The vital role of BAFF in the development of SLE

描述(由申请人提供)：这项建议的基本前提是，在体内增加属于肿瘤坏死因子家族(BAFF)的B细胞激活因子(BAFF)是许多(但不一定是所有)SLE患者疾病发展和/或维持的重要和核心因素。尽管BAFF拮抗剂进入了人体临床试验，但在BAFF拮抗剂治疗能够充分发挥其临床潜力之前，还需要对几个关键问题有更深入的了解。首先，在体内，BAFF过度表达导致疾病的情况与BAFF过度表达不导致疾病的情况相比，很大程度上是未知的。开发一种体内模型，使BAFF驱动的疾病迅速发展，将有助于对必要途径的实验解剖。相反，开发一个体内模型，其中BAFF的结构性过表达不能驱动自身免疫，将有助于剖析导致BAFF耐药的途径。其次，单个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，需要确定。第三，目前尚不清楚BAFF的促病作用是由于致病自身抗体的产生，还是由于对B细胞的作用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)持续的BAFF过度生产是否与SLE潜在的不完全遗传易感性协同作用，并导致疾病的快速发展？1B)SLE抑制基因区域是否针对持续BAFF过度表达的致病作用提供保护？2A)消除BAFF是否会改善易患SLE的宿主中自身免疫性疾病的发展？2B)消除BAFFR和/或BCMA是否会改善自然易患SLE的宿主或患有BAFF驱动的自身免疫性疾病的宿主的疾病发展？3)BAFF是否以一种自身抗体无关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驱动的疾病的重要信息，这将有助于为后续针对人类SLE患者的重点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.