Lindblom Julius, Barturen Guillermo, Beretta Lorenzo, Toro-Domínguez Daniel, Carnero-Montoro Elena, Borghi Maria Orietta, Castillo Jessica, Iacobaeus Ellen, Enman Yvonne, Mohan Chandra, Alarcón-Riquelme Marta E, Nikolopoulos Dionysis, Parodis Ioannis
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, SE-17176, Stockholm, Sweden.
Center for Molecular Medicine, Stockholm, Sweden.
J Transl Autoimmun. 2025 Jun 11;11:100296. doi: 10.1016/j.jtauto.2025.100296. eCollection 2025 Dec.
To gain insights into the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) and identify potential drug targets through investigation of whole-blood human transcriptome.
We analysed differentially expressed genes in peripheral blood from active central nervous system (CNS) lupus (n = 26) and active non-neuropsychiatric SLE (n = 38) patients versus healthy controls (n = 497) from the European PRECISESADS project (NTC02890121). We further explored dysregulated gene modules in active CNS lupus and their correlation with serological markers. Lastly, we performed regulatory network and druggability analysis.
Unsupervised weighted gene co-expression network analysis (WGCNA) revealed 23 dysregulated gene modules and two subgroups of active CNS lupus. The interferon gene module was prominently upregulated in subgroup 1, while the B cell, T cell, and cytotoxic/natural killer (NK) cell modules were downregulated. Subgroup 2 showed less marked dysregulation patterns. Subgroup 1 had lower estimated proportions of lymphoid cell subsets and proportionally more patients positive for anti-dsDNA antibodies compared to subgroup 2, pointing to molecularly distinct subgroups or misclassification of subgroup 2. prediction algorithms demonstrated a greater anticipated response to anifrolumab, C3 inhibitors, and calcineurin inhibitors for patients in CNS lupus subgroup 1 compared with subgroup 2.
Gene dysregulation patterns related to innate and adaptive lymphoid immunity separated active CNS lupus patients into two distinct subgroups with differential anticipated response to type I interferon, C3, and calcineurin inhibition. Our study provides a conceptual framework for precision medicine in NPSLE and implications for overcoming the major clinical challenge of attributing neuropsychiatric features to SLE versus other causes.
通过对全血人类转录组的研究，深入了解神经精神性系统性红斑狼疮（NPSLE）的发病机制，并确定潜在的药物靶点。
我们分析了来自欧洲PRECISESADS项目（NTC02890121）的活动性中枢神经系统（CNS）狼疮患者（n = 26）、活动性非神经精神性系统性红斑狼疮患者（n = 38）与健康对照者（n = 497）外周血中的差异表达基因。我们进一步探讨了活动性CNS狼疮中失调的基因模块及其与血清学标志物的相关性。最后，我们进行了调控网络和药物可及性分析。
无监督加权基因共表达网络分析（WGCNA）揭示了23个失调的基因模块和活动性CNS狼疮的两个亚组。干扰素基因模块在亚组1中显著上调，而B细胞、T细胞和细胞毒性/自然杀伤（NK）细胞模块下调。亚组2显示出不太明显的失调模式。与亚组2相比，亚组1中淋巴细胞亚群的估计比例较低，抗双链DNA抗体阳性的患者比例相对较高，这表明分子上不同的亚组或亚组2的错误分类。预测算法表明，与亚组2相比，CNS狼疮亚组1的患者对阿尼鲁单抗、C3抑制剂和钙调神经磷酸酶抑制剂的预期反应更大。
与先天性和适应性淋巴细胞免疫相关的基因失调模式将活动性CNS狼疮患者分为两个不同的亚组，对I型干扰素、C3和钙调神经磷酸酶抑制有不同的预期反应。我们的研究为NPSLE的精准医学提供了一个概念框架，并对克服将神经精神症状归因于SLE与其他原因这一主要临床挑战具有启示意义。
