CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes.
CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes.
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DOI：
10.1084/jem.186.11.1923
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发表时间：
1997-12-01
期刊：
影响因子：
--
通讯作者：
Tedder TF
中科院分区：
文献类型：
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作者：
Inaoki M;Sato S;Weintraub BC;Goodnow CC;Tedder TF
CD19细胞表面分子调节对B淋巴细胞发育和体液免疫至关重要的信号转导事件。CD19表达密度的增加使B淋巴细胞对跨膜信号反应过度，而过表达CD19的转基因小鼠自身抗体水平升高。因此，通过将过表达人CD19基因的小鼠与表达模型自身抗原（可溶性鸡蛋溶菌酶，sHEL）和高亲和力的hell特异性IgMa和IgDa （IgHEL）抗原受体的转基因小鼠杂交，研究了CD19在耐受调节和自身抗体产生中的作用。在这种外周耐受模型中，sHEL/IgHEL双转基因小鼠的B细胞在功能上是无能的，不产生自身抗体。然而，研究发现，在sHEL/IgHEL双转基因小鼠中，CD19的过表达导致外周耐受性的破坏和抗hel抗体的产生，其水平与缺乏sHEL自身抗原的IgHEL小鼠相似。因此，由于CD19过表达而改变的信号阈值导致外周耐受性的破坏。因此，CD19过表达通过增强抗原受体信号，将耐受性和免疫之间的平衡转变为自身免疫。
The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.