate gene, Nlrp1b.…”

mentioning

confidence: 85%

“…Subsequently, NOD congenic strains carrying Idd4 regions derived from C57L (10,11), B6 (12), and NOR (13,14) demonstrated that the Idd4 locus is comprised of multiple subloci. Previous work from our laboratory and others demonstrated that NOD-background congenic mice harboring NOR-derived Idd4 alleles (Idd4) are protected from T1D (13), and that Idd4 controls the expression of several genes involved in the type 1 IFN (T1IFN) response (15).…”

mentioning

confidence: 99%

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Identification of the Inflammasome Nlrp1b as the Candidate Gene Conferring Diabetes Risk at the Idd4.1 Locus in the Nonobese Diabetic Mouse

Motta

Markle

Gulban

et al. 2015

The Journal of Immunology

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Type 1 diabetes in the NOD mouse model has been linked to >30 insulin-dependent diabetes (Idd) susceptibility loci. Idd4 on chromosome 11 consists of two subloci, Idd4.1 and Idd4.2. Using congenic analysis of alleles in NOD and NOD-resistant (NOR) mice, we previously defined Idd4.1 as an interval containing >50 genes that controlled expression of genes in the type 1 IFN pathway. In this study, we report refined mapping of Idd4.1 to a 1.1-Mb chromosomal region and provide genomic sequence analysis and mechanistic evidence supporting its role in innate immune regulation of islet-directed autoimmunity. Genetic variation at Idd4.1 was mediated by radiation-sensitive hematopoietic cells, and type 1 diabetes protection conferred by the NOR allele was abrogated in mice treated with exogenous type 1 IFN-β. Next generation sequence analysis of the full Idd4.1 genomic interval in NOD and NOR strains supported Nlrp1b as a strong candidate gene for Idd4.1. Nlrp1b belongs to the Nod-like receptor (NLR) gene family and contributes to inflammasome assembly, caspase-1 recruitment, and release of IL-1β. The Nlrp1b of NOR was expressed as an alternative spliced isoform that skips exon 9, resulting in a premature stop codon predicted to encode a truncated protein. Functional analysis of the truncated NOR Nlrp1b protein demonstrated that it was unable to recruit caspase-1 and process IL-1β. Our data suggest that Idd4.1-dependent protection from islet autoimmunity is mediated by differences in type 1 IFN– and IL-1β–dependent immune responses resulting from genetic variation in Nlrp1b.

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“…4), some of which map to sites in close proximity to Itgae. Indeed, Itgae maps within the Idd4.2 locus (Ivakine et al 2006), hence it was important to perform studies with a ITGAE-depleting mAb to exclude the possibility that the delayed development of diabetes was due to carryover of closely linked genes during backcrossing. We observed the strongest effect in the Itgae knockout mice, but a depleting anti-ITGAE mAb (ChM90-IgG2a afucosyl) also decreased the development of diabetes in WT NOD mice and protected insulin-producing cells from immune destruction, strongly indicating that the effects are due to Itgae itself.…”

Section: Discussionmentioning

confidence: 99%

Role of ITGAE in the development of autoimmune diabetes in non-obese diabetic mice

Barrie¹,

Lodder²,

Weinreb³

et al. 2014

Journal of Endocrinology

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There is compelling evidence that autoreactive CD8 C T cells play a central role in precipitating the development of autoimmune diabetes in non-obese diabetic (NOD) mice, but the underlying mechanisms remain unclear. Given that ITGAE (CD103) recognizes an isletrestricted ligand (E-cadherin), we postulated that its expression is required for initiation of disease. We herein use a mouse model of autoimmune diabetes (NOD/ShiLt mice) to test this hypothesis. We demonstrate that ITGAE is expressed by a discrete subset of CD8 C T cells that infiltrate pancreatic islets before the development of diabetes. Moreover, we demonstrate that development of diabetes in Itgae-deficient NOD mice is significantly delayed at early but not late time points, indicating that ITGAE is preferentially involved in early diabetes development. To rule out a potential contribution by closely linked loci to this delay, we treated WT NOD mice beginning at 2 weeks of age through 5 weeks of age with a depleting anti-ITGAE mAb and found a decreased incidence of diabetes following anti-ITGAE mAb treatment compared with mice that received isotype control mAbs or non-depleting mAbs to ITGAE. Moreover, a histological examination of the pancreas of treated mice revealed that NOD mice treated with a depleting mAb were resistant to immune destruction. These results indicate that ITGAE C cells play a key role in the development of autoimmune diabetes and are consistent with the hypothesis that ITGAE C CD8 C T effectors initiate the disease process.

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The Idd4 Locus Displays Sex-Specific Epistatic Effects on Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice

Cited by 15 publications

References 52 publications

An Apparent Role for Alox15 in the Pathogenesis of Diabetes in the NOD Mouse

An Apparent Role for Alox15 in the Pathogenesis of Diabetes in the NOD Mouse

Identification of the Inflammasome Nlrp1b as the Candidate Gene Conferring Diabetes Risk at the Idd4.1 Locus in the Nonobese Diabetic Mouse

Role of ITGAE in the development of autoimmune diabetes in non-obese diabetic mice

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