Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Rheumatology and Immunology, Hannover Medical School, Hannover, Germany.
Front Immunol. 2022 May 9;13:860726. doi: 10.3389/fimmu.2022.860726. eCollection 2022.
Treatment of Systemic Lupus Erythematosus (SLE) is characterized by a largely empirical approach and relative paucity of novel compound development. We sought to stratify SLE patients based on their molecular phenotype and identify putative therapeutic compounds for each molecular fingerprint.
By the use of whole blood RNA-seq data from 120 SLE patients, and in a data-driven, clinically unbiased manner, we established modules of commonly regulated genes (molecular endotypes) and re-stratified patients through hierarchical clustering. Disease activity and severity were assessed using SLEDAI-2K and Lupus Severity Index, respectively. Through an drug prediction pipeline, we investigated drugs currently in use, tested in lupus clinical trials, and listed in the iLINCS prediction databases, for their ability to reverse the gene expression signatures in each molecular endotype. Drug repurposing analysis was also performed to identify perturbagens that counteract group-specific SLE signatures.
Molecular taxonomy identified five lupus endotypes, each characterized by a unique gene module enrichment pattern. Neutrophilic signature group consisted primarily of patients with active lupus nephritis, while the B-cell expression group included patients with constitutional features. Patients with moderate severity and serologic activity exhibited a signature enriched for metabolic processes. Mild disease was distributed in two groups, exhibiting enhanced basic cellular functions, myelopoiesis, and autophagy. Bortezomib was predicted to reverse disturbances in the "neutrophilic" cluster, azathioprine and ixazomib in the "B-cell" cluster, and fostamatinib in the "metabolic" patient subgroup.
The clinical spectrum of SLE encompasses distinct molecular endotypes, each defined by unique pathophysiologic aberrancies potentially reversible by distinct compounds.
治疗系统性红斑狼疮（SLE）的特点主要是基于经验的方法，新型化合物的开发相对较少。我们试图根据患者的分子表型对 SLE 患者进行分层，并确定针对每个分子特征的潜在治疗化合物。
通过使用来自 120 名 SLE 患者的全血 RNA-seq 数据，并以数据驱动、临床无偏倚的方式，我们建立了常见调节基因模块（分子内表型），并通过层次聚类对患者进行重新分层。使用 SLEDAI-2K 和狼疮严重程度指数分别评估疾病活动度和严重程度。通过药物预测管道，我们研究了目前在狼疮临床试验中使用的、测试过的药物，并在 iLINCS 预测数据库中列出了这些药物，以确定它们是否能够逆转每个分子内表型中的基因表达特征。还进行了药物再利用分析，以确定对抗特定于 SLE 的特征的扰动剂。
分子分类学确定了五个狼疮内表型，每个内表型都有独特的基因模块富集模式。中性粒细胞特征群主要由活动性狼疮肾炎患者组成，而 B 细胞表达群则包括具有体质特征的患者。具有中度严重程度和血清学活性的患者表现出丰富的代谢过程特征。轻度疾病分布在两个组中，表现出增强的基本细胞功能、髓样细胞生成和自噬。硼替佐米被预测可以逆转“中性粒细胞”簇的紊乱，阿扎胞苷和伊沙佐米可以逆转“B 细胞”簇的紊乱，福他替尼可以逆转“代谢”患者亚组的紊乱。
SLE 的临床谱包含不同的分子内表型，每个内表型都由独特的病理生理异常定义，这些异常可能通过不同的化合物逆转。
