Effect of a genetic deficiency of terminal deoxynucleotidyl transferase on autoantibody production by C57BL6 Fas(lpr) mice.
Terminal deoxynucleotidyl transferase (TdT) adds nontemplate coded nucleotides (N additions) between the recombining ends of immunoglobulin and T cell receptor genes. These nucleotides add significant diversity to the Ig and TCR repertoires. Amino acids coded for by these nucleotides play a key role in the binding of self antigens by autoantibodies and autoreactive T cells. To determine the effect of a lack of N additions on autoantibody production, we bred the TdT knockout genotype onto the autoimmune C57BL/6-Fas(lpr) background. TdT-deficient mice had significantly lower sera anti-DNA and rheumatoid factor activity than their TdT-producing littermates. C57BL/6-Fas(lpr) TdT-deficient mice had shorter VH CDR3 regions and fewer VH CDR3 arginines [0.6% versus 4. 7%] than their TdT-producing littermates. These data indicate that the absence of TdT limited the production of anti-DNA antibodies and rheumatoid factors in C57BL/6-Fas(lpr) mice, likely due to constraints on Ig diversity secondary to the lack of TdT-derived N additions.
Molano
I D
ID
Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Wloch
M K
MK
Alexander
A A
AA
Watanabe
H
H
Gilkeson
G S
GS
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001323:Autoantibodies / Q000276:immunology*; D022801:Complementarity Determining Regions; D004253:DNA Nucleotidylexotransferase / Q000172:deficiency* / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr / Q000235:genetics*; D018345:Mice, Knockout / Q000276:immunology*; D012217:Rheumatoid Factor / Q000097:blood; D019014:fas Receptor / Q000235:genetics*
D001323:Autoantibodies; D022801:Complementarity Determining Regions; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D019014:fas Receptor; D012217:Rheumatoid Factor; D004253:DNA Nucleotidylexotransferase