Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis.
Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis.
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DOI：
10.1182/blood-2008-02-140814
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发表时间：
2008-11-15
期刊：
影响因子：
20.3
通讯作者：
Rawlings DJ
中科院分区：
文献类型：
--
作者：
Meyer-Bahlburg A;Becker-Herman S;Humblet-Baron S;Khim S;Weber M;Bouma G;Thrasher AJ;Batista FD;Rawlings DJ
为了更精确地确定Wiskott-Aldrich综合征（WAS）的b细胞表型，我们使用了3种不同的小鼠体内模型来定义中央和外周b细胞发育中WAS蛋白（WASp）的细胞内在需求。虽然WASp在早期骨髓B细胞发育中是不可缺少的，但WASp缺乏导致每个主要成熟外周B细胞亚群的显著减少，对边缘区和B1a B细胞的影响最大。通过体内溴脱氧尿苷标记和体外功能分析，我们发现这些缺陷反映了外周内平衡的改变，部分原因是整合素功能受损，而不是发育缺陷。与这些观察结果一致，我们还表明：(1)WASp表达水平随着细胞成熟而增加，在对WASp缺乏最敏感的亚群中达到峰值；(2) WASp+小鼠B细胞在过渡性B细胞晚期开始表现出明显的选择优势；(3)成熟的WASp+人B细胞也表现出类似的体内选择性优势。总之，我们的数据为WAS的临床表型提供了更好的理解，并提示基因治疗可能是一种有效的方法来挽救这种疾病中改变的b细胞稳态。
To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro functional assays, we show that these deficits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that: (1) WASp expression levels increase with cell maturity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease.
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影响因子：
2.6
作者：
Andreansky, S;Liu, HY;Strom, TS
通讯作者：
Strom, TS
影响因子：
30.5
作者：
Guinamard, R;Okigaki, M;Ravetch, JV
通讯作者：
Ravetch, JV
淋巴细胞进入脾白髓的整合素依赖性。
DOI：
10.1084/jem.20021569
发表时间：
2003-02-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lo CG;Lu TT;Cyster JG
通讯作者：
Cyster JG
影响因子：
15.3
作者：
Li, Y S;Hayakawa, K;Hardy, R R
通讯作者：
Hardy, R R
影响因子：
32.4
作者：
Carrasco, YR;Fleire, SJ;Batista, FD
通讯作者：
Batista, FD