A bacterial artificial chromosome transgene with polymorphic Cd72 inhibits the development of glomerulonephritis and vasculitis in MRL-Faslpr lupus mice

Hisashi Oishi, Takahito Tsubaki, Tatsuhiko Miyazaki, Masao Ono, Masato Nose, Satoru Takahashi

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Systemic lupus erythematosus is considered to be under the control of polygenic inheritance, developing according to the cumulative effects of susceptibility genes with polymorphic alleles; however, the mechanisms underlying the roles of polygenes based on functional and pathological genomics remain uncharacterized. In this study, we substantiate that a CD72 polymorphism in the membrane-distal extracellular domain impacts on both the development of glomerulonephritis and vasculitis in a lupus model strain of mice, MRL/MpJ-Faslpr, and the reactivity of BCR signal stimulation. We generated mice carrying a bacterial artificial chromosome transgene originating from C57BL/6 (B6) mice that contains the Cd72b locus (Cd72 B6 transgenic [tg]) or the modified Cd72b locus with an MRL-derived Cd72c allele at the polymorphic region corresponding to the membrane-distal extracellular domain (Cd72B6/MRL tg). Cd72 B6 tg mice, but not Cd72B6/MRL tg mice, showed a significant reduction in mortality following a marked improvement of disease associated with decreased serum levels of IgG3 and anti-dsDNA Abs. The number of splenic CD4-CD8- T cells in Cd72B6 tg mice was decreased significantly in association with a reduced response to B cell receptor signaling. These results indicate that the Cd72 polymorphism affects susceptibility to lupus phenotypes and that novel functional rescue by a bacterial artificial chromosome transgenesis is an efficient approach with wide applications for conducting a genomic analysis of polygene diseases.

Original languageEnglish
Pages (from-to)2129-2137
Number of pages9
JournalJournal of Immunology
Volume190
Issue number5
DOIs
Publication statusPublished - 2013 Mar 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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