Activation-induced deaminase heterozygous MRL/lpr mice are delayed in the production of high-affinity pathogenic antibodies and in the development of lupus nephritis.
We previously reported that activation-induced deaminase (AID) heterozygous MRL/lpr mice have substantially lower levels of serum anti-dsDNA autoantibodies than AID wild-type littermates. Given the known functions of AID, here we examined whether this decrease in pathogenic autoantibodies in the heterozygotes was the result of a defect in class switch recombination, somatic hypermutation, or both. We report significant impairment of switch recombination to most isotypes except immunoglobulin G3 (IgG3) in vitro. However, serum levels of IgG were similar to AID wild-type levels even in very young mice. Mutation accumulation in the B cells from Peyer's patches also revealed reduced somatic hypermutation in the heterozygotes. Unlike the switch defect, the hypermutation defect probably resulted in an in vivo effect because the serum IgG antibodies from the heterozygotes were of strikingly lower affinity to dsDNA than serum IgG antibodies from wild-type littermates. This suggests that the somatic hypermutation defect resulted in impaired affinity maturation of autoantibodies in these mice and explains the low levels of specific anti-dsDNA antibodies in the heterozygotes. This correlated with a delay in the development of kidney damage. These results imply that AID levels impact the class switch recombination and somatic hypermutation mechanisms and directly implicate affinity maturation of autoantibodies in autoimmunity.
Jiang
Chuancang
C
Laboratory of Molecular Genetics, D3-01 National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, NC 27709, USA.
Zhao
Ming Lang
ML
Diaz
Marilyn
M
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000235:genetics*; D004247:DNA / Q000276:immunology; D006579:Heterozygote; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009154:Mutation; D010581:Peyer's Patches / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D007074:Immunoglobulin G; D012333:RNA, Messenger; D004247:DNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase