Modeling CTLA4-linked autoimmunity with RNA interference in mice

Zhibin Chen, John Stockton, Diane Mathis, Christophe Benoist

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The CTLA4 gene is important for T lymphocyte-mediated immunoregulation and has been associated with several autoimmune diseases, in particular, type 1 diabetes. To model the impact of natural genetic variants of CTLA4, we constructed RNA interference (RNAi) "knockdown" mice through lentiviral transgenesis. Variegation of expression was observed in founders but proved surmountable because it reflected parental imprinting, with derepression by transmission from male lentigenics. Unlike the indiscriminate multiorgan autoimmune phenotype of the corresponding knockout mice, Ctla4 knockdown animals had a disease primarily focused on the pancreas, with rapid progression to diabetes. As with the human disease, the knockdown phenotype was tempered by genetic-modifier loci. RNAi should be more pertinent than gene ablation in modeling disease pathogenesis linked to a gene-dosage variation.

Original languageEnglish (US)
Pages (from-to)16400-16405
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number44
DOIs
StatePublished - Oct 31 2006

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Keywords

  • Autoimmune diabetes
  • Imprinting
  • Lentiviral transgene
  • RNAi
  • Variegation

ASJC Scopus subject areas

  • Genetics
  • General

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