The vital role of BAFF in the development of SLE

该建议的基本前提是体内B细胞活化因子的产生增加 属于TNF家族（BAFF），一种重要的B细胞存活和共刺激因子，是一种重要的 在许多（但不一定是所有）SLE中， 患者尽管BAFF拮抗剂进入了人类临床试验，但更深入地了解 在BAFF拮抗剂治疗能够实现其完全临床应用之前， 潜力首先，在BAFF过表达导致疾病的体内条件下与在BAFF过表达导致疾病的体内条件下相比， BAFF过表达不导致疾病的情况在很大程度上尚未探索。开发一种 体内模型，其中BAFF驱动的疾病迅速发展，将有利于实验解剖的 必要的路径。相反，开发体内模型，其中组成型过表达的 BAFF不能驱动自身免疫，这将有助于解剖产生抗 呸。第二，单个BAFF受体对BAFF驱动的自身免疫的相对重要性， 疾病是未知的，需要被识别。第三，尚不清楚是否有促进疾病的作用 BAFF的产生是由于致病性自身抗体的产生或由于对B细胞的作用 它们在很大程度上独立于自身抗体的产生。 为了开始解决这些问题，提出了以下问题：1a）持续BAFF是否 过量生产与潜在的SLE不完全遗传易感性协同作用， 疾病的发展？1 B）SLE抑制基因区是否保护免受疾病促进因子的影响？ 持续性BAFF过度表达的影响？2a）消除BAFF是否会改善 自身免疫性疾病吗2b）消除BAFFR和/或BCMA是否会改善 在天然SLE易感性宿主或BAFF驱动的自身免疫性宿主中发生疾病 疾病？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驱动的 疾病，这将有助于为随后在人类SLE中进行的集中体内临床试验奠定坚实的基础 患者

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? 1 b) 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.