FIGURE 7.

Model delineating the distinct segments controlling pathogenic B and CD4 T cell function in the distal Chr. 4 locus of NOR mice. Results of our experiments in the NR4S1–S7 subcongenic strains have identified four regions (R1–R4) on distal Chr. 4 that contain genes controlling pathogenic B and CD4 T cell function. Markers demarcating the boundaries of each region are shown. T1D is independently controlled by NOR-derived genes in the R1 region and the R3–R4 region. The hyperresponsive phenotype of NR4 B cells to BCR stimulation is the result of an interaction of genes within R2 and R4. The maintenance of anergy in NR4 B cells is controlled by genes within R1 and R4, with counter-balancing negative regulation by R2. R3 contains the gene(s) responsible for dampening the diabetogenic activity of NR4 B cells. The penetrance of this gene is inhibited by genes within R2 and R4, potentially by making B cells hyperresponsive to BCR stimulation. Genes within R1 and R4 could also contribute to the dampening of B cell diabetogenic activity in the presence of the R3 region, potentially through their effects on B cell anergy. Finally, the R1 region contains a gene(s) responsible for dampening the diabetogenic function of NR4 CD4 T cells. For comparison, the most current Mb positions of the Idd9.1, Idd9.2, and Idd11 resistance loci from B10 or B6 mice are shown (27, 28).