Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis
Introduction: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. Methods: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n = 41)...
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Elsevier
2024-06-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024924015857 |
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| author | Ioannis Parodis Julius Lindblom Daniel Toro-Domínguez Lorenzo Beretta Maria O. Borghi Jessica Castillo Elena Carnero-Montoro Yvonne Enman Chandra Mohan Marta E. Alarcón-Riquelme Guillermo Barturen Dionysis Nikolopoulos Lorenzo Beretta Barbara Vigone Jacques-Olivier Pers Alain Saraux Valérie Devauchelle-Pensec Divi Cornec Sandrine Jousse-Joulin Bernard Lauwerys Julie Ducreux Anne-Lise Maudoux Carlos Vasconcelos Ana Tavares Esmeralda Neves Raquel Faria Mariana Brandão Ana Campar António Marinho Fátima Farinha Isabel Almeida Miguel Angel Gonzalez-Gay Mantecón Ricardo Blanco Alonso Alfonso Corrales Martínez Ricard Cervera Ignasi Rodríguez-Pintó Gerard Espinosa Rik Lories Ellen De Langhe Nicolas Hunzelmann Doreen Belz Torsten Witte Niklas Baerlecken Georg Stummvoll Michael Zauner Michaela Lehner Eduardo Collantes Rafaela Ortega-Castro 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 Maria Gerosa Tommaso Schioppo Carolina Artusi Carlo Chizzolini Aleksandra Zuber Donatienne Wynar Laszló Kovács Attila Balog Magdolna Deák Márta Bocskai Sonja Dulic Gabriella Kádár Falk Hiepe Velia Gerl Silvia Thiel Manuel Rodriguez Maresca Antonio López-Berrio Rocío Aguilar-Quesada Héctor Navarro-Linares |
| author_facet | Ioannis Parodis Julius Lindblom Daniel Toro-Domínguez Lorenzo Beretta Maria O. Borghi Jessica Castillo Elena Carnero-Montoro Yvonne Enman Chandra Mohan Marta E. Alarcón-Riquelme Guillermo Barturen Dionysis Nikolopoulos Lorenzo Beretta Barbara Vigone Jacques-Olivier Pers Alain Saraux Valérie Devauchelle-Pensec Divi Cornec Sandrine Jousse-Joulin Bernard Lauwerys Julie Ducreux Anne-Lise Maudoux Carlos Vasconcelos Ana Tavares Esmeralda Neves Raquel Faria Mariana Brandão Ana Campar António Marinho Fátima Farinha Isabel Almeida Miguel Angel Gonzalez-Gay Mantecón Ricardo Blanco Alonso Alfonso Corrales Martínez Ricard Cervera Ignasi Rodríguez-Pintó Gerard Espinosa Rik Lories Ellen De Langhe Nicolas Hunzelmann Doreen Belz Torsten Witte Niklas Baerlecken Georg Stummvoll Michael Zauner Michaela Lehner Eduardo Collantes Rafaela Ortega-Castro 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 Maria Gerosa Tommaso Schioppo Carolina Artusi Carlo Chizzolini Aleksandra Zuber Donatienne Wynar Laszló Kovács Attila Balog Magdolna Deák Márta Bocskai Sonja Dulic Gabriella Kádár Falk Hiepe Velia Gerl Silvia Thiel Manuel Rodriguez Maresca Antonio López-Berrio Rocío Aguilar-Quesada Héctor Navarro-Linares |
| author_sort | Ioannis Parodis |
| collection | DOAJ |
| description | Introduction: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. Methods: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n = 41) and active nonrenal lupus (n = 62) versus healthy controls (HCs) (n = 497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n = 26) and a replication (n = 15) set of active LN cases. Results: Replicated gene modules qualified for correlation analyses with serologic markers, and regulatory network and druggability analysis. Unsupervised coexpression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into 3 distinct subgroups. These subgroups were characterized by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the “B cell” and “plasma cells/Ig” modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 (CCR1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, and irinotecan; whereas the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the “plasma cells/Ig” signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B-cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab whereas daratumumab appeared beneficial to the intermediate-IFN and high-IFN subgroups. Conclusion: IFN upregulation and B and plasma cell gene dysregulation patterns revealed 3 subgroups of LN, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN. |
