Terminal deoxynucleotidyl transferase deficiency decreases autoimmune disease in MRL-Fas(lpr) mice.
The neonatal Ab and TCR repertoires are much less diverse, and also very different from, the adult repertoires due to the delayed onset of terminal deoxynucleotidyl transferase (TdT) expression in ontogeny. TdT adds nontemplated N nucleotides to the junctions of Igs and TCRs, and thus its absence removes one of the major components of junctional diversity in complementarity-determining region 3 (CDR3). We have generated TdT-deficient MRL/lpr, Fas-deficient (MRL-Fas(lpr)) mice, and show that they have an increased lifespan, decreased incidence of skin lesions, and much lower serum levels of anti-dsDNA, anti-chromatin, and IgM rheumatoid factors. The generalized hypergammaglobulinemia characteristic of MRL-Fas(lpr) mice is also greatly reduced, as is the percentage of CD4(-)CD8(-)B220(+) (double-negative) T cells. IgG deposits in the kidney are significantly reduced, although evidence of renal disease is present in many mice at 6 mo. CDR3 regions of both IgH and TCR from peripheral lymphocytes of MRL-Fas(lpr) mice are shorter in the absence of TdT, and there is a paucity of arginines in the IgH CDR3 regions of the MRL-Fas(lpr) TdT(-/-) mice. Because the amelioration of symptoms is so widespread, it is likely that the absence of N regions has more of an affect than merely decreasing the precursor frequency of anti-dsDNA B cells. Hence, either the T or B cell repertoires, or more likely both, require N region diversity to produce the full spectrum of autoimmune lupus disease.
Feeney
A J
AJ
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA. feeney@scripps.edu
Lawson
B R
BR
Kono
D H
DH
Theofilopoulos
A N
AN
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000235:genetics; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics; D002843:Chromatin / Q000276:immunology; D022801:Complementarity Determining Regions / Q000235:genetics*; D003433:Crosses, Genetic; D004247:DNA / Q000097:blood; D004253:DNA Nucleotidylexotransferase / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006965:Hyperplasia; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008181:Lupus Nephritis / Q000201:enzymology / Q000235:genetics; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets; D008232:Lymphoproliferative Disorders / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D012217:Rheumatoid Factor / Q000032:analysis; D012867:Skin / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000974:Antibodies, Antinuclear; D002843:Chromatin; D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta; D004247:DNA; D012217:Rheumatoid Factor; D004253:DNA Nucleotidylexotransferase