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 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 <i>in vitro</i> experiments to better understand the role of miRNAs in guiding treatment responses.