Rheumatology Department, Sandwell and West Birmingham NHS Trust, Birmingham, UK.
Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Arthritis Res Ther. 2023 Jun 30;25(1):111. doi: 10.1186/s13075-023-03089-5.
Systemic lupus erythematosus (SLE) is a clinically and biologically heterogeneous autoimmune disease. We explored whether the deconvolution of whole blood transcriptomic data could identify differences in predicted immune cell frequency between active SLE patients, and whether these differences are associated with clinical features and/or medication use.
Patients with active SLE (BILAG-2004 Index) enrolled in the BILAG-Biologics Registry (BILAG-BR), prior to change in therapy, were studied as part of the MASTERPLANS Stratified Medicine consortium. Whole blood RNA-sequencing (RNA-seq) was conducted at enrolment into the registry. Data were deconvoluted using CIBERSORTx. Predicted immune cell frequencies were compared between active and inactive disease in the nine BILAG-2004 domains and according to immunosuppressant use (current and past).
Predicted cell frequency varied between 109 patients. Patients currently, or previously, exposed to mycophenolate mofetil (MMF) had fewer inactivated macrophages (0.435% vs 1.391%, p = 0.001), naïve CD4 T cells (0.961% vs 2.251%, p = 0.002), and regulatory T cells (1.858% vs 3.574%, p = 0.007), as well as a higher proportion of memory activated CD4 T cells (1.826% vs 1.113%, p = 0.015), compared to patients never exposed to MMF. These differences remained statistically significant after adjusting for age, gender, ethnicity, disease duration, renal disease, and corticosteroid use. There were 2607 differentially expressed genes (DEGs) in patients exposed to MMF with over-representation of pathways relating to eosinophil function and erythrocyte development and function. Within CD4 + T cells, there were fewer predicted DEGs related to MMF exposure. No significant differences were observed for the other conventional immunosuppressants nor between patients according disease activity in any of the nine organ domains.
MMF has a significant and persisting effect on the whole blood transcriptomic signature in patients with SLE. This highlights the need to adequately adjust for background medication use in future studies using whole blood transcriptomics.
系统性红斑狼疮（SLE）是一种临床表现和生物学特征高度异质性的自身免疫性疾病。我们探索了全血转录组数据分析能否识别活动期 SLE 患者预测免疫细胞频率的差异，以及这些差异是否与临床特征和/或药物使用相关。
在治疗方案改变之前，登记在 BILAG-Biologics 注册研究（BILAG-BR）中的活动期 SLE 患者（BILAG-2004 指数）作为 MASTERPLANS 分层医学联盟的一部分进行研究。在登记入组时进行全血 RNA 测序（RNA-seq）。使用 CIBERSORTx 对数据进行去卷积。在 BILAG-2004 的九个领域以及根据免疫抑制剂的使用（当前和过去）比较活动期和非活动期疾病之间的预测免疫细胞频率。
在 109 名患者中预测细胞频率存在差异。目前或以前使用霉酚酸酯（MMF）的患者，失活的巨噬细胞（0.435%对 1.391%，p=0.001）、幼稚 CD4 T 细胞（0.961%对 2.251%，p=0.002）和调节性 T 细胞（1.858%对 3.574%，p=0.007）的比例较低，而记忆激活的 CD4 T 细胞（1.826%对 1.113%，p=0.015）的比例较高，与从未使用过 MMF 的患者相比。在调整年龄、性别、种族、疾病持续时间、肾脏疾病和皮质类固醇使用后，这些差异仍具有统计学意义。暴露于 MMF 的患者有 2607 个差异表达基因（DEGs），这些基因与嗜酸性粒细胞功能和红细胞发育和功能相关的途径过度表达。在 CD4+T 细胞中，与 MMF 暴露相关的预测 DEGs 较少。在任何九个器官领域的疾病活动中，其他常规免疫抑制剂或患者之间均未观察到显著差异。
MMF 对 SLE 患者的全血转录组特征有显著且持续的影响。这强调了在未来使用全血转录组学的研究中，需要充分调整背景药物使用的必要性。
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