Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus
Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus
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DOI：
10.1172/jci24179
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发表时间：
2005-11-01
影响因子：
15.9
通讯作者：
Sanz, I
中科院分区：
文献类型：
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作者：
Cappione, A;Anolik, JH;Sanz, I
B细胞耐受性的破坏是系统性红斑狼疮（SLE）发病机制的核心。然而，B细胞耐受性在人类SLE中是如何被破坏的，由于在鉴定相关的自身反应性B细胞和获得淋巴组织方面的困难而知之甚少。我们通过扁桃体活检研究自身反应性B细胞（9G4 B细胞），避开了这些局限性。在这里，我们表明，9 G4 B细胞在GC反应的早期阶段，在获得一个中心母细胞表型的生理排除。此外，我们提供的证据表明，对B细胞受体刺激的无反应性反应可能是这种行为的原因。相反，在SLE中，9G4 B细胞不受阻碍地通过该检查点，成功地参与GC反应，并在GC后IgG记忆和浆细胞内扩增。隔间类风湿性关节炎患者不存在9G4 B细胞调节异常。据我们所知，这项工作代表了第一次比较分析的命运，一个特定的自身反应性人类B细胞群体。结果确定了一个有缺陷的耐受性检查点，似乎是特定于人类SLE。
Breach of B cell tolerance is central to the pathogenesis of systemic lupus erythematosus (SLE). However, how B cell tolerance is subverted in human SLE is poorly understood due to difficulties in identifying relevant autoreactive B cells and in obtaining lymphoid tissue. We have circumvented these limitations by using tonsil biopsies to study autoreactive B cells (9G4 B cells), whose regulation is abnormal in SLE. Here we show that 9G4 B cells are physiologically excluded during the early stages of the GC reaction before acquiring a centroblast phenotype. Furthermore, we provide evidence to indicate that an anergic response to B cell receptor stimulation may be responsible for such behavior. In contrast, in SLE, 9G4 B cells progressed unimpeded through this checkpoint, successfully participated in GC reactions, and expanded within the post-GC IgG memory and plasma cell. compartments. The faulty regulation of 9G4 B cells was not shared by RA patients. To our knowledge, this work represents the first comparative analysis of the fate of a specific autoreactive human B cell population. The results identify a defective tolerance checkpoint that appears to be specific for human SLE.