Polmear Jack, Hailes Lauren, Olshansky Moshe, Rischmueller Maureen, L'Estrange-Stranieri Elan, Fletcher Anne L, Hibbs Margaret L, Bryant Vanessa L, Good-Jacobson Kim L
Department of Biochemistry and Molecular Biology Monash University Clayton VIC Australia.
Immunity Program, Biomedicine Discovery Institute Monash University Clayton VIC Australia.
Clin Transl Immunology. 2023 Oct 4;12(10):e1470. doi: 10.1002/cti2.1470. eCollection 2023.
B cells drive the production of autoreactive antibody-secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long-term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-1 could deplete ASCs in autoimmune conditions and .
Use of a BMI-1 inhibitor in both mouse and human autoimmune settings was investigated. mice, a model of SLE, were treated with the BMI-1 small molecule inhibitor PTC-028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-028 on ASCs derived from Sjögren's syndrome patients was evaluated.
BMI-1 inhibition significantly decreased splenic and bone marrow ASCs in mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti-DNA IgG. PTC-028 was also efficacious in reducing plasma cell survival from both Sjögren's syndrome patients and age-matched healthy donors.
These data provide evidence that inhibiting BMI-1 can deplete ASC in a variety of contexts and thus BMI-1 is a viable therapeutic target for antibody-mediated autoimmune diseases.
在系统性红斑狼疮（SLE）和干燥综合征等自身免疫性疾病中，B细胞驱动自身反应性抗体分泌细胞（ASC）的产生，导致长期器官损伤。目前针对抗体介导的自身免疫性疾病的治疗方法以B细胞为靶点或广泛抑制免疫系统。然而，预先存在的长寿ASC通常对治疗具有抗性，留下了持续产生抗体的自身反应性细胞库。因此，开发针对ASC的新型治疗方法对于改善患者预后至关重要。我们的目标是测试靶向表观遗传调节因子BMI-1是否可以在自身免疫条件下耗尽ASC。
研究了BMI-1抑制剂在小鼠和人类自身免疫环境中的应用。在评估ASC、血清抗体和免疫复合物之前，用BMI-1小分子抑制剂PTC-028治疗SLE模型小鼠。为了检测人类ASC的存活情况，建立了一种基于新型人类成纤维细胞的检测方法，并评估了PTC-028对干燥综合征患者来源的ASC的影响。
抑制BMI-1可显著降低SLE模型小鼠脾脏和骨髓中的ASC。ASC的减少与异常的细胞周期基因表达有关，并导致血清IgG3、免疫复合物和抗DNA IgG显著降低。PTC-028在降低干燥综合征患者和年龄匹配的健康供体的浆细胞存活率方面也有效。
这些数据提供了证据，表明抑制BMI-1可以在多种情况下耗尽ASC，因此BMI-1是抗体介导的自身免疫性疾病的一个可行治疗靶点。
