B-CELL ACTIVATING FACTOR INDUCES SYSTEMIC LUPUS ERYTHEMATOSUS-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION VIA GZMK+ CD8+ T CELL-MEDIATED ENDOTHELIAL CELL APOPTOSIS

O002 / #224 Topic: AS06 - Comorbidities SCIENTIFIC HYBRID SESSION: BASIC TRACK PRESENTATIONS - OUTSTANDING ABSTRACT PRESENTATIONS 23-05-2025 9:00 AM - 10:00 AM Background/Purpose Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE) and a leading cause of mortality among SLE patients. PAH is marked by early-stage endothelial cell dysfunction. SLE pathology involves excessive autoantibody production by B cells, driving inflammatory cascades and systemic inflammation. B cell activating factor (BAFF) supports autoimmune B cell survival, proliferation, and differentiation, and the BAFF-targeted therapeutic, Belimumab, is in clinical use for SLE. However, the role of BAFF, and B cells more broadly, in the development and progression of PAH in SLE remains unclear. Methods We conducted transcriptomic analysis on peripheral blood samples from SLE and SLE-PAH patients. Mice overexpressing human BAFF (hBAFF-Tg mice) were used to establish a model of SLE-PAH. Serum assays, flow cytometry, hemodynamic measurements, right ventricular hypertrophy evaluation, and histological analysis were conducted. Additionally, single-cell transcriptome sequencing was performed on lung tissue from hBAFF-Tg mice to elucidate downstream mechanisms, and female MRL/lpr mice, a widely accepted model of SLE-PAH, were treated with Belimumab to assess therapeutic efficacy. Results BAFF expression was significantly elevated in the peripheral blood of SLE-PAH patients, with upregulation of inflammation-associated pathways compared to SLE patients without PAH (Figure 1A). hBAFF-Tg mice showed spontaneous SLE phenotypes by 20 weeks, including increased dsDNA and IgG levels, reduced plasma C3, B cell activation and aggregation, and splenomegaly (Figure 1B). These mice also displayed increased right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary arteriole thickenin (Figure 1C-E). Single-cell transcriptome analysis revealed that BAFF overexpression led to increases in B and T cell populations in lung tissue, identifying 2 novel immune cell subtypes: (1) IL9R+ mature B cells showing features of upregulated T cell activation, and (2) GZMK+ CD8+ T cells, an effector population capable of recruiting additional T cells. Mechanistically, IL9R+ B cells activated GZMK+ T cells, which induced apoptosis in endothelial cells (Figure 1F-I). Intravenous administration of Belimumab at 5 mg/kg and 50 mg/kg alleviated established SLE-PAH in MRL/lpr mice (Figure 2). Figure 1: hBAFF-Tg exhibits spontaneous SLE and PAH Figure 2: Belimumab alleviates murine SLE-PAH Figure 3: Graphic abstract Conclusions BAFF contributes to SLE-PAH development by activating IL9R+ B cells and aggregating GZMK+ CD8+ T cells, leading to endothelial cell apoptosis and pulmonary vascular remodeling. These findings suggest a unique therapeutic potential of Belimumab in targeting BAFF and the critical process of B cell activation in SLE-PAH treatment.