Autoimmunity and antibody affinity maturation are modulated by genetic variants on mouse chromosome 12
DOI: 10.1016/j.jaut.2015.01.007
Title: Autoimmunity and antibody affinity maturation are modulated by genetic variants on mouse chromosome 12
Journal Title: Journal of Autoimmunity
Volume: 58
Publication Date: April 2015
Start Page: 90
End Page: 99
Published online: online 24 January 2015
ISSN: 0896-8411

  • a Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montréal, Québec, H1T 2M4, Canada

  • b Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada

  • c Mitacs, Computer Research Institute of Montreal, Montréal, Québec, H3N 1M3, Canada

  • d Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montréal, Québec, H3G 1A4, Canada

  • e Division of Immunology and Viral Infections, Institut de Recherches Cliniques de Montréal, Montréal, Québec, H2W 1R7, Canada

  • f Département de Médecine, Université de Montréal, Montréal, Québec, H3T 1J4, Canada
  • Abstract: ne 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.
    Accepted: 13 January 2015
    Received: 21 November 2014
    Revised: 12 January 2015
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