Effect of genetic deficiency of terminal deoxynucleotidyl transferase on autoantibody production and renal disease in MRL/lpr mice.
Terminal deoxynucleotidyl transferase (TdT) places non-template-coded nucleotides (N additions) in the VH CDR3 of T cell receptors and immunoglobulins. Amino acids coded for by N additions are important in autoantibody binding of dsDNA in lupus. We hypothesized that a genetic lack of TdT would modulate disease in lupus-prone mice. To test this hypothesis, we derived TdT-deficient MRL/lpr mice. Serum levels of anti-dsDNA antibodies and anti-dsDNA producing splenocytes were significantly lower in the TdT(-) versus TdT(+) littermates. Albuminuria, glomerular IgG deposition, and pathologic renal disease were significantly reduced in the TdT(-) mice. Sequence analysis of anti-dsDNA hybridomas derived from TdT(-) mice revealed a lack of N additions, short VH CDR3 segments, yet the presence of VH CDR3 arginines. Thus, the genetic absence of TdT reduces autoantibody production and clinical disease in MRL/lpr mice, confirming the importance of N additions in the autoimmune response in these mice.
Molano
Ivan D
ID
Medical Research Service, Ralph H. Johnson VAMC, and the Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA. gilkeson@musc.edu
Redmond
Shakisha
S
Sekine
Hideharu
H
Zhang
Xian Kui
XK
Reilly
Chris
C
Hutchison
Florence
F
Ruiz
Phil
P
Gilkeson
Gary S
GS
D000419:Albuminuria / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D015415:Biomarkers; D004253:DNA Nucleotidylexotransferase / Q000235:genetics* / Q000378:metabolism*; D005921:Glomerulonephritis / Q000473:pathology; D007074:Immunoglobulin G / Q000235:genetics; D007592:Joint Diseases / Q000276:immunology / Q000473:pathology; D007596:Joints / Q000473:pathology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D001323:Autoantibodies; D015415:Biomarkers; D007074:Immunoglobulin G; D004253:DNA Nucleotidylexotransferase