Eslami Mahya, Meinl Edgar, Eibel Hermann, Willen Laure, Donzé Olivier, Distl Ottmar, Schneider Holm, Speiser Daniel E, Tsiantoulas Dimitrios, Yalkinoglu Özkan, Samy Eileen, Schneider Pascal
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Institute of Clinical Neuroimmunology, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany.
Front Cell Dev Biol. 2020 Nov 6;8:577662. doi: 10.3389/fcell.2020.577662. eCollection 2020.
B cell activation factor of the TNF family (BAFF/BLyS), an essential B cell survival factor of which circulating levels are elevated in several autoimmune disorders, is targeted in the clinic for the treatment of systemic lupus erythematosus (SLE). The soluble form of BAFF can exist as 3-mer, or as 60-mer that results from the ordered assembly of twenty 3-mers and that can be obtained from naturally cleaved membrane-bound BAFF or made as a recombinant protein. However, which forms of soluble BAFF exist and act in humans is unclear. In this study, BAFF 3-mer and 60-mer in biological fluids were characterized for size, activity and response to specific stimulators or inhibitors of BAFF. Human cerebrospinal fluids (CSF) from patients with multiple sclerosis and adult human sera contained exclusively BAFF 3-mer in these assays, also when BAFF concentrations were moderately SLE or highly (BAFFR-deficient individual) increased. Human sera, but not CSF, contained a high molecular weight, saturable activity that dissociated preformed recombinant BAFF 60-mer into 3-mer. This activity was lower in cord blood. Cord blood displayed BAFF levels 10-fold higher than in adults and consistently contained a fair proportion of active high molecular weight BAFF able to dissociate into 3-mer but not endowed with all properties of recombinant BAFF 60-mer. If BAFF 60-mer is produced in humans, it is dissociated, or at least attenuated in the circulation.
肿瘤坏死因子家族的B细胞活化因子（BAFF/BLyS）是一种重要的B细胞存活因子，在几种自身免疫性疾病中其循环水平会升高，目前在临床上已成为治疗系统性红斑狼疮（SLE）的靶点。BAFF的可溶性形式可以以三聚体形式存在，也可以以六十聚体形式存在，六十聚体由二十个三聚体有序组装而成，可以从天然裂解的膜结合BAFF中获得，也可以作为重组蛋白制备。然而，尚不清楚在人类中存在并起作用的可溶性BAFF是哪些形式。在本研究中，对生物体液中的BAFF三聚体和六十聚体的大小、活性以及对BAFF特异性刺激剂或抑制剂的反应进行了表征。在这些检测中，来自多发性硬化症患者的人脑脊液（CSF）和成人血清中仅含有BAFF三聚体，即使BAFF浓度适度升高（SLE患者）或高度升高（BAFFR缺陷个体）时也是如此。人血清而非脑脊液中含有一种高分子量的、可饱和的活性物质，该物质可将预先形成的重组BAFF六十聚体解离为三聚体。这种活性在脐带血中较低。脐带血中的BAFF水平比成人高10倍，并且始终含有相当比例的活性高分子量BAFF，能够解离为三聚体，但不具备重组BAFF六十聚体的所有特性。如果BAFF六十聚体在人体内产生，它会在循环中解离，或者至少会减弱。
