The vital role of BAFF in the development of SLE

描述（由申请人提供）：该提议的基本前提是，属于TNF家族的B细胞活化因子（BAFF）（一种重要的B细胞存活和共刺激因子）的体内产生增加是许多（但不一定是所有）SLE患者疾病发展和/或维持的重要和中心因素。 尽管BAFF拮抗剂进入人体临床试验，但在BAFF拮抗剂治疗能够实现其全部临床潜力之前，需要更深入地了解几个关键问题。 首先，BAFF过表达导致疾病的体内条件与BAFF过表达不导致疾病的体内条件在很大程度上尚未探索。 在体内模型中，BAFF驱动的疾病迅速发展的发展将促进必要的途径的实验解剖。 相反，开发一种体内模型，其中BAFF的组成型过表达不能驱动自身免疫，这将有助于解剖产生BAFF抗性的途径。 其次，个别BAFF受体对BAFF驱动的自身免疫性疾病的相对重要性尚不清楚，需要加以鉴定。 第三，尚不清楚BAFF的疾病促进作用是由于致病性自身抗体的产生，还是由于对B细胞的作用，而这种作用在很大程度上不依赖于自身抗体的产生。 为了开始解决这些问题，提出了以下问题：1a）持续的BAFF过量产生是否与潜在的SLE不完全遗传易感性协同作用并导致疾病的快速发展？1b）SLE抑制基因区是否能防止持续性BAFF过表达的疾病促进作用？2a）BAFF的消除会改善SLE易感宿主中自身免疫性疾病的发展吗？2b）BAFFR和/或BCMA的消除是否会改善天然易患SLE的宿主或患有BAFFR驱动的自身免疫性疾病的宿主中疾病的发展？3)BAFF是否以不依赖自身抗体的方式促进自身免疫性疾病？ 这些小鼠体内研究的结果应该产生关于BAFF驱动疾病的重要信息，这将有助于为随后在人类SLE患者中进行的集中体内临床试验奠定坚实的基础。

DESCRIPTION (provided by applicant): The underlying premise of this proposal is that increased in vivo production of B cell activating factor belonging to the TNF family (BAFF), a vital B cell survival and costimulatory factor, is an important and central contributor to disease development and/or maintenance in many, but not necessarily all, SLE patients. The entry of BAFF antagonists into human clinical trials notwithstanding, a greater insight into several critical issues is needed before treatment with BAFF antagonists can realize their full clinical potential. First, in vivo conditions under which BAFF overexpression leads to disease versus those under which BAFF overexpression does not lead to disease have largely been unexplored. Development of an in vivo model in which BAFF-driven disease rapidly develops would facilitate experimental dissection of the requisite pathways. Conversely, development of an in vivo model in which constitutive overexpression of BAFF is incapable of driving autoimmunity would facilitate dissection of pathways that render resistance to BAFF. Second, the relative importance of the individual BAFF receptors to BAFF-driven autoimmune disease is not known and needs to be identified. Third, it is not known whether the disease-promoting effects of BAFF are consequent to production of pathogenic autoantibodies or are consequent to effects on B cells that are largely independent of autoantibody production. To begin to address these issues, the following questions are posed: 1a) Does persistent BAFF overproduction synergize with an underlying incomplete genetic predisposition to SLE and result in rapid development of disease? 1b) Does a SLE suppressor genetic region protect against the disease-promoting effects of persistent BAFF overexpression? 2a) Will elimination of BAFF ameliorate development of autoimmune disease in a SLE-prone host? 2b) Will elimination of BAFFR and/or BCMA ameliorate development of disease in a host that naturally is SLE-prone or in a host with BAFF-driven autoimmune disease? 3) Does BAFF promote autoimmune disease in an autoantibody-independent manner? The results from these in vivo studies in mice should yield important information regarding BAFF-driven disease that will help set a solid foundation for subsequent focused in vivo clinical trials in human SLE patients.