Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity.
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.
Guo
Wenzhong
W
Integrated Department of Immunology, National Jewish Health and 2 University of Colorado, Denver, CO 80206, USA.
Smith
Diana
D
Aviszus
Katja
K
Detanico
Thiago
T
Heiser
Ryan A
RA
Wysocki
Lawrence J
LJ
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
D000974:Antibodies, Antinuclear; D022801:Complementarity Determining Regions; D001120:Arginine
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