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J Autoimmun. 2015 Apr;58:90-9. doi: 10.1016/j.jaut.2015.01.007. Epub 2015 Jan 24.

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

Author information

1
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.
2
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.
3
Immunology-Oncology Section, Maisonneuve-Rosemont Hospital, Montréal, Québec, H1T 2M4, Canada. Electronic address: g.chabot.roy@gmail.com.
4
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.
5
Division of Immunology and Viral Infections, Institut de Recherches Cliniques de Montréal, Montréal, Québec, H2W 1R7, Canada. Electronic address: astrid.zahn@ircm.qc.ca.
6
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.
7
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.
8
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.

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.

KEYWORDS:

Affinity maturation; Autoantibodies; Autoimmune diabetes; NOD congenic mice; Systemic lupus erythematosus; Transgenic model

PMID:
25623266
DOI:
10.1016/j.jaut.2015.01.007
[Indexed for MEDLINE]

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