Allergic dysregulation and hyperimmuno-globulinemia E in Foxp3 mutant mice
Allergic dysregulation and hyperimmuno-globulinemia E in Foxp3 mutant mice
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DOI：
10.1016/j.jaci.2005.08.046
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发表时间：
2005-11-01
影响因子：
14.2
通讯作者：
Chatila, TA
中科院分区：
文献类型：
--
作者：
Lin, W;Truong, N;Chatila, TA
背景：调节性 T 细胞已被认为在调节过敏性炎症中发挥重要作用。转录因子 Foxp3 是控制天然和适应性 CD4(+)CD25(+) 调节性 T (T-R) 细胞发育和功能的主开关基因。在人类受试者中，功能丧失的 Foxp3 突变会引发淋巴细胞增殖、自身免疫和严重的过敏性炎症，这种疾病被称为免疫失调多内分泌病 X 连锁肠病综合征。 概括了已知的导致疾病的人类Foxp3突变。方法：通过敲入诱变产生Foxp3突变小鼠，并分析其组织学、免疫学和血液学异常。使用Stat6和Foxp3双突变小鼠分析信号转导子和转录激活子6（Stat6）在疾病发病机制中的作用。结果：Foxp3突变小鼠出现与过敏性气道炎症相关的强烈多器官炎症反应、显着的高免疫球蛋白血症E、嗜酸性粒细胞增多以及T(H)1和T(H)2细胞因子失调 在没有明显 T(H)2 倾斜的情况下进行生产。同时 Stat6 缺陷可逆转高免疫球蛋白血症 E 和嗜酸性粒细胞增多以及延迟死亡，这与 Foxp3 缺陷中过敏性炎症的致病作用一致。结论：过敏性失调是不同物种中由 Foxp3 缺陷引起的 CD4(+)CD25(+) T-R 细胞丢失的常见且根本的后果。 TR 细胞的异常可能导致多种过敏性疾病。
Background: Regulatory T cells have been proposed to play an important role in regulating allergic inflammation. The transcription factor Foxp3 is a master switch gene that controls the development and function of natural and adaptive CD4(+)CD25(+) regulatory T (T-R) cells. In human subjects loss-of-function Foxp3 mutations trigger lymphoproliferation, autoimmunity, and intense allergic inflammation in a disease termed immune dysregulation polyendocrinopathy enteropathy-X-linked syndrome.Objective: We sought to examine the evolution and attributes of allergic inflammation in mice with a targeted loss-of-function mutation in the murine Foxp3 gene that recapitulates a known disease-causing human Foxp3 mutation.Methods: Foxp3 mutant mice were generated by means of knock-in mutagenesis and were analyzed for histologic, immunologic, and hematologic abnormalities. The role of signal transducer and activator of transcription 6 (Stat6) in disease pathogenesis was analyzed by using Stat6 and Foxp3 double-mutant mice.Results: Foxp3 mutant mice developed an intense multiorgan inflammatory response associated with allergic airway inflammation, a striking hyperimmunoglobulinemia E, eosinophilia, and dysregulated T(H)1 and T(H)2 cytokine production in the absence of overt T(H)2 skewing. Concurrent Stat6 deficiency reversed the hyperimmunoglobulinemia E and eosinophilia and delayed mortality, which is consistent with a pathogenic role for allergic inflammation in Foxp3 deficiency.Conclusion: Allergic dysregulation is a common and fundamental consequence of loss of CD4(+)CD25(+) T-R cells caused by Foxp3 deficiency in different species. Abnormalities affecting TR cells might contribute to a variety of allergic diseases.