1. A novel mouse model for the hyper-IgM syndrome: a spontaneous activation-induced cytidine deaminase mutation leading to complete loss of Ig class switching and reduced somatic hypermutation.
- Author
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Dahlberg CI, He M, Visnes T, Torres ML, Cortizas EM, Verdun RE, Westerberg LS, Severinson E, and Ström L
- Subjects
- Animals, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets metabolism, Cytidine Deaminase metabolism, DNA Mutational Analysis, Female, Germinal Center immunology, Hyper-IgM Immunodeficiency Syndrome metabolism, Immunophenotyping, Inheritance Patterns, Lymphocyte Count, Male, Mice, Pedigree, Phenotype, Quantitative Trait, Heritable, Cytidine Deaminase genetics, Disease Models, Animal, Hyper-IgM Immunodeficiency Syndrome genetics, Hyper-IgM Immunodeficiency Syndrome immunology, Immunoglobulin Class Switching genetics, Immunoglobulin Class Switching immunology, Mutation, Somatic Hypermutation, Immunoglobulin
- Abstract
We describe a spontaneously derived mouse line that completely failed to induce Ig class switching in vitro and in vivo. The mice inherited abolished IgG serum titers in a recessive manner caused by a spontaneous G → A transition mutation in codon 112 of the aicda gene, leading to an arginine to histidine replacement (AID(R112H)). Ig class switching was completely reconstituted by expressing wild-type AID. Mice homozygous for AID(R112H) had peripheral B cell hyperplasia and large germinal centers in the absence of Ag challenge. Immunization with SRBCs elicited an Ag-specific IgG1 response in wild-type mice, whereas AID(R112H) mice failed to produce IgG1 and had reduced somatic hypermutation. The phenotype recapitulates the human hyper-IgM (HIGM) syndrome that is caused by point mutations in the orthologous gene in humans, and the AID(R112H) mutation is frequently found in HIGM patients. The AID(R112H) mouse model for HIGM provides a powerful and more precise tool than conventional knockout strategies., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
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