B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin.
B-lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-immunoglobulin.
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DOI：
10.1186/ar2959
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发表时间：
2010
影响因子：
4.9
通讯作者：
Gross JA
中科院分区：
文献类型：
--
作者：
Dillon SR;Harder B;Lewis KB;Moore MD;Liu H;Bukowski TR;Hamacher NB;Lantry MM;Maurer M;Krejsa CM;Ellsworth JL;Pederson S;Elkon KB;Wener MH;Dall'Era M;Gross JA
B淋巴细胞刺激因子（BLyS）和增殖诱导配体（APRIL）是调节B细胞成熟、存活和功能的肿瘤坏死因子（TNF）家族的成员。它们在多种自身免疫性疾病中过表达，并且据报道在体内不仅以同源三聚体存在，而且以BLyS/APRIL异源三聚体存在。专有的N-末端三聚化结构域用于产生重组BLyS/APRIL异源三聚体。通过使用跨膜激活剂和CAML相互作用物（TACI）转染的Jurkat细胞在4小时信号传导测定中以及在4天原代人B细胞增殖测定中将异源三聚体生物活性与BLyS和APRIL的生物活性进行比较。开发了基于珠的免疫测定来定量来自健康供体（n = 89）和患有系统性红斑狼疮（SLE; n = 89）或类风湿性关节炎（RA; n = 30）的患者的人血清中的天然异源三聚体。在这些样品的子集中，将异源三聚体水平与BLyS和APRIL同源三聚体水平进行比较。重组异源三聚体主要由一个BLyS和两个APRIL分子组成。在TACI-Jurkat测定中，与APRIL相比，异源三聚体信号传导未显示任何显著差异。异源三聚体是比同源三聚体BLyS或APRIL更弱的B细胞增殖诱导剂（EC 50，nMol/L：BLyS，0.02; APRIL，0.17;异源三聚体，4.06）。可溶性受体融合蛋白atacicept和B细胞成熟抗原（BCMA）-免疫球蛋白（IG）在两种细胞试验中中和BLyS、APRIL和异源三聚体的活性，而属于TNF家族受体的B细胞活化因子（BAFF-R）-IG仅中和BLyS的活性。在人类血清中，与健康供体相比，SLE患者显著更多地检测到BLyS（67%对18%; P < 0.0001）、APRIL（38%对3%; P < 0.0002）和异源三聚体（27%对8%; P = 0.0013）水平。与健康供体相比，更多的RA患者可检测到APRIL，但不能检测到BLyS或异源三聚体水平（83%对3%; P < 0.0001）。异源三聚体水平与BLyS水平弱相关，但与APRIL水平无关。重组BLyS/APRIL异源三聚体具有生物学活性，可被atacicept和BCMA-IG抑制，但不被BAFF-R-IG抑制。一种新的免疫测定表明，天然BLyS/APRIL异源三聚体以及BLyS和APRIL同源三聚体在自身免疫性疾病患者中升高。
B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are members of the tumor necrosis factor (TNF) family that regulate B-cell maturation, survival, and function. They are overexpressed in a variety of autoimmune diseases and reportedly exist in vivo not only as homotrimers, but also as BLyS/APRIL heterotrimers. A proprietary N-terminal trimerization domain was used to produce recombinant BLyS/APRIL heterotrimers. Heterotrimer biologic activity was compared with that of BLyS and APRIL in a 4-hour signaling assay by using transmembrane activator and CAML interactor (TACI)-transfected Jurkat cells and in a 4-day primary human B-cell proliferation assay. A bead-based immunoassay was developed to quantify native heterotrimers in human sera from healthy donors (n = 89) and patients with systemic lupus erythematosus (SLE; n = 89) or rheumatoid arthritis (RA; n = 30). Heterotrimer levels were compared with BLyS and APRIL homotrimer levels in a subset of these samples. The recombinant heterotrimers consisted mostly of one BLyS and two APRIL molecules. Heterotrimer signaling did not show any significant difference compared with APRIL in the TACI-Jurkat assay. Heterotrimers were less-potent inducers of B-cell proliferation than were homotrimeric BLyS or APRIL (EC50, nMol/L: BLyS, 0.02; APRIL, 0.17; heterotrimers, 4.06). The soluble receptor fusion proteins atacicept and B-cell maturation antigen (BCMA)-immunoglobulin (Ig) neutralized the activity of BLyS, APRIL, and heterotrimers in both cellular assays, whereas B-cell activating factor belonging to the TNF family receptor (BAFF-R)-Ig neutralized only the activity of BLyS. In human sera, significantly more patients with SLE had detectable BLyS (67% versus 18%; P < 0.0001), APRIL (38% versus 3%; P < 0.0002), and heterotrimer (27% versus 8%; P = 0.0013) levels compared with healthy donors. Significantly more patients with RA had detectable APRIL, but not BLyS or heterotrimer, levels compared with healthy donors (83% versus 3%; P < 0.0001). Heterotrimer levels weakly correlated with BLyS, but not APRIL, levels. Recombinant BLyS/APRIL heterotrimers have biologic activity and are inhibited by atacicept and BCMA-Ig, but not by BAFF-R-Ig. A novel immunoassay demonstrated that native BLyS/APRIL heterotrimers, as well as BLyS and APRIL homotrimers, are elevated in patients with autoimmune diseases.
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