title: Genetic interactions among Idd3, Idd5.1, Idd5.2, and Idd5.3 protective loci in the nonobese diabetic mouse model of type 1 diabetes.
abstract: In the NOD mouse model of type 1 diabetes, insulin-dependent diabetes (Idd) loci control the development of insulitis and diabetes. Independently, protective alleles of Idd3/Il2 or Idd5 are able to partially protect congenic NOD mice from insulitis and diabetes, and to partially tolerize islet-specific CD8(+) T cells. However, when the two regions are combined, mice are almost completely protected, strongly suggesting the existence of genetic interactions between the two loci. Idd5 contains at least three protective subregions/causative gene candidates, Idd5.1/Ctla4, Idd5.2/Slc11a1, and Idd5.3/Acadl, yet it is unknown which of them interacts with Idd3/Il2. Through the use of a series of novel congenic strains containing the Idd3/Il2 region and different combinations of Idd5 subregion(s), we defined these genetic interactions. The combination of Idd3/Il2 and Idd5.3/Acadl was able to provide nearly complete protection from type 1 diabetes, but all three Idd5 subregions were required to protect from insulitis and fully restore self-tolerance. By backcrossing a Slc11a1 knockout allele onto the NOD genetic background, we have demonstrated that Slc11a1 is responsible for the diabetes protection resulting from Idd5.2. We also used Slc11a1 knockout-SCID and Idd5.2-SCID mice to show that both loss-of-function alleles provide protection from insulitis when expressed on the SCID host alone. These results lend further support to the hypothesis that Slc11a1 is Idd5.2.
authors: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Xiaotian
authors: X
authors: Lin
authors: Emma E
authors: EE
authors: Hamilton-Williams
authors: Daniel B
authors: DB
authors: Rainbow
authors: Kara M
authors: KM
authors: Hunter
authors: Yang D
authors: YD
authors: Dai
authors: Jocelyn
authors: J
authors: Cheung
authors: Laurence B
authors: LB
authors: Peterson
authors: Linda S
authors: LS
authors: Wicker
authors: Linda A
authors: LA
authors: Sherman
mesh_terms: D000483:Alleles; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005952:Glucose-6-Phosphatase / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011506:Proteins / Q000276:immunology; D040641:Quantitative Trait Loci; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D027682:Cation Transport Proteins; D005952:Glucose-6-Phosphatase; D011506:Proteins; D000099173:Natural Resistance-associated Macrophage Protein 1; C117983:G6pc2 protein, mouse