Disease relevance of Idd3

• Most significant, however, is the co-localization of Aod2 to Idd3, a susceptibility gene that plays a role in autoimmune insulin-dependent type 1 diabetes mellitus in the nonobese diabetic mouse [1].
• In the present study, we bred the Idd3 and Idd5 chromosomal intervals from NOD mice into non-autoimmune C57BL/6 mice to determine if these intervals recreate a Sjögren's syndrome (SS)-like phenotype [2].

High impact information on Idd3

• On the basis of comparative maps of the mouse and human genomes, the homologue of Idd-3 may reside on human chromosomes 1 or 4 and Idd-4 on chromosome 17 [3].
• It is important to note that only partial protection is provided by two doses of the resistance allele at either Idd3 or Idd10 [4].
• Development of these congenic strains has allowed Idd3 to be localized between Glut2 and D3Mit6, close to the Il2 locus [4].
• In (F1 x NOD) backcross analyses using the B10.H-2g7 or B6.PL-Thy1a strains as the outcross partner, we previously identified several non-MHC Idd loci, including two located on chromosome 3 (Idd3 and Idd10) [4].
• To investigate whether sequence variation exists in the promoter region of the Il2 gene, which might alter its expression, we sequenced the promoter region of the Il2 gene from mouse strains carrying either an Idd3 susceptibility or resistance allele [5].

Biological context of Idd3

• CONCLUSION: Alleles on chromosomes 1 (Idd5) and 3 (Idd3) in combination appear to greatly influence susceptibility and resistance to development of autoimmune exocrinopathy [6].
• 3. One haplotype of this ancestral segment of DNA is found in mouse strains carrying an Idd3 susceptibility allele and another is found in mouse strains carrying an Idd3 protective allelle [5].
• To refine further the Idd3 interval we developed a series of novel single nucleotide polymorphisms (SNPs) and carried out haplotype analysis on DNA from mouse strains known to carry either Idd3 susceptibility or protective alleles [5].
• These data, taken together with the immunomodulatory role of IL-2, provide circumstantial evidence in support of the hypothesis that Idd3 is an allelic variation of the Il2 gene, or a variant in strong linkage disequilibrium [7].
• For Idd3 and Idd5 we would also not reject a model of additivity on the penetrance scale, which might indicate a disease model mediated by more than one pathway leading to beta-cell destruction and development of diabetes [8].

Anatomical context of Idd3

• Additionally, we showed that the Ctex and the Idd3 regions do not influence inducible T-cell costimulator (ICOS) protein expression in NOD mice [9].
• In Idd3/5 mice, tolerance occurs during the initial activation of islet Ag-specific CD8+ and CD4+ T cells in the pancreatic lymph nodes where CD25+ regulatory T cells (Tregs) effectively prevent their accumulation [10].
• Bone marrow derived macrophages (BMM) were grown from NOD, C57BL/6J, non-obese non-diabetic (NON) mice, and NOD-related congenic variants differing in the Idd-3, Idd-10/18, or major histocompatibility complex (MHC) region [11].

Regulatory relationships of Idd3

• Pancreatic IL-10 induces diabetes in NOD.B6 Idd3 Idd10 mice [12].

Other interactions of Idd3

• Defective induction of CTLA-4 in the NOD mouse is controlled by the NOD allele of Idd3/IL-2 and a novel locus (Ctex) telomeric on chromosome 1 [9].
• We have mapped the Idd10 and Idd18 loci to 1.3- and 2.0-cM intervals, respectively, by holding the Idd3 allele constant [13].
• Interestingly, although Idd10 and Idd17 participate in a genetic interaction with each other, Idd10 but not Idd17 participates in the genetic interaction with Idd3 [14].
• Idd1 and Idd3 are necessary but not sufficient for development of type 1 diabetes in NOD mouse [15].
• Insulitis and diabetes developed in almost all IL-10 transgenic backcross 1 (BC1) mice of the H2g(7/g7) haplotype regardless of the allelic status at Idd3 and Idd10 [12].

Analytical, diagnostic and therapeutic context of Idd3

• Restriction mapping of the BAC contig placed the maximum size of the Idd3 interval at 780 kb between the markers D3Nds36 and D3Nds76 [5].
• Genetic dissection of type 1 diabetes susceptibility gene, Idd3, by ancestral haplotype congenic mapping [16].
• Islet allograft survival induced by costimulation blockade in NOD mice is controlled by allelic variants of Idd3 [17].

References