The vital role of BAFF in the development of SLE

这一提议的基本前提是增加体内B细胞激活因子的产生 属于肿瘤坏死因子家族(BAFF)，是一种重要的B细胞生存和共刺激因子，是一种重要的 许多(但不一定是全部)系统性红斑狼疮的疾病发展和/或维持的主要因素 病人。尽管BAFF拮抗剂进入人体临床试验，但对 在BAFF拮抗剂实现全面临床治疗之前，需要解决几个关键问题 潜力。首先，在体内条件下，BAFF过度表达会导致疾病，而不是 哪些BAFF的过度表达不会导致疾病，在很大程度上还没有被探索。一种智能网的开发 BAFF驱动的疾病快速发展的活体模型将有助于实验解剖 必经之路。相反，体内模型的发展，其中结构性过表达 BAFF不能驾驶自身免疫力会促进对导致抵抗的通路的解剖 太棒了。第二，单个BAFF受体在BAFF驱动的自身免疫中的相对重要性 疾病是未知的，需要被识别。第三，尚不清楚该药是否具有促病作用 BAFF的产生是由于产生致病性自身抗体或由于对B细胞的影响 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：1)持久的BAFF 生产过剩与系统性红斑狼疮潜在的不完全遗传易感性协同作用，导致快速 疾病的发展？1b)系统性红斑狼疮抑制基因区域是否能预防疾病的发生？ BAFF持续过表达的影响？2A)消除BAFF是否会改善BAFF的发展 易患系统性红斑狼疮的宿主中的自身免疫性疾病？消除BAFFR和/或BCMA是否会改善 在自然易患系统性红斑狼疮的宿主或具有BAFF驱动的自身免疫的宿主中发生疾病 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会产生关于BAFF驱动的重要信息 这种疾病将有助于为随后的人类系统性红斑狼疮的体内临床试验奠定坚实的基础 病人。

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.