Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, NY 11030, USA.
J Immunol. 2011 Aug 1;187(3):1506-13. doi: 10.4049/jimmunol.1004142. Epub 2011 Jun 24.
The critical role of IFN-α in the pathogenesis of human systemic lupus erythematosus has been highlighted in recent years. Exposure of young lupus-prone NZB/W F1 mice to IFN-α in vivo leads to an accelerated lupus phenotype that is dependent on T cells and is associated with elevated serum levels of BAFF, IL-6, and TNF-α, increased splenic expression of IL-6 and IL-21, formation of large germinal centers, and the generation of large numbers of short-lived plasma cells that produce IgG2a and IgG3 autoantibodies. In this study, we show that both IgG2a and IgG3 autoantibodies are pathogenic in IFN-α-accelerated lupus, and their production can be dissociated by using low-dose CTLA4-Ig. Only high-dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody production and significantly delays death from lupus nephritis. In contrast, BAFF/APRIL blockade has no effect on germinal centers or the production of IgG anti-dsDNA Abs but, if given at the time of IFN-α challenge, delays the progression of lupus by attenuating systemic and renal inflammation. Temporary remission of nephritis induced by combination therapy with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal centers and depletion of short-lived plasma cells, but relapse occurs more rapidly than in conventional NZB/W F1 mice. This study demonstrates that IFN-α renders NZB/W F1 relatively resistant to therapeutic intervention and suggests that the IFN signature should be considered when randomizing patients into groups and analyzing the results of human clinical trials in systemic lupus erythematosus.
近年来，IFN-α 在人类系统性红斑狼疮发病机制中的关键作用得到了强调。在体内暴露于 IFN-α 的年轻狼疮易感 NZB/W F1 小鼠中，会导致加速的狼疮表型，该表型依赖于 T 细胞，并与 BAFF、IL-6 和 TNF-α 血清水平升高、脾脏中 IL-6 和 IL-21 表达增加、大型生发中心形成以及产生大量产生 IgG2a 和 IgG3 自身抗体的短命浆细胞有关。在这项研究中，我们表明 IgG2a 和 IgG3 自身抗体在 IFN-α 加速的狼疮中均具有致病性，并且可以通过使用低剂量 CTLA4-Ig 将其产生分离。只有高剂量 CTLA4-Ig 才能减弱 IgG2a 和 IgG3 自身抗体的产生，并显著延迟狼疮肾炎导致的死亡。相比之下，BAFF/APRIL 阻断对生发中心或 IgG 抗 dsDNA Abs 的产生没有影响，但如果在 IFN-α 挑战时给予，通过减轻全身和肾脏炎症来延迟狼疮的进展。环磷酰胺、抗 CD40L Ab 和 CTLA4-Ig 联合治疗诱导的肾炎暂时缓解与生发中心的消除和短命浆细胞的耗竭有关，但比传统的 NZB/W F1 小鼠更快地复发。这项研究表明，IFN-α 使 NZB/W F1 对治疗干预相对耐药，并表明在将患者随机分组并分析系统性红斑狼疮人类临床试验的结果时，应考虑 IFN 特征。
