B lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse
B lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse
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DOI：
10.1016/s0002-9440(10)63328-7
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发表时间：
2004-08-01
影响因子：
6
通讯作者：
Sato, S
中科院分区：
文献类型：
--
作者：
Asano, N;Fujimoto, M;Sato, S
系统性硬化症（SSc）以纤维化和自身免疫为特征。SSc患者外周血B细胞特异性过表达CD19，这是B细胞中一个关键的细胞表面信号转导分子。B细胞中CD 19缺乏也会减轻紧皮肤（TSK/+）小鼠（SSc的遗传模型）的皮肤纤维化。本研究分析了两种过表达CD19的转基因小鼠系。值得注意的是，小鼠体内CD19表达增加20%，可自发诱导ssc特异性抗dna拓扑异构酶I （topo 1）抗体（Ab）的产生，过表达量可进一步增加200%。在过表达CD19的TSK/+小鼠中，皮肤厚度没有增加，尽管抗topo I Ab水平显著增加，这表明异常CD19信号影响TSK/+小鼠的自身免疫，并且抗topo I Ab不具有致病作用。进一步评估CD19信号异常的分子机制。在TSK/+ B细胞中，B细胞抗原受体交联诱导了过度的钙反应和细胞外信号调节激酶的增强激活。CD22功能在TSK/+ B细胞中特异性受损。CD19作为cd22负调控的主要靶点，在TSK/+ B细胞中被过度磷酸化。这些发现表明，CD22提供的抑制信号减少导致TSK/+小鼠中包括CD19在内的信号通路的异常激活，并表明这种被破坏的B细胞信号有助于特异性自身抗体的产生。
Systemic sclerosis (SSc) is characterized by fibrosis and autoimmmunity. Peripheral blood B cells from SSc patients specifically overexpress CD19, a critical cell-surface signal transduction molecule in B cells. CD 19 deficiency in B cells also attenuates skin fibrosis in the tight-skin (TSK/+) mouse, a genetic model for SSc. Herein we analyzed two transgenic mouse lines that overexpress CD19. Remarkably, 20% increase of CD19 expression in mice spontaneously induced SSc-specific anti-DNA topoisomerase I (topo 1) antibody (Ab) production, which was further augmented by 200% overexpression. In TSK/+ mice overexpressing CD19, skin thickness did not increase, although antitopo I Ab levels were significantly augmented, indicating that abnormal CD19 signaling influences autoimmunity in TSK/+ mice and also that anti-topo I Ab does not have a pathogenic role. The molecular mechanisms for abnormal CD19 signaling were further assessed. B-cell antigen receptor crosslinking induced exaggerated calcium responses and augmented activation of extracellular signal-regulated kinase in TSK/+ B cells. CD22 function was specifically impaired in TSK/+ B cells. Consistently, CD19, a major target of CD22-negative regulation, was hyperphosphorylated in TSK/+ B cells. These findings indicate that reduced inhibitory signal provided by CD22 results in abnormal activation of signaling pathways including CD19 in TSK/+ mice and also suggest that this disrupted B cell signaling contribute to specific autoantibody production.