Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder driven by autoreactive B cells and characterized by the production of pathogenic autoantibodies. Belimumab, an anti-BAFF monoclonal antibody, has demonstrated efficacy in reducing disease activity and corticosteroid use in SLE patie...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1553971/full |
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| author | Maria Royo Blanca Joseph-Mullol Sebastian Sandoval Teresa Moliné Cristina Solé Josefina Cortés-Hernández |
| author_facet | Maria Royo Blanca Joseph-Mullol Sebastian Sandoval Teresa Moliné Cristina Solé Josefina Cortés-Hernández |
| author_sort | Maria Royo |
| collection | DOAJ |
| description | Systemic lupus erythematosus (SLE) is a complex autoimmune disorder driven by autoreactive B cells and characterized by the production of pathogenic autoantibodies. Belimumab, an anti-BAFF monoclonal antibody, has demonstrated efficacy in reducing disease activity and corticosteroid use in SLE patients, although responses remain variable. B-cell activating factor (BAFF) is essential for B cell survival and autoantibody production, positioning it as a key target in SLE pathogenesis. MicroRNAs (miRNAs), critical regulators of gene expression and immune homeostasis, have an emerging role in SLE pathophysiology. However, their regulation in response to anti-BAFF therapies, such as belimumab, remains unexplored. This study investigates miRNA-mRNA interactions in T cells, B cells, and myeloid cells from SLE patients before and after belimumab treatment. A total of 79 miRNAs associated with treatment response and 525 miRNA-gene interactions were identified. Validation in 18 SLE responders revealed significant changes in miRNA expression in T and myeloid cells, but not in B cells. Belimumab was found to modulate B cell development by regulating genes such as BLNK, BANK1, and MEF2C, as well as the CD40/CD40L axis. In T cells, miRNAs influenced interferon signaling and inflammatory cytokines via NF-κB activation. Changes in myeloid cells, characterized by the downregulation of KLF13, CCL5, and IL4, appear to be secondary to T cell modulation. These findings provide novel insights into the miRNA-mediated regulatory networks underlying belimumab’s immunomodulatory effects in SLE. Further research is required to validate these findings and through in vitro experiments to better understand the role of miRNAs in guiding treatment responses. |
| format | Article |
| id | doaj-art-3d835201a74d4cec8ddbc8cd9f1418c5 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-3d835201a74d4cec8ddbc8cd9f1418c52025-08-20T02:57:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-03-011610.3389/fimmu.2025.15539711553971Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosusMaria Royo0Blanca Joseph-Mullol1Sebastian Sandoval2Teresa Moliné3Cristina Solé4Josefina Cortés-Hernández5Rheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainRheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainRheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainDepartment of Pathology, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainRheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainRheumatology Research Group, Lupus Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, SpainSystemic lupus erythematosus (SLE) is a complex autoimmune disorder driven by autoreactive B cells and characterized by the production of pathogenic autoantibodies. Belimumab, an anti-BAFF monoclonal antibody, has demonstrated efficacy in reducing disease activity and corticosteroid use in SLE patients, although responses remain variable. B-cell activating factor (BAFF) is essential for B cell survival and autoantibody production, positioning it as a key target in SLE pathogenesis. MicroRNAs (miRNAs), critical regulators of gene expression and immune homeostasis, have an emerging role in SLE pathophysiology. However, their regulation in response to anti-BAFF therapies, such as belimumab, remains unexplored. This study investigates miRNA-mRNA interactions in T cells, B cells, and myeloid cells from SLE patients before and after belimumab treatment. A total of 79 miRNAs associated with treatment response and 525 miRNA-gene interactions were identified. Validation in 18 SLE responders revealed significant changes in miRNA expression in T and myeloid cells, but not in B cells. Belimumab was found to modulate B cell development by regulating genes such as BLNK, BANK1, and MEF2C, as well as the CD40/CD40L axis. In T cells, miRNAs influenced interferon signaling and inflammatory cytokines via NF-κB activation. Changes in myeloid cells, characterized by the downregulation of KLF13, CCL5, and IL4, appear to be secondary to T cell modulation. These findings provide novel insights into the miRNA-mediated regulatory networks underlying belimumab’s immunomodulatory effects in SLE. Further research is required to validate these findings and through in vitro experiments to better understand the role of miRNAs in guiding treatment responses.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1553971/fullsystemic lupus erythematosusmiRNAmRNAintegrative “omics”belimumabmechanism of action |
| spellingShingle | Maria Royo Blanca Joseph-Mullol Sebastian Sandoval Teresa Moliné Cristina Solé Josefina Cortés-Hernández Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus Frontiers in Immunology systemic lupus erythematosus miRNA mRNA integrative “omics” belimumab mechanism of action |
| title | Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus |
| title_full | Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus |
| title_fullStr | Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus |
| title_full_unstemmed | Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus |
| title_short | Integrative miRNA-mRNA profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus |
| title_sort | integrative mirna mrna profiling uncovers mechanisms of belimumab action in systemic lupus erythematosus |
| topic | systemic lupus erythematosus miRNA mRNA integrative “omics” belimumab mechanism of action |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1553971/full |
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