BTLA-Expressing Memory B Cells Are Associated with Belimumab-Induced Improvement in Systemic Lupus Erythematosus

Belimumab, a fully humanized B cell-activating factor (BAFF)-targeting monoclonal antibody, inhibits autoreactive B cell survival and improves systemic lupus erythematosus (SLE) clinical outcomes. However, its administration criteria remain unclear. To establish a basis for defining these criteria, we characterized the immune cell subpopulation alterations post-belimumab treatment and elucidated the underlying mechanisms. We hypothesized that belimumab modulates specific cell subsets and investigated the post-therapy changes. Flow cytometry and correlation analysis revealed that the frequency of B- and T-lymphocyte attenuator (BTLA)^high memory B cells in peripheral blood and clinical improvement after belimumab treatment. Western blotting analysis of healthy control B cells revealed that BTLA engagement suppressed Bruton tyrosine kinase and phospholipase C-gamma 2 phosphorylation, which was enhanced by B cell and BAFF receptor co-stimulation. BTLA-expressing memory B cells, which positively correlate with disease improvement, possibly contributed to SLE improvement via BTLA-mediated signaling that attenuated B cell- and BAFF receptor-induced intracellular pathways. To validate these findings, we plan to further assess the effects of belimumab on BTLA expression and B cell signaling pathways in treatment-naive patients with SLE by western blotting. Collectively, our results provide a novel foundation for establish appropriate belimumab administration criteria.