Disease relevance of Dgcr2

• Identifying Idd genes and defining their biologic functions should further our understanding of autoimmune disease pathogenesis and facilitate development of new treatments for diabetes [1].
• These results suggest that IL-10 may be necessary and sufficient for producing autoimmune diabetes in conjunction with NOD MHC homozygosity and that some Idd genes may be related to the regulation of IL-10 [2].
• Two NOD Idd-associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjögren's syndrome) on a healthy murine background [3].
• More than 19 chromosomal intervals (referred to as Idd regions) that contribute to diabetes susceptibility in the NOD mouse model have been identified, but only 2 chromosomal intervals (associated with Idd3 and Idd5) have been shown to control sialadenitis [3].
• Neuroblastoma (N18, Lan 1) and melanoma (B16, G361, S91) cell lines exhibited a significantly greater percentage of cells adhering to one or more C-GAG matrices compared with C matrices [4].

High impact information on Dgcr2

• The first Idd locus recognized, Idd1, is linked to the major histocompatibility complex (MHC), and its inheritance and expression are a paradigm for the other non-MHC Idd genes [1].
• Genetic linkage analysis of congenic lines segregating PWK chromosome 6 segments in a NOD background confirmed the presence of the Idd locus within this region [5].
• A systematic analysis of iNKT cell number and function in Idd congenic mice revealed that neither iNKT cell number nor their inability to rapidly secrete IL-4 in response to acute in vivo activation by Ag underlies the mechanism of protection from diabetes in Idd congenic mice [6].
• To determine whether a diabetes-associated NOD chromosomal locus (i.e., Idd) was responsible for this defect, LPS-stimulated macrophages from several recombinant congenic inbred mice with Idd loci on a C57BL/6 background or with different combinations of NOD and CBA genomic segments were screened for IL-12p40 production [7].
• This is the first evidence that a subset of Idd susceptibility loci independently regulate T-cell and APC participation in insulitis progression [8].

Biological context of Dgcr2

• Therefore, we reasoned that the genetic determinant(s) that controls iNKT cell number and function might lie within Idd (insulin-dependent diabetes susceptibility locus) regions, which are known to contain TID resistance or susceptibility genes [6].
• Genetic susceptibility to type 1 diabetes in the nonobese diabetic (NOD) mouse involves at least 17 Idd loci [8].
• This experiment was accelerated by typing for microsatellites linked to known diabetes susceptibility (Idd) loci, and included a control backcross of the wild-type 129/SvJ-derived IL-4 gene, the original target locus [9].
• The construction of NOD congenic strains containing selected segments of the diabetes-resistant strain genome allows analysis of the joint effects of alleles of different loci in isolation, without the complication of other segregating Idd loci [10].
• Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified [11].

Analytical, diagnostic and therapeutic context of Dgcr2

• In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade [12].
• These data indicate that single or multiple combinations of evaluated Idd loci that dramatically reduce diabetes frequency do not correct resistance to peripheral transplantation tolerance induced by costimulation blockade [12].

References