| format | Article |
| id | doaj-art-9dedea90ccbb4e8685df6b273e67ec5a |
| institution | Kabale University |
| issn | 2468-0249 |
| language | English |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Kidney International Reports |
| spelling | doaj-art-9dedea90ccbb4e8685df6b273e67ec5a2025-08-20T03:25:53ZengElsevierKidney International Reports2468-02492024-06-01961817183510.1016/j.ekir.2024.03.014Interferon and B-cell Signatures Inform Precision Medicine in Lupus NephritisIoannis Parodis0Julius Lindblom1Daniel Toro-Domínguez2Lorenzo Beretta3Maria O. Borghi4Jessica Castillo5Elena Carnero-Montoro6Yvonne Enman7Chandra Mohan8Marta E. Alarcón-Riquelme9Guillermo Barturen10Dionysis Nikolopoulos11Lorenzo BerettaBarbara VigoneJacques-Olivier PersAlain SarauxValérie Devauchelle-PensecDivi CornecSandrine Jousse-JoulinBernard LauwerysJulie DucreuxAnne-Lise MaudouxCarlos VasconcelosAna TavaresEsmeralda NevesRaquel FariaMariana BrandãoAna CamparAntónio MarinhoFátima FarinhaIsabel AlmeidaMiguel Angel Gonzalez-Gay MantecónRicardo Blanco AlonsoAlfonso Corrales MartínezRicard CerveraIgnasi Rodríguez-PintóGerard EspinosaRik LoriesEllen De LangheNicolas HunzelmannDoreen BelzTorsten WitteNiklas BaerleckenGeorg StummvollMichael ZaunerMichaela LehnerEduardo CollantesRafaela Ortega-CastroMa Angeles Aguirre-ZamoranoAlejandro Escudero-ContrerasMa Carmen Castro-VillegasNorberto OrtegoMaría Concepción Fernández RoldánEnrique RayaInmaculada Jiménez MoleónEnrique de RamonIsabel Díaz QuinteroPier Luigi MeroniMaria GerosaTommaso SchioppoCarolina ArtusiCarlo ChizzoliniAleksandra ZuberDonatienne WynarLaszló KovácsAttila BalogMagdolna DeákMárta BocskaiSonja DulicGabriella KádárFalk HiepeVelia GerlSilvia ThielManuel Rodriguez MarescaAntonio López-BerrioRocío Aguilar-QuesadaHéctor Navarro-LinaresDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Gastroenterology, Dermatology, and Rheumatology, Karolinska University Hospital, Stockholm, Sweden; Department of Rheumatology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Correspondence: Ioannis Parodis, Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, SE-171 76, Stockholm, Sweden.Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Gastroenterology, Dermatology, and Rheumatology, Karolinska University Hospital, Stockholm, SwedenGENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, SpainReferral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, ItalyDepartment of Clinical Sciences and Community Health, Università Degli Studi di Milano, Milan, Italy; IRCCS, Istituto Auxologico Italiano, Milan, ItalyDepartment of Biomedical Engineering, University of Houston, Houston, Texas, USAGENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, SpainDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, SwedenDepartment of Biomedical Engineering, University of Houston, Houston, Texas, USAGENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain; Department of Environmental Medicine, Karolinska Institute, Stockholm, SwedenGENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain; Department of Genetics, Faculty of Sciences, University of Granada, Granada, SpainDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Gastroenterology, Dermatology, and Rheumatology, Karolinska University Hospital, Stockholm, SwedenIntroduction: Current therapeutic management of lupus nephritis (LN) fails to induce long-term remission in over 50% of patients, highlighting the urgent need for additional options. Methods: We analyzed differentially expressed genes (DEGs) in peripheral blood from patients with active LN (n = 41) and