Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Germany.
German Rheumatism Research Center (DRFZ), a Leibniz Institute, Autoimmunology Group, Berlin, Germany.
Eur J Immunol. 2018 Sep;48(9):1573-1579. doi: 10.1002/eji.201847492. Epub 2018 Jul 30.
Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19 phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.
长寿浆细胞（PCs）不仅提供保护性体液免疫，也是自身反应性免疫记忆的重要组成部分，可能在系统性自身免疫疾病（如系统性红斑狼疮[SLE]）中驱动慢性免疫反应。在临床前模型和使用蛋白酶体抑制剂硼替佐米治疗严重、难治性自身免疫疾病的病例中，已经证明了针对这些细胞的治疗相关性。在此，我们详细描述了 8 例 SLE 患者在接受中位数为 2 个周期、剂量为 1.3mg/m2 的静脉用硼替佐米治疗后的血清学动态变化和对免疫效应细胞的影响。蛋白酶体抑制后，免疫球蛋白水平逐渐下降约 30%，与自身抗体和血清补体的显著减少相关，而 B 细胞激活因子水平增加。虽然蛋白酶体抑制与外周血和骨髓中短寿命和长寿命 PCs 的显著耗竭（约 50%）相关，包括具有明显成熟 CD19 表型的 PCs，但它们的前体细胞 B 细胞和 T 细胞基本上未受影响，导致硼替佐米停药后短寿命 PCs 迅速重新增殖，同时自身抗体水平升高。总之，这些发现将蛋白酶体抑制剂确定为治疗难治性 SLE 的一种有前途的治疗选择，但也表明 PC 耗竭需要与靶向 B 细胞治疗相结合，以在系统性自身免疫中实现持续反应。
