A single recessive non-MHC diabetogenic gene determines the development of insulitis in the presence of an MHC-linked diabetogenic gene in NOD mice

Abstract

To study the genetic control of insulitis in non-obese diabetic (NOD) mice, we performed breeding studies in crosses of NOD with non-diabetic strains, ICR-L-line Ishibe (ILI), non-obese non-diabetic (NON) and C3H/He mice. The ILI mouse serologically shared the same MHC Class I and Class II as the NOD mouse. Insulitis was defined as islets invaded by lymphoid cells. Periductular, perivascular and peri-insular lymphoid cell infiltrations were often observed in NOD mice and appear to be the initial lesion leading to insulitis. Such lesions, however, were found in 1-year-old ICR, ILI, NON and Cataract Shionogi (CTS) mice of the NOD's sister strain. The lymphoid cells did not invade the islets in ICR, ILI, NON and CTS mice. The incidence of insulitis was 0% in F1 generations and 40% in female backcrosses (BC) [(ILI × NOD)F1 × NOD] at 9 weeks of age, 48 and 50% in BC[(NON × NOD)F1 × NOD] and BC[( C3H He × NOD)F1 × NOD] at 1 year of age, respectively. Backcross animals were typed for the MHC to investigate correlation between the development of insulitis and MHC haplotypes. Among the backcross females with insulitis, approximately half the animals were heterozygous for MHC( non nod ) in BC[(NON × NOD)F1 × NOD] and MHC( k nod ) in BC[(C3H × NOD)F1 × NOD]. Among the backcross females with no insulitis, approximately half the animals were homozygous for MHC( nod nod ) in BC[(NON × NOD)F1 × NOD] and in BC[(C3H × NOD)F1 × NOD]. The results suggest that a single recessive non-MHC diabetogenic gene determines the development of insulitis regardless of NOD MHC homozygosity or heterozygosity.