Negative selection by IgM superantigen defines a B cell central tolerance compartment and reveals mutations allowing escape.
Negative selection by IgM superantigen defines a B cell central tolerance compartment and reveals mutations allowing escape.
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DOI：
10.4049/jimmunol.1102479
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发表时间：
2011-12-01
期刊：
影响因子：
--
通讯作者：
Nemazee D
中科院分区：
文献类型：
--
作者：
Duong BH;Ota T;Aoki-Ota M;Cooper AB;Ait-Azzouzene D;Vela JL;Gavin AL;Nemazee D
为了分析多克隆免疫系统中的B淋巴细胞中枢耐受性，将小鼠工程化以表达对同种异型B的IgM（IgM B）反应的超抗原。携带超抗原的IgM B/B小鼠出现严重的B淋巴细胞减少，但少量B细胞成熟。他们的血清中含有低水平的IgG和偶尔高水平的伊加。在骨髓中，未成熟的B细胞在数量上是正常的，但内化IgM，并有一个独特的基因表达谱，与那些表达高水平的表面IgM相比，包括重组酶激活基因表达升高。在野生型骨髓中定义了一个相当的B细胞群，其丰度表明在稳态下约20%的正常发育的B细胞在原位不断遇到自身抗原。在表达超抗原的小鼠中，以及在携带3 H9抗DNA IG重链转基因或3 H9 H沿着鼠κ缺失元件RS突变的小鼠中，IgM内化与CD 19下调相关。来自3 H9;RS−/−小鼠的CD 19低骨髓细胞富含促进DNA结合的轻链。我们的研究结果表明，中枢耐受性和伴随的轻链受体编辑影响了大部分正常发育的B细胞。携带超抗原的IgHa/B小鼠的滤泡B细胞数量减少了约50%，这表明通过从一个IgH等位基因到另一个的受体编辑逃避中枢耐受性不是主要机制。用实验性骨髓重建的IgMb超抗原宿主被证明在揭示中枢耐受的途径中是有用的。
To analyze B lymphocyte central tolerance in a polyclonal immune system, mice were engineered to express a superantigen reactive to IgM of allotype b (IgMb). IgMb/b mice carrying superantigen were severely B cell lymphopenic, butsmall numbers of Bcells matured. Their sera contained low levels of IgG andoccasionally high levels of IgA. In bone marrow, immature B cells were normal in number, but internalized IgM and had a unique gene expression profile, compared to thoseexpressing high levels of surface IgM, including elevated recombinase activator gene expression. A comparable B cell population was defined in wild-type bone marrows, with an abundance suggesting that at steady state ∼20% of normal developing B cells are constantly encountering autoantigens in situ. In superantigen-expressing mice, as well as in mice carrying the 3H9 anti-DNA Ig heavy chain transgene, or 3H9 H along with mutation in the murine kappa deleting element RS, IgM internalization was correlated with CD19 downmodulation. CD19low bone marrow cells from 3H9;RS−/− mice were enriched in light chains that promote DNA binding. Our results suggest that central tolerance and attendant light chain receptor editing affect a large fraction of normal developing B cells.IgHa/b mice carrying the superantigen had a ∼50% loss in follicular B cell numbers, suggesting that escape from central tolerance by receptor editing from one IgH allele to another was not a major mechanism. IgMb superantigen hosts reconstituted withexperimental bone marrow were demonstrated to be useful in revealing pathways involved in central tolerance.
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DOI：
10.1084/jem.186.9.1513
发表时间：
1997-11-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Nemazee D
影响因子：
64.5
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影响因子：
30.5
作者：
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通讯作者：
Pelanda, R
DOI：
10.1084/jem.194.8.1151
发表时间：
2001-10-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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Rajewsky K