Integrative miRNA-mRNA Profiling Uncovers Mechanisms of Belimumab Action in Systemic Lupus Erythematosus

Maria Royo ^1,2 Blanca Joseph-Mullol ^1,2 Sebastian Sandoval ^1,2 Teresa Moliné ³ Cristina Sole ^1,2* Josefina Cortés-Hernández ^1,2

• ¹ Rheumatology Research Group - Lupus Unit, Vall d'Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain
• ² Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain
• ³ Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain

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 like belimumab remains largely unexplored. This study investigates miRNA-mRNA interactions in T cells, B cells, and myeloid cells from SLE patients before and after belimumab treatment. We identified 79 miRNAs associated with treatment response and 525 miRNA-gene interactions. Validation in 18 SLE responders revealed significant changes in miRNA expression in T and myeloid cells, but not in B cells. Belimumab modulated 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 through NF-κB activation. Changes in myeloid cells, characterized by the downregulation of KLF13, CCL5, and IL-4, appear to be secondary to Tcell modulation. These findings provide novel insights into the miRNA-mediated regulatory networks underlying belimumab's immunomodulatory effects in SLE. Further research including in vitro experiments, is needed to validate these findings and better understand the role of miRNAs in guiding treatment responses.