Modeling CTLA4-linked autoimmunity with RNA interference in mice
Modeling CTLA4-linked autoimmunity with RNA interference in mice
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DOI：
10.1073/pnas.0607854103
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发表时间：
2006-10-31
影响因子：
11.1
通讯作者：
Benoist, Christophe
中科院分区：
文献类型：
--
作者：
Chen, Zhibin;Stockton, John;Benoist, Christophe
CTLA4基因对于T淋巴细胞介导的免疫调节是重要的，并且与几种自身免疫性疾病，特别是1型糖尿病相关。为了模拟CTLA4的天然遗传变体的影响，我们通过慢病毒转基因构建了RNA干扰（RNAi）“敲低”小鼠。在创始人中观察到表达的多样性，但证明是可以克服的，因为它反映了父母的印记，与男性lentigenics传输的去抑制。与相应敲除小鼠的不加选择的多器官自身免疫表型不同，Ctla4敲除动物的疾病主要集中在胰腺上，并迅速进展为糖尿病。与人类疾病一样，基因修饰基因座调节了敲低表型。RNAi应该比基因消融在与基因剂量变化相关的疾病发病机制建模中更相关。
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.