Autoimmunity and antibody affinity maturation are modulated by genetic variants on mouse chromosome 12

•Generation of NOD.H2k-B10 chromosome 12 congenic mice.•The chromosome 12 (Chr12) locus defines a new autoimmune susceptibility locus.•The quantity and affinity of IgG autoantibodies are influenced by the Chr12 locus.•The Chr12 locus reveals novel candidate genes for antibody affinity maturation.

Autoimmune diseases result from a break in immune tolerance leading to an attack on self-antigens. Autoantibody levels serve as a predictive tool for the early diagnosis of many autoimmune diseases, including type 1 diabetes. We find that a genetic locus on mouse chromosome 12 influences the affinity maturation of antibodies as well as autoantibody production. Thus, we generated a NOD.H2k congenic strain bearing B10 alleles at the locus comprised within the D12Mit184 and D12Mit12 markers, which we named NOD.H2k-Chr12. We determined the biological relevance of the Chr12 locus on the autoimmune process using an antigen-specific TCR transgenic autoimmune mouse model. Specifically, the 3A9 TCR transgene, which recognizes a peptide from hen egg lysozyme (HEL) in the context of I-Ak, and the HEL transgene, which is expressed under the rat-insulin promoter (iHEL), were bred into the NOD.H2k-Chr12 congenic strain. In the resulting 3A9 TCR:iHEL NOD.H2k-Chr12 mice, we observed a significant decrease in diabetes incidence as well as a decrease in both the quantity and affinity of HEL-specific IgG autoantibodies relative to 3A9 TCR:iHEL NOD.H2k mice. Notably, the decrease in autoantibodies due to the Chr12 locus was not restricted to the TCR transgenic model, as it was also observed in the non-transgenic NOD.H2k setting. Of importance, antibody affinity maturation upon immunization and re-challenge was also impeded in NOD.H2k-Chr12 congenic mice relative to NOD.H2k mice. Together, these results demonstrate that a genetic variant(s) present within the Chr12 locus plays a global role in modulating antibody affinity maturation.