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Functional analysis of BAFF, APRIL and their receptors, and the study of their role in the pathogenesis of autoimmune disease

BAFF、APRIL及其受体的功能分析及其在自身免疫性疾病发病机制中的作用研究

基本信息

批准号：
18591113
负责人：
TSUKAMOTO Hiroshi
金额：
$ 2.57万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591113/
关键词：
BAFF APRIL autoimmune disease BR3 svnovial fibroblast-like cells polymorphism rheumatoid arthritis Furin転換酵素共刺激

项目摘要

Objective. To investigate the role of BAFF, APRIL and their receptors in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).Results. By exon-specific PCR/SSCP, we identified a novel polymorphism, P21R, in BR3 gene. P21R is located in the cystein-rich domain of BR3, a specific receptor for BAFF, and could be functionally important. To investigate the reverse-signal through membrane BAFF, we constructed cDNA for membrane BAFF, which was not cleaved by furin convertase, by site-directed mutagenesis. Expression of membrane BAFF was observed on transfected Jurkat cells by flow cytometry. When we analyzed the expression of BR3, TACI and BCMA on each peripheral B cell subset by flow cytometry, BR3 was highly expressed on naive B cells while BCMA was highly expressed on plasmablasts. The number of plasmablasts was increased in patients with SLE. Synovial fibroblast-like cells synthesized APRIL when they were cultured in the presence of TNF-a and IFN-y. BCMA-Ig, which was common receptor for BAFF and APRIL, but not BR3-Ig, receptor for BAFF, inhibited the proliferation of synovial fibroblast-like cells in the presence of TNF-α and IFN-γ.Conclusions. These data suggest that BCMA has important role in the survival of plasmablasts in SLE patients. APRIL is associated with the proliferation of synovial fibroblast-like cells in autocrine fashon. APRIL and BAFF could be a therapeutic target in the treatment of autoimmune disease.

Objective.探讨BAFF、APRIL及其受体在系统性红斑狼疮（SLE）、类风湿关节炎（RA）等自身免疫性疾病发病中的作用。采用外显子特异性PCR/SSCP技术，在BR 3基因上发现了一个新的多态性位点P21 R。P21 R位于BR 3的富含半胱氨酸的结构域，BR 3是BAFF的特异性受体，并且可能具有重要的功能。为了研究通过膜BAFF的反向信号，我们构建了膜BAFF的cDNA，它不被弗林蛋白酶转化酶切割，通过定点突变。流式细胞仪检测转染细胞膜BAFF的表达。当我们通过流式细胞术分析BR 3、TACI和BCMA在每个外周B细胞亚群上的表达时，BR 3在幼稚B细胞上高度表达，而BCMA在浆母细胞上高度表达。SLE患者浆母细胞数量增加。滑膜成纤维细胞样细胞在TNF-α和IFN-γ存在下培养时合成APRIL。BAFF和APRIL共同受体BCMA-IG对TNF-α和IFN-γ诱导的滑膜成纤维细胞样细胞增殖有抑制作用，而BAFF受体BR 3-IG则无此作用。这些数据表明BCMA在SLE患者浆母细胞的存活中具有重要作用。APRIL与滑膜成纤维细胞样细胞自分泌方式的增殖有关。APRIL和BAFF可能成为治疗自身免疫性疾病的靶点。