Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice.
Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice.
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DOI：
10.4049/jimmunol.1000698
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发表时间：
2010-07-15
期刊：
影响因子：
--
通讯作者：
Theofilopoulos AN
中科院分区：
文献类型：
--
作者：
Aït-Azzouzene D;Kono DH;Gonzalez-Quintial R;McHeyzer-Williams LJ;Lim M;Wickramarachchi D;Gerdes T;Gavin AL;Skog P;McHeyzer-Williams MG;Nemazee D;Theofilopoulos AN
在T细胞依赖性抗体（Ab）反应中，B细胞经历Ab类转换和可变区超突变，后一过程可能使先前无害的B细胞产生自身反应。类转换和超突变在时间上和解剖学上都与依赖于酶（激活诱导脱氨酶）的两个过程有关，并且主要发生在生发中心，但不完全发生在生发中心。为了了解这一阶段的耐受性调节，我们建立了一种新的转基因（Tg）小鼠模型，表达一种膜系γ2a反应性超抗原（γ2a-macroself Ag），并评估了新兴的表达igg2a的B细胞的命运，这些细胞在类别转换后获得了其Ag受体对macroself Ag的自反应性。在正常小鼠中，自我反应性IgG2a开关B细胞被删除，导致IgG2a记忆反应的选择性缺失。这些发现确定了一种新的负选择机制，用于删除对自身银具有反应性的成熟B细胞。该过程仅部分依赖于Bcl-2途径，但在MRL-Faslpr狼疮小鼠中明显无效，这表明同型转换的自身反应性B细胞的缺陷凋亡是Fas突变相关的系统性自身免疫的核心。
During a T cell-dependent antibody (Ab) response, B cells undergo Ab class-switching and variable region hypermutation, with the latter process potentially rendering previously innocuous B cells autoreactive. Class switching and hypermutation are temporally and anatomically linked with both processes dependent on the enzyme, activation-induced deaminase, and occurring principally, but not exclusively, in germinal centers. To understand tolerance regulation at this stage, we generated a new transgenic (Tg) mouse model expressing a membrane-tethered γ2a-reactive superantigen (γ2a-macroself Ag) and assessed the fate of emerging IgG2a-expressing B cells that have, following class switch, acquired self-reactivity of its Ag receptor to the macroself-Ag. In normal mice, self-reactive IgG2a-switched B cells were deleted, leading to the selective absence of IgG2a memory responses. These findings identify a novel negative selection mechanism for deleting mature B cells that acquire reactivity to self-Ag. This process was only partly dependent on the Bcl-2 pathway, but markedly inefficient in MRL-Faslpr lupus mice, suggesting that defective apoptosis of isotype-switched autoreactive B cells is central to Fas mutation-associated systemic autoimmunity.
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