Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation
Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class-switch recombination: parallels with somatic hypermutation
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DOI：
10.1093/emboj/18.12.3484
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发表时间：
1999-06-15
期刊：
影响因子：
11.4
通讯作者：
Neuberger, MS
中科院分区：
文献类型：
--
作者：
Ehrenstein, MR;Neuberger, MS
在免疫反应成熟的过程中，免疫球蛋白M(+)B细胞转换为下游亚型之一(免疫球蛋白G、A或E)的表达。这种类别转换是通过一种未知的机制在IgH基因座内通过区域特定的重组发生的。在缺乏DNA依赖蛋白激酶(DNA-PK)-Ku复合体成分的小鼠中，缺乏开关重组，这表明了非同源末端连接的作用。在这里，我们描述了缺乏参与DNA错配识别的蛋白质的小鼠的开关缺陷。Msh2基因缺陷的小鼠在受到T细胞依赖和T细胞非依赖抗原的攻击后，其免疫球蛋白G(但不是IgM)反应减弱。这似乎反映了B细胞的固有缺陷，因为Msh2缺陷小鼠的B细胞在体外与脂多糖的培养中也表现出开关受损(但不是爆裂或增殖)。此外，在缺乏Msh2的B细胞中确实发生了这些开关，表明使用的重组位点的分布发生了变化：断点更有可能发生在共识基序中。这些结果有趣地平行于Msh2缺乏对超突变的影响，表明Msh2在类别转换重组的机制中发挥了作用。
During maturation of the immune response, IgM(+) B cells switch to expression of one of the downstream isotypes (IgG, A or E). This class switching occurs by region-specific recombination within the IgH locus through an unknown mechanism. A lack of switch recombination in mice deficient in components of the DNA-dependent protein kinase (DNA-PK)-Ku complex has pointed to a role for non-homologous end joining. Here we characterize a switching defect in mice lacking a protein involved in DNA mismatch recognition. Mice deficient in Msh2 give diminished IgG (but not IgM) responses following challenge with both T cell-dependent and T cell-independent antigens. This appears to reflect a B cell-intrinsic defect since B cells from Msh2-deficient mice also exhibit impaired switching (but not blasting or proliferation) on in vitro culture with lipopolysaccharide. Furthermore, those switches that do occur in Msh2-deficient B cells reveal a shift in the distribution of recombination sites used: the breakpoints are more likely to occur in consensus motifs. These results, which intriguingly parallel the effects of Msh2 deficiency on hypermutation, suggest a role for Msh2 in the mechanics of class-switch recombination.