Mapping the diabetes polygene Idd3 on mouse Chromosome 3 by use of novel congenic strains

Lord, Christopher J.; Bohlander, Stefan K.; Hopes, Elaine; Montague, Carl; Hill, Natasha J.; Prins, Jan–Bas; Renjilian, R. J.; Peterson, Laurence B.; Wicker, Linda S.; Todd, John; Denny, Paul

doi:10.1007/bf00352359

Cited by 39 publications

(30 citation statements)

References 26 publications

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“…The strain NOD.B10Idd5R1 (N8F2-4), referred to as Idd5R1, was the founding congenic strain and contains the greatest amount of introgressive B10 DNA. Founders of the Idd5R1 strain were tested for the presence of B10 chromosomal segments throughout the genome using a panel of microsatellite markers that differentiate NOD and B10 genomic segments (20). All non-chromosome 1 markers examined were of NOD origin in the Idd5R1 strain.…”

Section: Methodsmentioning

confidence: 99%

NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans.

et al. 2000

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A genome scan for B10-derived loci that reduce the frequency of diabetes and insulitis in NOD mice demonstrated a large region (34 cM) of linkage on the proximal end of chromosome 1. This locus was designated Idd5 and encompassed candidate genes including Il1r1, Il1r2, Stat1, Stat4, Nramp1, and Bcl2. In the current study, we have confirmed the existence of Idd5 by developing a series of congenic mouse strains that are resistant to diabetes and determined that Idd5 is actually two genes located within a 9.4-cM interval. Idd5.1 is in the proximal 1.5-cM portion of the interval and contains the candidates Casp8, Cflar (FLIP), Cd28, and Cd152 (CTLA4). Idd5.1 overlaps the orthologous CTLA4/IDDM12 locus in humans. Idd5.2 is in the distal 5.1-cM portion of the 9.4-cM interval and contains the candidates Nramp1, which has a functional polymorphism between NOD and B10, and Cmkar2 (CXCR2, interleukin [IL]-8 receptor ␣). Candidate genes eliminated by this analysis include Il1r1, Ilr2, Zap70, Orch5, Stat1, Stat4, Bcl2, Cmkar4 (CXCR4), and Il10. On its own, the Idd5 locus provides a significant amount of protection from diabetes (50% reduction from parental frequency) and when combined with another resistance locus (Idd3 on chromosome 3), provides nearly complete protection from diabetes and insulitis. Diabetes

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Section: Methodsmentioning

confidence: 99%

NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans.

et al. 2000

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“…The derivation of the congenic strains R450 (N13F5-6) and NOD.B6 Idd10R2 (N8F9) has been previously described (9,14). During their development, progenitor mice for both strains were tested for the presence of non-NOD-derived DNA at microsatellite markers spread across the genome and were found to be NOD at all loci (10). The congenic strains NOD.…”

Section: Methodsmentioning

confidence: 99%

Mapping by Genetic Interaction

et al. 2001

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As many of the linked chromosome regions that predispose to type 1 diabetes in the NOD mouse have been dissected, it has become apparent that the initially observed effect is in fact attributable to several loci. One such cluster of loci on distal chromosome 3, originally described as Idd10, is now known to comprise three separate loci, Idd10, Idd17, and Idd18. Although these loci have a significant combined effect on diabetes development, their individual effects are barely detectable when diabetes is used as a read-out, which makes fine-mapping them by use of a conventional congenic approach impractical. In this study, we demonstrate that it is possible to map loci, with modest effects, to regions small enough for systematic gene identification by capitalizing on the fact that the combined loci provide more profound, measurable protection. We have mapped the Idd10 and Idd18 loci to 1.3-and 2.0-cM intervals, respectively, by holding the Idd3 allele constant. In addition, we have excluded Csf1 and Nras as candidates for both loci.

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“…NOD. B6 Idd3 mice, introgressed with the protective T1D-resistant Idd3 locus, show a marked resistance to reduced T1D onset (15,18,19), while also affecting susceptibility to other organ-specific autoimmune diseases like experimental autoimmune encephalomyelitis and ovarian disease provoked by day 3 thymectomy (20,21). Interestingly, fine mapping and positional cloning studies of the Idd3 B6 locus have demonstrated that the Il2 gene is the primary candidate for Idd3-mediated protection in a model of CD8 ϩ T cell-induced T1D and a likely contributor to increased CD4 ϩ T reg cell activity in these mice (19,22).…”

Section: Foxp3mentioning

confidence: 99%

Impact of Protective IL-2 Allelic Variants on CD4+Foxp3+ Regulatory T Cell Function In Situ and Resistance to Autoimmune Diabetes in NOD Mice

Sgouroudis

Albanese

Piccirillo

2008

The Journal of Immunology

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Type I diabetes (T1D) susceptibility is inherited through multiple insulin-dependent diabetes (Idd) genes. NOD.B6 Idd3 congenic mice, introgressed with an Idd3 allele from T1D-resistant C57BL/6 mice (Idd3B6), show a marked resistance to T1D compared with control NOD mice. The protective function of the Idd3 locus is confined to the Il2 gene, whose expression is critical for naturally occurring CD4+Foxp3+ regulatory T (nTreg) cell development and function. In this study, we asked whether Idd3B6 protective alleles in the NOD mouse model confer T1D resistance by promoting the cellular frequency, function, or homeostasis of nTreg cells in vivo. We show that resistance to T1D in NOD.B6 Idd3 congenic mice correlates with increased levels of IL-2 mRNA and protein production in Ag-activated diabetogenic CD4+ T cells. We also observe that protective IL2 allelic variants (Idd3B6 resistance allele) also favor the expansion and suppressive functions of CD4+Foxp3+ nTreg cells in vitro, as well as restrain the proliferation, IL-17 production, and pathogenicity of diabetogenic CD4+ T cells in vivo more efficiently than control do nTreg cells. Lastly, the resistance to T1D in Idd3 congenic mice does not correlate with an augmented systemic frequency of CD4+Foxp3+ nTreg cells but more so with the ability of protective IL2 allelic variants to promote the expansion of CD4+Foxp3+ nTreg cells directly in the target organ undergoing autoimmune attack. Thus, protective, IL2 allelic variants impinge the development of organ-specific autoimmunity by bolstering the IL-2 producing capacity of self-reactive CD4+ T cells and, in turn, favor the function and homeostasis of CD4+Foxp3+ nTreg cells in vivo.

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Mapping the diabetes polygene Idd3 on mouse Chromosome 3 by use of novel congenic strains

Cited by 39 publications

References 26 publications

NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans.

NOD Idd5 locus controls insulitis and diabetes and overlaps the orthologous CTLA4/IDDM12 and NRAMP1 loci in humans.

Mapping by Genetic Interaction

Impact of Protective IL-2 Allelic Variants on CD4+Foxp3+ Regulatory T Cell Function In Situ and Resistance to Autoimmune Diabetes in NOD Mice

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