The B cell activating factor (BAFF) inhibitor, belimumab, is the first biologic drug approved for the treatment of SLE, and exhibits modest, but durable, efficacy in decreasing disease flares and organ damage. BAFF and its homolog APRIL are TNF-like cytokines that support the survival and differentiation of B cells at distinct developmental stages. BAFF is a crucial survival factor for transitional and mature B cells that acts as rheostat for the maturation of low-affinity autoreactive cells. In addition, BAFF augments innate B cell responses via complex interactions with the B cell receptor (BCR) and Toll like receptor (TLR) pathways. In this manner, BAFF impacts autoreactive B cell activation via extrafollicular pathways and fine tunes affinity selection within germinal centers (GC). Finally, BAFF and APRIL support plasma cell survival, with differential impacts on IgM- and IgG-producing populations. Therapeutically, BAFF and combined BAFF/APRIL inhibition delays disease onset in diverse murine lupus strains, although responsiveness to BAFF inhibition is model dependent, in keeping with heterogeneity in clinical responses to belimumab treatment in humans. In this review, we discuss the mechanisms whereby BAFF/APRIL signals promote autoreactive B cell activation, discuss whether altered selection accounts for therapeutic benefits of BAFF inhibition, and address whether new insights into BAFF/APRIL family complexity can be exploited to improve human lupus treatments.

中文翻译：

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SLE 中的 BAFF 抑制 - 耐受性是否恢复？


B 细胞激活因子 (BAFF) 抑制剂贝利尤单抗 (belimumab) 是第一个被批准用于治疗 SLE 的生物药物，在减少疾病发作和器官损伤方面表现出适度但持久的功效。 BAFF 及其同源物 APRIL 是 TNF 样细胞因子，支持不同发育阶段 B 细胞的存活和分化。 BAFF 是过渡和成熟 B 细胞的关键生存因子，可充当低亲和力自身反应细胞成熟的变阻器。此外，BAFF 通过与 B 细胞受体 (BCR) 和 Toll 样受体 (TLR) 途径的复杂相互作用增强先天 B 细胞反应。通过这种方式，BAFF 通过滤泡外途径影响自身反应性 B 细胞激活，并微调生发中心 (GC) 内的亲和力选择。最后，BAFF 和 APRIL 支持浆细胞存活，对 IgM 和 IgG 产生群体具有不同的影响。在治疗上，BAFF 和组合的 BAFF/APRIL 抑制可延迟不同鼠类狼疮菌株的疾病发作，尽管对 BAFF 抑制的反应依赖于模型，这与人类对贝利尤单抗治疗的临床反应的异质性保持一致。在这篇综述中，我们讨论了 BAFF/APRIL 信号促进自身反应性 B 细胞激活的机制，讨论改变选择是否可以解释 BAFF 抑制的治疗益处，并讨论是否可以利用对 BAFF/APRIL 家族复杂性的新见解来改善人类狼疮治疗。