B细胞刺激因子受体融合蛋白改善BXSB狼疮鼠病变的研究

BAFF-R-IgG4 fusion protein isoforms improves lupus-like syndrome in autoimmune BXSB mice

目的观察腹腔注射B细胞刺激因子受体融合蛋白（BAFF—R—IgG4mut）对狼疮鼠病变的影响。方法100μl的磷酸盐缓冲液（PBS）、200μg人IgG4和100μgBAFF—R—IgG4mut融合蛋白分别经腹腔注入10周龄BXSB狼疮鼠，每周注射3次，共注射5周。分别检测狼疮鼠外周血BAFF水平、外周血和脾脏组织中B220^＋CD5^-B细胞、CD3^＋CD4^-CD8^＋T细胞和CD3^＋CD4^＋CD8^-T细胞的表达，检测尿蛋白、IgG型抗双链DNA（dsDNA）抗体、肾脏病理损伤指标和狼疮鼠的存活率。以方差分析和，检验进行数据统计。结果实验组9、10、12、15周龄鼠外周血BAFF水平分别是（2．0±1．6）ng/ml、（4．1±2．2）ng／ml、（3．7±1．9）ng／ml、（3．9±1．8）ng／ml，较对照组下降（P〈0．01）；外周血、脾脏组织中B220^＋CD5^-细胞比率较对照组下降（P〈0．01），蛋白尿、IgG型抗dsDNA抗体产生减少，IgG在肾组织沉积及肾组织病理损伤较对照组明显减轻（P〈0．01），存活率较对照组延长（P〈0．01）。结论BAFF—R～IgG4mut融合蛋白改善BXSB狼疮鼠病变。

Objective Study the role of BAFF pathway blocked with BAFF-R-IgG4mut fusion protein on preventing the onset of murine BXSB lupus. Methods Ten weeks old BXSB male mice were randomly divided into three groups and treated with PBS, human IgG4 （200 μg/body） and 100 μg doses of BAFF-R- IgG4mut fusion protein three times a week for five weeks respectively. All the above reagents were administrated intraperitoneally. Blood samples were collected from the tail veins of the treated BXSB mice to examine the lymphocyte profile in the spleen and the peripheral blood by FACS and BAFF level in the peripheral blood were measured by ELISA. Proteinuria, anti-double stranded DNA antibody in serum were also tested and the severity of nephritis was also examined. Variance statistics and chi-square test were used for data statistics. Results The peripheral blood BAFF level of the experimental groups in the 9, 10, 12, 15 weeks old mice was （2.0±1.6） ng/ml, （4.1±2.2） ng/ml, （3.7±1.9） ng/ml, （3.9±1.8） ng/ml respectively, which was lower than that of the control groups（P〈0.01 ）. Treated with BAFF-R-IgG4 mut fusion protein for 5 weeks resulted in significant B-cell reduction both in the peripheral blood and in the spleen. BAFF blockade reversed B cell-mediated lupus-like pathology in the setting BXSB lupus mice with established disease. BAFF blockade inhibited the production of spontaneously produced IgG autoantibodies and proteinuria and glomerulonephritis was reduced. Conclusion These findings provide very evidence in guiding the desired therapeutic effect of BAFF-R-IgG4mut fusion protein for lupus nephritis.