Nikolopoulos Dionysis, Sentis George, Kitsios Iasonas, Garantziotis Panagiotis, Kapsala Noemin, Pieta Antigone, Flouda Sofia, Manolakou Theodora, Nikoloudaki Myrto, Banos Aggelos, Chavatza Katerina, Parodis Ioannis, Filia Anastasia, Bertsias George, Fanouriakis Antonis, Boumpas Dimitrios T
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, and Center for Molecular Medicine (CMM), Stockholm, Sweden; Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece; 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece.
Ann Rheum Dis. 2025 Aug;84(8):1342-1353. doi: 10.1016/j.ard.2025.04.006. Epub 2025 May 9.
The management of neuropsychiatric systemic lupus erythematosus (NPSLE) remains challenging because of clinical heterogeneity and the complexity of pathophysiologic mechanisms involved. We sought to determine the molecular signature of NPSLE and its endotypes towards novel biomarkers and targeted therapies.
Whole-blood RNA sequencing from 308 patients with systemic lupus erythematosus (119 with NPSLE, 189 non-NPSLE) and 72-matched healthy controls (HCs) were performed. Supervised pathway enrichment analysis and unsupervised weighted gene coexpression network analysis were applied to distinguish clinically and molecularly defined NPSLE endotypes.
Compared with HCs, patients with NPSLE demonstrated dysregulation of adaptive immune responses along with upregulation of interleukin (IL)-1, IL-6, IL-17, and IL-12/IL-23 signalling pathways. The comparison between NPSLE and non-NPSLE groups revealed a robust upregulation of complement cascade, DNA damage response, adaptive immunity, and IL-1 and IL-6 signalling. Furthermore, active NPSLE exhibited a strong autophagy signature. The B cell and complement cascade signatures exhibited a gradual upregulation across the non-NPSLE, inactive NPSLE, and active NPSLE subgroups. Within NPSLE, diffuse syndromes correlated positively with the oxidative phosphorylation module, while antiphospholipid antibody-positive NPSLE was not associated with specific signatures by unsupervised analysis. NPSLE endotypes such as cognitive dysfunction, seizures, psychosis, and optic neuritis were associated with distinct transcriptomic signatures namely IL-6 signalling and leukocyte migration, DNA damage response, inflammation, and type-I interferon, respectively.
The clinical heterogeneity of NPSLE appears to be associated with molecular diversity, with certain endotypes or syndromes exhibiting distinct gene signatures. Upregulation of adaptive immune response and complement cascade suggests that complement inhibitors and B cell-targeted therapies could be further explored in NPSLE.
由于临床异质性以及所涉及的病理生理机制的复杂性，神经精神性系统性红斑狼疮（NPSLE）的管理仍然具有挑战性。我们试图确定NPSLE及其内型的分子特征，以寻找新的生物标志物和靶向治疗方法。
对308例系统性红斑狼疮患者（119例NPSLE患者，189例非NPSLE患者）和72例匹配的健康对照（HCs）进行全血RNA测序。应用监督通路富集分析和无监督加权基因共表达网络分析来区分临床和分子定义的NPSLE内型。
与HCs相比，NPSLE患者表现出适应性免疫反应失调，同时白细胞介素（IL）-1、IL-6、IL-17和IL-12/IL-23信号通路上调。NPSLE组与非NPSLE组的比较显示补体级联、DNA损伤反应、适应性免疫以及IL-1和IL-6信号通路显著上调。此外，活动性NPSLE表现出强烈的自噬特征。B细胞和补体级联特征在非NPSLE、非活动性NPSLE和活动性NPSLE亚组中呈逐渐上调趋势。在NPSLE中，弥漫性综合征与氧化磷酸化模块呈正相关，而抗磷脂抗体阳性的NPSLE通过无监督分析未与特定特征相关联。NPSLE内型如认知功能障碍、癫痫发作、精神病和视神经炎分别与不同的转录组特征相关，即IL-6信号通路和白细胞迁移、DNA损伤反应、炎症以及I型干扰素。
NPSLE的临床异质性似乎与分子多样性相关，某些内型或综合征表现出独特的基因特征。适应性免疫反应和补体级联的上调表明，补体抑制剂和B细胞靶向治疗可能在NPSLE中得到进一步探索。
