Somatic diversification and affinity maturation of IgM and IgG anti-DNA antibodies in murine lupus.
Molecular events occurring during the process of generation of pathogenic immunoglobulin (Ig)G anti-DNA antibodies in systemic lupus erythematosus (SLE) were studied using a newly established method. We analyzed the Ig variable (V) region gene sequence and DNA-binding activity of IgM and IgG anti-DNA monoclonal antibodies (mAb) from individual SLE-prone (NZB x NZW) F1 mice. The first event appeared to be clonal selection and expansion of IgM anti-DNA clones, in which several clones had intraclonal V gene mutations. Although the number of mutations was small, the mutated IgM clones were associated with an increase in DNA-binding activity. The somatic mutations located in complementarity-determining regions (CDR) and in framework regions (FR) of V genes were apparently related to changes in DNA-binding activity. IgG anti-DNA clones that progressively increased in number with aging had numerous somatic mutations in the V region genes and there was a pair of clones which showed an intraclonal accumulation of mutations, in association with increase in the DNA-binding activity. All these findings show that somatic mutations associated with affinity maturation of the V region begin immediately before isotype-switching from IgM to IgG of the clones that have been selected and expanded, in an antigen-driven manner and/or by other forces. We propose that further accumulations of intraclonal somatic hypermutation, in association with selection and expansion of high affinity IgG clones, may lead to formation of highly pathogenic anti-DNA antibodies.
Hirose
S
S
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Wakiya
M
M
Kawano-Nishi
Y
Y
Yi
J
J
Sanokawa
R
R
Taki
S
S
Shimamura
T
T
Kishimoto
T
T
Tsurui
H
H
Nishimura
H
H
D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics*; D000911:Antibodies, Monoclonal / Q000235:genetics; D000915:Antibody Affinity; D000916:Antibody Diversity / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D007074:Immunoglobulin G / Q000235:genetics; D007132:Immunoglobulin Isotypes / Q000235:genetics; D007075:Immunoglobulin M / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D009154:Mutation
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D004247:DNA