Modeling CTLA4 -linked autoimmunity with RNA interference in mice
- 31 October 2006
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 103 (44) , 16400-16405
- https://doi.org/10.1073/pnas.0607854103
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.Keywords
This publication has 30 references indexed in Scilit:
- Promoter region ‐318 C/ T and ‐1661 A/G CTLA‐4 single nucleotide polymorphisms and type 1 diabetes in North IndiansTissue Antigens, 2006
- Silencing and Variegation of Gammaretrovirus and Lentivirus VectorsHuman Gene Therapy, 2005
- Unlocking the potential of the human genome with RNA interferenceNature, 2004
- An Autoimmune Disease-Associated CTLA-4 Splice Variant Lacking the B7 Binding Domain Signals Negatively in T CellsImmunity, 2004
- Induction of an interferon response by RNAi vectors in mammalian cellsNature Genetics, 2003
- Expression profiling reveals off-target gene regulation by RNAiNature Biotechnology, 2003
- Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune diseaseNature, 2003
- The Emerging Role of CTLA-4 as an Immune AttenuatorImmunity, 1997
- Insulin-Dependent Diabetes MellitusCell, 1996
- Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4Science, 1995