CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse
CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse
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DOI：
10.1172/jci200215078
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发表时间：
2002-06-01
影响因子：
15.9
通讯作者：
Sato, S
中科院分区：
文献类型：
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作者：
Saito, E;Fujimoto, M;Sato, S
紧皮肤（TSK/+）小鼠是人类系统性硬化症（SSc）的遗传模型，可发生皮肤纤维化和针对SSc特异性靶自身抗原的自身抗体。尽管SSc患者或TSK/+小鼠纤维化和自身免疫发生的分子机制尚不清楚，但我们最近证明SSc患者过表达cd19，这是一种由B淋巴细胞表达的重要调节分子。CD19缺陷小鼠的B细胞对跨膜信号反应低，而过表达CD19的B细胞反应高，产生自身抗体。在这项研究中，TSK/+ B细胞也表现出高反应表型，表面IgM表达降低，血清Ig产生增强，自发自身抗体产生。此外，CD19酪氨酸磷酸化在TSK/+ B细胞中组成性增强。cd19介导的[Ca2+](i)反应、Vav磷酸化和Lyn激酶活性也同样增强。对CD19表达缺失的TSK/+小鼠的研究表明，CD19缺失显著降低了TSK/+小鼠的皮肤纤维化。此外，TSK/+小鼠的CD19缺失上调了表面IgM表达，并完全消除了高γ -球蛋白血症和自身抗体的产生。cd19缺乏也抑制了TSK/+ B细胞产生IL-6。因此，在TSK/+小鼠中，由CD19信号增强引起的慢性B细胞激活可能通过IL-6过量产生和自身免疫导致皮肤硬化。
The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD 19, an important regulatory molecule expressed by B lymphocytes. B cells from CD 19-deficient mice are hyporesponsive to transmembrane signals, while B cells overexpressing CD19 are hyperresponsive and generate autoantibodies. In this study, TSK/+ B cells also exhibited a hyperresponsive phenotype with decreased surface IgM expression, enhanced serum Ig production, and spontaneous autoantibody production. Moreover, CD19 tyrosine phosphorylation was constitutively augmented in TSK/+ B cells. CD19-mediated [Ca2+](i) responses, Vav phosphorylation, and Lyn kinase activity were similarly enhanced. Studies of TSK/+ mice deficient in CD19 expression demonstrated that CD19 deficiency significantly decreased skin fibrosis in TSK/+ mice. Additionally, CD19 loss in TSK/+ mice upregulated surface IgM expression and completely abrogated hyper-gamma-globulinemia and autoantibody production. CD 19 deficiency also inhibited IL-6 production by TSK/+ B cells. Thus, chronic B cell activation resulting from augmented CD19 signaling in TSK/+ mice leads to skin sclerosis possibly through IL-6 overproduction as well as autoimmunity.