title: Autoimmunity and antibody affinity maturation are modulated by genetic variants on mouse chromosome 12.
abstract: 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.H2(k) congenic strain bearing B10 alleles at the locus comprised within the D12Mit184 and D12Mit12 markers, which we named NOD.H2(k)-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-A(k), and the HEL transgene, which is expressed under the rat-insulin promoter (iHEL), were bred into the NOD.H2(k)-Chr12 congenic strain. In the resulting 3A9 TCR:iHEL NOD.H2(k)-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.H2(k) 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.H2(k) setting. Of importance, antibody affinity maturation upon immunization and re-challenge was also impeded in NOD.H2(k)-Chr12 congenic mice relative to NOD.H2(k) mice. Together, these results demonstrate that a genetic variant(s) present within the Chr12 locus plays a global role in modulating antibody affinity maturation.
authors.affiliation: Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montréal, Québec, H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada. Electronic address: roxanne.collin@umontreal.ca.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Collin
authors.affiliation: Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montréal, Québec, H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada; Mitacs, Computer Research Institute of Montreal, Montréal, Québec, H3N 1M3, Canada. Electronic address: vdugas@mitacs.ca.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dugas
authors.affiliation: Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montréal, Québec, H1T 2M4, Canada. Electronic address: g.chabot.roy@gmail.com.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Chabot-Roy
authors.affiliation: Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montréal, Québec, H3G 1A4, Canada. Electronic address: david.salem@mail.mcgill.ca.
authors.forename: David
authors.initials: D
authors.lastname: Salem
authors.affiliation: Division of Immunology and Viral Infections, Institut de Recherches Cliniques de Montréal, Montréal, Québec, H2W 1R7, Canada. Electronic address: astrid.zahn@ircm.qc.ca.
authors.forename: Astrid
authors.initials: A
authors.lastname: Zahn
authors.affiliation: Division of Immunology and Viral Infections, Institut de Recherches Cliniques de Montréal, Montréal, Québec, H2W 1R7, Canada; Département de Médecine, Université de Montréal, Montréal, Québec, H3T 1J4, Canada. Electronic address: javier.marcelo.di.noia@ircm.qc.ca.
authors.forename: Javier M
authors.initials: JM
authors.lastname: Di Noia
authors.affiliation: Division of Rheumatology, Department of Medicine, Research Institute of the McGill University Health Centre, Montréal, Québec, H3G 1A4, Canada. Electronic address: joyce.rauch@mcgill.ca.
authors.forename: Joyce
authors.initials: J
authors.lastname: Rauch
authors.affiliation: Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montréal, Québec, H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, H3C 3J7, Canada. Electronic address: sylvie.lesage@umontreal.ca.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesage
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis* / Q000235:genetics; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000235:genetics; D051379:Mice; D020297:Mice, Congenic; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology; D051381:Rats
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007328:Insulin; C421864:hen egg lysozyme; D009113:Muramidase
keywords: Affinity maturation; Autoantibodies; Autoimmune diabetes; NOD congenic mice; Systemic lupus erythematosus; Transgenic model