Development of the new animal model for systemic sclerosis using the immunologic function of CD19 and CD22

CD19调节内在B淋巴细胞信号传导阈值。为了确定CD19表达在自身抗体产生中的作用，我们在CD19TG中评估了CD19轻微增加15-29%的转基因小鼠的自身免疫。CD19TG小鼠可产生多种自身抗体，表明CD19表达的微小变化可诱导自身抗体的产生。在系统性硬化症（SSc）患者的B细胞中也发现了类似的CD19表达变化。SSc患者血B细胞CD19密度明显高于正常人（约20%），CD20、CD22、CD40表达正常。这些结果表明，CD19表达或功能的适度变化可能会改变耐受和自身免疫之间的平衡。紧致皮肤（Tsk）小鼠总体上反映了人类SSc的皮肤硬化，但并不完全模仿人类SSc的免疫异常。基于上述结果，我们选择CD19的免疫功能来开发新的小鼠SSc模型。将Tsk小鼠与过表达CD19 2.6倍的CD19TG小鼠或CD19敲除（KO）小鼠交配，产生CD19TG Tsk或CD19KO Tsk小鼠。与野生型小鼠相比，CD19TG Tsk小鼠抗拓扑异构酶I抗体水平升高，而Tsk小鼠未见此现象。此外，CD19TG诱导小鼠产生多种自身抗体。这表明CD19TG Tsk小鼠可能是最准确反映人SSc免疫异常的SSc动物模型。然而，与Tsk小鼠相比，CD19TG小鼠的皮肤硬化没有增加。相比之下，皮肤硬化的发展在CD19KO Tsk小鼠中被显著抑制，其中各种免疫异常几乎完全被消除。因此，CD19的表达和功能也可能在Tsk小鼠皮肤硬化的发展中发挥关键作用。

CD19 regulates intrinsic B lymphocyte signaling thresholds. To determine a role of CD19 expression in autoantibody production, we have assessed autoimmunity in a transgenic mice (CD19TG) with subtle 15-29% CD19 increases. Various autoantibodies were produced in CD19TG mice, demonstrating that small changes in CD19 expression can induce autoantibody production. Similar changes in CD19 expression were found on B cells from patients with systemic sclerosis (SSc). CD19 density on blood B cells from SSc patients was significantly (〜20%) higher compared with normal individuals, while CD20, CD22, and CD40 expression were normal. These results suggest that modest changes in the expression or function of CD19 may shift the balance between tolerance and immunity to autoimmunity.Tight skin (Tsk) mice overall reflect the skin sclerosis in human SSc, but do not precisely mimic the immunologic abnormalities in human SSc. Based upon the results described above, we chose the immunologic function of CD19 for the development of new mouse model of SSc. Tsk mice were mated with CD19TG mice that overexpress CD19 by 2.6-fold or CD19 knock-out (KO) mice to generate CD19TG Tsk or CD19KO Tsk mice. In CD19TG Tsk mice, IgG anti-topoisomerase I antibody levels were elevated compared with wild-type mice, which was not observed in Tsk mice. Furthermore, the production of various autoantibodies was induced in CD19TG mice. This suggests that CD19TG Tsk mice would be the SSc animal model that most precisely reflect immunologic abnormalities in human SSc. However, skin sclerosis in CD19TG Tsk mice did not increase compared with Tsk mice. In contrast, the development of skin sclerosis was significantly inhibited in CD19KO Tsk mice in which the various immunologic abnormalities were almost completely abolished. Thus, expression and function of CD19 may also play a critical role in the development of skin sclerosis in Tsk mice.