Effect of genetic deficiency of terminal deoxynucleotidyl transferase on autoantibody production and renal disease in MRL/lpr mice

Ivan D. Molano, Shakisha Redmond, Hideharu Sekine, Xian Kui Zhang, Chris Reilly, Florence Hutchison, Phil Ruiz, Gary S. Gilkeson

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)186-197
Number of pages12
JournalClinical Immunology
Volume107
Issue number3
DOIs
StatePublished - Jun 1 2003

Keywords

  • Albuminuria
  • Autoantibodies
  • Autoimmune
  • CDR3 sequence
  • Lupus
  • MRL/lpr
  • MRLMpJ/Fas
  • N additions
  • Nephritis
  • TdT

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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