active nonrenal lupus (n = 62) versus healthy controls (HCs) (n = 497) from the European PRECISESADS project (NTC02890121), and dysregulated gene modules in a discovery (n = 26) and a replication (n = 15) set of active LN cases. Results: Replicated gene modules qualified for correlation analyses with serologic markers, and regulatory network and druggability analysis. Unsupervised coexpression network analysis revealed 20 dysregulated gene modules and stratified the active LN population into 3 distinct subgroups. These subgroups were characterized by low, intermediate, and high interferon (IFN) signatures, with differential dysregulation of the “B cell” and “plasma cells/Ig” modules. Drugs annotated to the IFN network included CC-motif chemokine receptor 1 (CCR1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, and irinotecan; whereas the anti-CD38 daratumumab and proteasome inhibitor bortezomib showed potential for counteracting the “plasma cells/Ig” signature. In silico analysis demonstrated the low-IFN subgroup to benefit from calcineurin inhibition and the intermediate-IFN subgroup from B-cell targeted therapies. High-IFN patients exhibited greater anticipated response to anifrolumab whereas daratumumab appeared beneficial to the intermediate-IFN and high-IFN subgroups. Conclusion: IFN upregulation and B and plasma cell gene dysregulation patterns revealed 3 subgroups of LN, which may not necessarily represent distinct disease phenotypes but rather phases of the inflammatory processes during a renal flare, providing a conceptual framework for precision medicine in LN.http://www.sciencedirect.com/science/article/pii/S2468024924015857lupus nephritissystemic lupus erythematosusprecision medicinedruggabilitybiologicstranscriptome |
| spellingShingle | Ioannis Parodis Julius Lindblom Daniel Toro-Domínguez Lorenzo Beretta Maria O. Borghi Jessica Castillo Elena Carnero-Montoro Yvonne Enman Chandra Mohan Marta E. Alarcón-Riquelme Guillermo Barturen Dionysis Nikolopoulos Lorenzo Beretta Barbara Vigone Jacques-Olivier Pers Alain Saraux Valérie Devauchelle-Pensec Divi Cornec Sandrine Jousse-Joulin Bernard Lauwerys Julie Ducreux Anne-Lise Maudoux Carlos Vasconcelos Ana Tavares Esmeralda Neves Raquel Faria Mariana Brandão Ana Campar António Marinho Fátima Farinha Isabel Almeida Miguel Angel Gonzalez-Gay Mantecón Ricardo Blanco Alonso Alfonso Corrales Martínez Ricard Cervera Ignasi Rodríguez-Pintó Gerard Espinosa Rik Lories Ellen De Langhe Nicolas Hunzelmann Doreen Belz Torsten Witte Niklas Baerlecken Georg Stummvoll Michael Zauner Michaela Lehner Eduardo Collantes Rafaela Ortega-Castro 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 Maria Gerosa Tommaso Schioppo Carolina Artusi Carlo Chizzolini Aleksandra Zuber Donatienne Wynar Laszló Kovács Attila Balog Magdolna Deák Márta Bocskai Sonja Dulic Gabriella Kádár Falk Hiepe Velia Gerl Silvia Thiel Manuel Rodriguez Maresca Antonio López-Berrio Rocío Aguilar-Quesada Héctor Navarro-Linares Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis Kidney International Reports lupus nephritis systemic lupus erythematosus precision medicine druggability biologics transcriptome |
| title | Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis |
| title_full | Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis |
| title_fullStr | Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis |
| title_full_unstemmed | Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis |
| title_short | Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis |
| title_sort | interferon and b cell signatures inform precision medicine in lupus nephritis |
| topic | lupus nephritis systemic lupus erythematosus precision medicine druggability biologics transcriptome |
| url | http://www.sciencedirect.com/science/article/pii/S2468024924015857 |
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