title: Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity.
abstract: Systemic lupus erythematosus (SLE) is characterized by high-avidity IgG antinuclear antibodies (ANAs) that are almost certainly products of T cell-dependent immune responses. Whether critical amino acids in the third complementarity-determining region (CDR3) of the ANA originate from V(D)J recombination or somatic hypermutation (SHM) is not known. We studied a mouse model of SLE in which all somatic mutations within ANA V regions, including those in CDR3, could be unequivocally identified. Mutation reversion analyses revealed that ANA arose predominantly from nonautoreactive B cells that diversified immunoglobulin genes via SHM. The resolution afforded by this model allowed us to demonstrate that one ANA clone was generated by SHM after a V(H) gene replacement event. Mutations producing arginine substitutions were frequent and arose largely (66%) from base changes in just two codons: AGC and AGT. These codons are abundant in the repertoires of mouse and human V genes. Our findings reveal the predominant role of SHM in the development of ANA and underscore the importance of self-tolerance checkpoints at the postmutational stage of B cell differentiation.
authors.affiliation: Integrated Department of Immunology, National Jewish Health and 2 University of Colorado, Denver, CO 80206, USA.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Guo
authors.forename: Diana
authors.initials: D
authors.lastname: Smith
authors.forename: Katja
authors.initials: K
authors.lastname: Aviszus
authors.forename: Thiago
authors.initials: T
authors.lastname: Detanico
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Heiser
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wysocki
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D001120:Arginine; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000235:genetics; D004195:Disease Models, Animal; D005803:Genes, Immunoglobulin; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D051379:Mice; D011995:Recombination, Genetic; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D000974:Antibodies, Antinuclear; D022801:Complementarity Determining Regions; D001120:Arginine
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