Sex-Specific Effect of Insulin-Dependent Diabetes 4 on Regulation of Diabetes Pathogenesis in the Nonobese Diabetic Mouse

Abstract

Many human autoimmune diseases are more frequent in females than males, and their clinical severity is affected by sex hormone levels. A strong female bias is also observed in the NOD mouse model of type I diabetes (T1D). In both NOD mice and humans, T1D displays complex polygenic inheritance and T cell-mediated autoimmune pathogenesis. The identities of many of the insulin-dependent diabetes (Idd) loci, their influence on specific stages of autoimmune pathogenesis, and sex-specific effects of Idd loci in the NOD model are not well understood. To address these questions, we analyzed cyclophosphamide-accelerated T1D (CY-T1D) that causes disease with high and similar frequencies in male and female NOD mice, but not in diabetes-resistant animals, including the nonobese diabetes-resistant (NOR) strain. In this study we show by genetic linkage analysis of (NOD × NOR) × NOD backcross mice that progression to severe islet inflammation after CY treatment was controlled by the Idd4 and Idd9 loci. Congenic strains on both the NOD and NOR backgrounds confirmed the roles of Idd4 and Idd9 in CY-T1D susceptibility and revealed the contribution of a third locus, Idd5. Importantly, we show that the three loci acted at distinct stages of islet inflammation and disease progression. Among these three loci, Idd4 alleles alone displayed striking sex-specific behavior in CY-accelerated disease. Additional studies will be required to address the question of whether a sex-specific effect of Idd4, observed in this study, is also present in the spontaneous model of the disease with striking female bias.

Molecular Genetic Analysis of the Idd4 Locus Implicates the IFN Response in Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice

“…CY accelerates T1D onset in NOD males and females from months to 2-4 wk, with the cumulative incidence reaching 80 -100% (20,21). Similarly, treated NOR mice demonstrate disease protection (20).…”

“…Similarly, treated NOR mice demonstrate disease protection (20). We recently showed that differential susceptibility to CY-T1D in NOD and NOR strains resides in the Idd4, Idd5, and Idd9 loci (20).…”

“…C57BLKS/J is a recombinant inbred strain derived from C57BL/6 and DBA/2 stocks (16). NOD and NOR mice share all Idd loci identified to date, with the exception of Idd4, Idd5, Idd9, and Idd13 (17)(18)(19)(20), which are sufficient to protect NOR animals from both spontaneous and cyclophosphamide-accelerated T1D (CY-T1D).…”

“…Previously described NOR.NOD-Idd4 mice (20) were backcrossed with the NOR strain, their pups were intercrossed, and the resulting progeny genotyped for D11Mit74, D11Mit340, D11Mit230, D11Mit135, D11Mit217, D11Mit310, D11Mit164, D11Mit157, D11Mit177, D11Mit4, D11Mit368, D11Mit30, D11Mit90, D11Mit364, D11Mit219, D11Mit322, and D11Bhm149 to capture recombinant animals. NOR.NOD-Idd4 (R1) and NOR.NOD-Idd4 (R2) subcongenic strains were generated by backcrossing corresponding recombinants to the NOR and intercrossing the progeny to fix NOD-derived subcongenic intervals.…”

The Size of the Plasmacytoid Dendritic Cell Compartment Is a Multigenic Trait Dominated by a Locus on Mouse Chromosome 7

“…First, NOD.NZW-Chr7 mice present a low proportion of pDC relative to NOD mice, but both strains show a comparable incidence of autoimmune diabetes (17), demonstrating that elevated proportion of pDC is not necessary for autoimmune diabetes progression. Second, both NOR mice, which are highly genetically related to NOD mice (47)(48)(49), and 129Sv mice (4) exhibit a high proportion of pDC similar to NOD mice, yet do not develop insulitis or diabetes. This observation indicates that elevated pDC levels are not sufficient to promote T1D pathogenesis.…”