Modeling CTLA4-linked autoimmunity with RNA interference in mice.

Zhibin Chen; John Stockton; Diane Mathis; Christophe Benoist

doi:10.1073/pnas.0607854103

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Modeling CTLA4-linked autoimmunity with RNA interference in mice.

Zhibin Chen·John Stockton·Diane Mathis·Christophe Benoist

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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.

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Animals Antigens, CD Antigens, Differentiation Autoimmunity CTLA-4 Antigen Diabetes Mellitus Female Genetic Vectors Histocompatibility Antigens Lentivirus Male Mice Models, Immunological RNA Interference Transgenes Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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Zhibin Chen, John Stockton, Diane Mathis, Christophe Benoist. 2006-10-23. Modeling CTLA4-linked autoimmunity with RNA interference in mice.. https://doi.org/10.1073/pnas.0607854103

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