Lupus-prone MRL/faslpr/lpr mice display increased AID expression and extensive DNA lesions, comprising deletions and insertions, in the immunoglobulin locus: Concurrent upregulation of somatic hypermutation and class switch DNA recombination

Hong Zan, Jinsong Zhang, Sona Ardeshna, Zhenming Xu, Seok Rae Park, Paolo Casali

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of an array of pathogenic autoantibodies, including high-affinity anti-dsDNA IgG antibodies. These autoantibodies are mutated and class-switched, mainly to IgG, indicating that immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) are important in their generation. Lupus-prone MRL/faslpr/lpr mice develop a systemic autoimmune syndrome that shares many features with human SLE. We found that Ig genes were heavily mutated in MRL/faslpr/lpr mice and contained long stretches of DNA deletions and insertions. The spectrum of mutations in MRL/faslpr/lpr B cells was significantly altered, including increased dG/dC transitions, increased targeting of the RGYW/WRCY mutational hotspot and the WGCW AID-targeting hotspot. We also showed that MRL/faslpr/lpr greatly upregulated CSR, particularly to IgG2a and IgA in B cells of the spleen, lymph nodes and Peyer's patches. In MRL/faslpr/lpr mice, the significant upregulation of SHM and CSR was associated with increased expression of activation-induced cytidine deaminase (AID), which mediates DNA lesion, the first step in SHM and CSR, and translesion DNA synthesis (TLS) polymerase (pol) θ, pol η and pol ζ, which are involved in DNA synthesis/ repair process associated with SHM and, possibly, CSR. Thus, in lupus-prone MRL/faslpr/lpr mice, SHM and CSR are upregulated, as a result of enhanced AID expression and, therefore, DNA lesions, and dysregulated DNA repair factors, including TLS polymerases, which are involved in the repair process of AID-mediated DNA lesions.

Original languageEnglish (US)
Pages (from-to)89-103
Number of pages15
JournalAutoimmunity
Volume42
Issue number2
DOIs
StatePublished - 2009
Externally publishedYes

Keywords

  • Activation-induced cytidine deaminase (AID)
  • Antibody
  • Autoantibody
  • B cell
  • Class switch DNA recombination (CSR)
  • DNA deletion
  • DNA insertion
  • Lupus
  • Somatic hypermutation (SHM)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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