Genomic instability resulting from Blm deficiency compromises development, maintenance, and function of the B cell lineage.
Genomic instability resulting from Blm deficiency compromises development, maintenance, and function of the B cell lineage.
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DOI：
10.4049/jimmunol.182.1.347
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Leder P
中科院分区：
文献类型：
--
作者：
Babbe H;McMenamin J;Hobeika E;Wang J;Rodig SJ;Reth M;Leder P
RecQ家族解旋酶BLm在维持基因组稳定性方面起着至关重要的作用，BLm突变导致了遗传性疾病--Bloom综合征。受影响的个人易患多种癌症类型，并患有定义不清的免疫缺陷，包括血清抗体效价低。为了研究其在B细胞生物学中的作用，我们在体内灭活了B淋巴细胞中的小鼠BLM。骨髓中发育中的B淋巴样细胞和外周成熟的B细胞在BLM灭活后显著减少。在主要的外周B细胞亚群中，B1a细胞受到的影响最大。在BLM缺陷幼稚小鼠的血清中，所有Ig亚型的浓度都很低，尤其是Ig G3。免疫后的特异性抗体反应差，突变的B细胞在体外表现出普遍降低的抗体类别转换能力。我们没有发现BLM在类转换重组机制中起关键作用的证据。然而，在BLM缺陷的B细胞中观察到了轻微的向微同源介导的开关连接形成的转变。最后，一组p53缺陷的条件性BLM基因敲除小鼠显示出发生B细胞淋巴瘤的倾向增加。突变B细胞的细胞周期进程和存活率受损以及高染色体结构异常率被认为是观察到的效应的基础。总而言之，我们的数据强调了依赖BLM的基因组监测对于B细胞免疫的重要性，通过确保各种B细胞亚群的适当发育和功能，同时对抗淋巴瘤。
The RecQ family helicase BLM is critically involved in the maintenance of genomic stability and BLM mutation causes the heritable disorder, Bloom’s syndrome. Affected individuals suffer from a predisposition to a multitude of cancer types and an ill-defined immunodeficiency involving low serum antibody titers. To investigate its role in B cell biology, we inactivated murine Blm specifically in B lymphocytes in vivo. Numbers of developing B lymphoid cells in the bone marrow and mature B cells in the periphery were drastically reduced upon Blm-inactivation. Of the major peripheral B cell subsets, B1a cells were most prominently affected. In the sera of Blm-deficient naïve mice, concentrations of all Ig isotypes were low, particularly IgG3. Specific IgG antibody responses upon immunization were poor and mutant B cells exhibited a generally reduced antibody class switch-capacity in vitro. We did not find evidence for a crucial role of Blm in the mechanism of class switch recombination. However, a modest shift towards microhomology-mediated switch junction formation was observed in Blm-deficient B cells. Finally, a cohort of p53-deficient, conditional Blm knockout mice revealed an increased propensity for B cell lymphoma development. Impaired cell cycle progression and survival as well as high rates of chromosomal structural abnormalities in mutant B cell blasts was identified as the basis for the observed effects. Collectively, our data highlight the importance of BLM-dependent genome surveillance for B cell immunity by ensuring proper development and function of the various B cell subsets while counteracting lymphomagenesis.
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DOI：
10.1073/pnas.72.2.758
发表时间：
1975-01-01
影响因子：
11.1
作者：
HAND, R;GERMAN, J
通讯作者：
GERMAN, J
影响因子：
64.5
作者：
Bassing, CH;Suh, H;Alt, FW
通讯作者：
Alt, FW
DOI：
10.1073/pnas.87.12.4781
发表时间：
1990-06-01
影响因子：
11.1
作者：
FORSTER, I;RAJEWSKY, K
通讯作者：
RAJEWSKY, K
影响因子：
10.5
作者：
Duquette, ML;Handa, P;Maizels, N
通讯作者：
Maizels, N
DOI：
10.1073/pnas.241525998
发表时间：
2001-12-04
影响因子：
11.1
作者：
Ehrenstein, MR;Rada, C;Neuberger, MS
通讯作者：
Neuberger, MS