Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells
Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells
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DOI：
10.1016/j.molimm.2008.08.278
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发表时间：
2008-12-01
影响因子：
3.6
通讯作者：
Satterthwaite, Anne B.
中科院分区：
文献类型：
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作者：
Halcomb, Kristina E.;Musuka, Sandirai;Satterthwaite, Anne B.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是对核抗原如染色质、DNA和RNA的耐受性丧失。这种集中的自身反应性被认为是由DNA或RNA特异性B细胞分别从BCR和TLR 9或TLR 7接收双重信号的能力引起的。Tec激酶Btk是在几种SLE小鼠模型中产生抗DNA抗体所必需的。为了评估Btk在DNA反应性B细胞命运中的作用，我们在C57 BL/6背景下产生了携带56 R抗DNA IG转基因的Btk-/-小鼠。dsDNA特异性B细胞存在于56 R. Btk-/-小鼠中，尽管它们不优先定位于边缘区。这些细胞能够响应于含有需要BCR诱导的内化以接近TLR 9的片段的大CpG DNA而增殖。然而，在56R.Btk-/-小鼠的血清中未观察到抗DNA抗体。在B细胞中表达低水平Btk的转基因（Btk（lo））恢复了这些小鼠中的抗DNA IgM。这与Btk（lo）B细胞中对BCR接合和TLR 9诱导的IL-10分泌的增殖反应的部分拯救相关。然而，在56R.Btk（lo）小鼠中未观察到抗DNA IgG。这可能至少部分是由于Btk在用CpG DNA刺激的细胞中控制T-bet和AID表达中的作用。因此，Btk是DNA耐受性最初丧失和随后一旦耐受性被破坏就产生致病性自身抗体所必需的。(c)2008爱思唯尔有限公司保留所有权利。
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens such as chromatin, DNA, and RNA. This focused autoreactivity is thought to arise from the ability of DNA or RNA specific B cells to receive dual signals from the BCR and TLR9 or TLR7, respectively. The Tec kinase Btk is necessary for the production of anti-DNA antibodies in several murine models ofSLE. To assess the role of Btk in the fate of DNA reactive B cells, we generated Btk-/- mice carrying the 56R anti-DNA Ig transgene on the C57BL/6 background. dsDNA specific B cells were present in 56R.Btk-/- mice, although they were not preferentially localized to the marginal zone. These cells were able to proliferate in response to large CpG DNA containing fragments that require BCR-induced internalization to access TLR9. However, anti-DNA antibodies were not observed in the serum of 56R.Btk-/- mice. A transgene expressing a low level of Btk in B cells (Btk(lo)) restored anti-DNA IgM in these mice. This correlated with partial rescue of proliferative response to BCR engagement and TLR9-induced IL-10 secretion in Btk(lo) B cells. anti-DNA IgG was not observed in 56R.Btk(lo) mice, however. This was likely due, at least in part, to a role for Btk in controlling the expression of T-bet and AID in cells stimulated with CpG DNA. Thus, Btk is required for the initial loss of tolerance to DNA and the subsequent production of pathogenic autoantibodies once tolerance is breached. (c) 2008 Elsevier Ltd. All rights reserved.