Dysregulation of innate and adaptive lymphoid immunity may have implications for symptom attribution and predict responses to targeted therapies in neuropsychiatric systemic lupus erythematosus
Year: 2025
Type: article
Abstract: Objectives To gain insights into the pathogenesis neuropsychiatric systemic lupus erythematosus (NPSLE) and identify potential drug targets through investigation of whole-blood human transcriptome. Methods 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. Results 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. In silico 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. Conclusions 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.
Authors: Julius Lindblom, Guillermo Barturen, Lorenzo Beretta, Daniel Toro-Domínguez, Elena Carnero-Montoro, Maria Orietta Borghi, Jessica Castillo, Ellen Iacobaeus, Yvonne Enman, Jacques-Olivier Pers, Alain Saraux, Valérie Devauchelle-Pensec, Sandrine Jousse-Joulin, Bernard Lauwerys, Julie Ducreux, Anne-Lise Maudoux, Ana Tavares, Isabel Almeida, Miguel Angel Gonzalez-Gay Mantecón, Ricardo Blanco Alonso, Alfonso Corrales Martínez, Ignasi Rodríguez-Pintó, Gerard Espinosa, Rik Lories, Nicolas Hunzelmann, Doreen Belz, Niklas Baerlecken, Michael Zauner, Michaela Lehner, Eduardo Collantes, Ma Angeles Aguirre-Zamorano, Alejandro Escudero-Contreras, Ma Carmen Castro-Villegas, Norberto Ortego, María Concepción Fernández Roldán, Enrique Raya, Inmaculada Jiménez Moleón, Enrique de Ramon, Isabel Díaz Quintero, Pier Luigi Meroni, Tommaso Schioppo, Carolina Artusi, Carlo Chizzolini, Aleksandra Zuber, Donatienne Wynar, Attila Balog, Magdolna Deák, Márta Bocskai, Sonja Dulic, Gabriella Kádár, Falk Hiepe, Silvia Thiel, Manuel Rodriguez Maresca, Antonio López-Berrio, Rocío Aguilar-Quesada, Héctor Navarro-Linares, Chandra Mohan, Marta E. Alarcón-Riquelme, Dionysis Nikolopoulos, Ioannis Parodis
Institutions: Karolinska University Hospital, Karolinska Institutet, Universidad de Granada, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, IRCCS Istituto Auxologico Italiano, University of Houston, Centre Hospitalier Régional Universitaire de Brest, Örebro University, UCLouvain, KU Leuven
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,180
Funders: Nyckelfonden, Knowledge Foundation, European Federation of Pharmaceutical Industries and Associations, European Commission, Örebro Universitet, Karolinska Institutet, Svenska Läkaresällskapet, Stiftelsen Konung Gustaf V:s 80-årsfond, Reumatikerförbundet, Stiftelsen Professor Nanna Svartz Fond, Ulla och Gustaf af Ugglas Stiftelse, Innovative Medicines Initiative, Horizon 2020 Framework Programme
OpenAlex ID: W4411200662