Congenic mapping and functional analysis of a second component of the MHC-linked diabetogenic gene (Idd16)

By using a congenic non-obese diabetic (NOD) mouse strain that possesses a recombinant major histocompatibility complex (MHC) from a diabetes-resistant sister strain, the CTS mouse, we have previously mapped a second component of the MHC linked susceptibility gene (Idd16) to the <11.8centiMorgan (cM) segment of chromosome 17 adjacent to, but distinct from class II A and E genes (Idd1). To further localise and characterise Idd16, CTS-derived non-diabetogenic genetic interval, identified in our previous study, was transferred onto the NOD background, and a new recombinant with recombination breakpoint at 1.3-cM proximal to the previous congenic chromosome was obtained among 49 intercrosses of heterozygous mice. The frequency of type 1 diabetes in mice possessing the new recombinant chromosome was lower than that in the parental NOD strain, as in the case of the previous congenic strain. The tumor necrosis factor α gene (Tnf), a strong candidate gene for type 1 diabetes, is located within the newly localized Idd16 interval. Although our previous study indicated that the sequences of exons and exon-intron junctions of Tnf in the NOD mouse were identical to those in the control mouse, defective expression of TNFα may well contribute to Idd16 effect. We therefore determined plasma TNFα levels in NOD and CTS mice. TNFα levels under basal conditions and after stimulation with interferon gamma (IFN-gamma) and lipopolysaccharide (LPS), however, were comparable among NOD, CTS and control mice. These data suggest that Idd16 is located in the <10.5cM segment of chromosome 17 adjacent to Idd1, and that defective expression of TNFα may not be responsible for Idd16 effect, at least under the condition used in the present study.