A Murine Model of X-Linked Moesin-Associated Immunodeficiency (X-MAID) Reveals Defects in T Cell Homeostasis and Migration.
A Murine Model of X-Linked Moesin-Associated Immunodeficiency (X-MAID) Reveals Defects in T Cell Homeostasis and Migration.
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DOI：
10.3389/fimmu.2021.726406
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发表时间：
2021
影响因子：
7.3
通讯作者：
Burkhardt JK
中科院分区：
文献类型：
--
作者：
Avery L;Robertson TF;Wu CF;Roy NH;Chauvin SD;Perkey E;Vanderbeck A;Maillard I;Burkhardt JK
x连锁moesin相关免疫缺陷（X-MAID）是一种原发性免疫缺陷疾病，患者患有严重淋巴细胞减少症，导致复发性感染。该疾病是由单点突变导致蛋白moesin （moesinR171W）的R171W氨基酸改变引起的。Moesin是ERM蛋白家族的一员，它将皮质肌动蛋白细胞骨架与质膜可逆地连接起来。在这里，我们描述了一种具有moesinR171W全局表达的新型小鼠模型，该模型概括了患者疾病的多个方面，包括严重淋巴细胞减少症。进一步的分析表明，这些小鼠胸腺细胞和骨髓前体的数量减少。X-MAID小鼠也表现出全身性炎症，通过繁殖到rag1缺陷背景，消除成熟淋巴细胞可以改善这种炎症。X-MAID小鼠外周的少数T细胞高度活化，大部分丢失了moesinR171W的表达。相比之下，单阳性（SP）胸腺细胞没有被激活，并保持高水平的moesinR171W表达。对离体CD4 SP胸腺细胞的分析揭示了趋化反应的缺陷和对整合素配体的迁移减少。虽然趋化因子信号通路似乎完好无损，但X-MAID小鼠的CD4 SP胸腺细胞无法极化和重排细胞骨架元件。该小鼠模型将成为梳理由moesinR171W引起的免疫缺陷复杂性的有价值的工具，并将为肌动蛋白皮层如何调节淋巴细胞功能提供新的见解。
X-linked moesin associated immunodeficiency (X-MAID) is a primary immunodeficiency disease in which patients suffer from profound lymphopenia leading to recurrent infections. The disease is caused by a single point mutation leading to a R171W amino acid change in the protein moesin (moesinR171W). Moesin is a member of the ERM family of proteins, which reversibly link the cortical actin cytoskeleton to the plasma membrane. Here, we describe a novel mouse model with global expression of moesinR171W that recapitulates multiple facets of patient disease, including severe lymphopenia. Further analysis reveals that these mice have diminished numbers of thymocytes and bone marrow precursors. X-MAID mice also exhibit systemic inflammation that is ameliorated by elimination of mature lymphocytes through breeding to a Rag1-deficient background. The few T cells in the periphery of X-MAID mice are highly activated and have mostly lost moesinR171W expression. In contrast, single-positive (SP) thymocytes do not appear activated and retain high expression levels of moesinR171W. Analysis of ex vivo CD4 SP thymocytes reveals defects in chemotactic responses and reduced migration on integrin ligands. While chemokine signaling appears intact, CD4 SP thymocytes from X-MAID mice are unable to polarize and rearrange cytoskeletal elements. This mouse model will be a valuable tool for teasing apart the complexity of the immunodeficiency caused by moesinR171W, and will provide new insights into how the actin cortex regulates lymphocyte function.
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DOI：
10.1083/jcb.201504137
发表时间：
2016-02-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mattila PK;Batista FD;Treanor B
通讯作者：
Treanor B
影响因子：
3.7
作者：
Chen EJ;Shaffer MH;Williamson EK;Huang Y;Burkhardt JK
通讯作者：
Burkhardt JK
磷酸肌醇的结合和磷酸化在ezrin的激活机理中依次起作用。
影响因子：
7.8
作者：
Fievet, BT;Gautreau, A;Roy, C;Del Maestro, L;Mangeat, P;Louvard, D;Arpin, M
通讯作者：
Arpin, M
影响因子：
4.8
作者：
Doi, Y;Itoh, M;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
20.3
作者：
Liu, Yin;Belkina, Natalya V.;Shaw, Stephen
通讯作者：
Shaw, Stephen