Pathogenic B-T Cell Axis Driven by BAFF Induces Endothelial Apoptosis in SLE-PAH

Pulmonary arterial hypertension (PAH) is a fatal complication of systemic lupus erythematosus (SLE), yet the mechanisms linking autoimmune dysregulation to progressive pulmonary vascular remodeling are poorly defined, leading to inadequate therapies. This study investigated BAFF (B-cell activating factor), a key cytokine in SLE, as a potential driver of SLE-PAH pathogenesis.

BAFF expression was assessed in patients with SLE-PAH and animal models. Humanized BAFF-transgenic mice were generated to investigate the effects of BAFF elevation on serological, hemodynamic, and histological parameters of SLE and PAH. Single-cell RNA sequencing, flow cytometry, histological analyses, and cell-based experiments were performed to elucidate cellular and molecular mechanisms. The therapeutic efficacy of the BAFF-neutralizing antibody Belimumab was tested in 2 distinct SLE-PAH animal models.

BAFF was significantly upregulated in both SLE-PAH patient cohorts and animal models. Humanized BAFF-transgenic mice exhibited systemic B-cell hyperactivation and pulmonary infiltration and spontaneously developed hallmark features of both SLE and PAH. Single-cell transcriptomic analysis of lung tissues revealed that BAFF overexpression drove the increase of a novel, disease-specific S100a6⁺ mature B-cell subset, which orchestrated a pathogenic immune cascade by activating a cytotoxic Gzmk⁺ CD8⁺ T-cell population via MHC-I (major histocompatibility complex class I)-mediated antigen presentation and CD80-CD28 costimulation. This B-T cell crosstalk triggered apoptosis of a susceptible endothelial cell subpopulation through Fas/Fas ligand signaling, ultimately culminating in pulmonary vascular remodeling. The BAFF-neutralizing antibody Belimumab effectively ameliorated both autoimmune and cardiopulmonary manifestations in 2 distinct SLE-PAH animal models, while improving survival.

These findings establish BAFF as a key mediator in SLE-PAH, driving a previously unrecognized pathogenic immune axis connecting dysregulated B cells to T-cell-mediated endothelial injury. BAFF inhibition may represent a therapeutic strategy for SLE-PAH.