OBJECTIVE: Cardiovascular disease in SLE is not fully explained by traditional risk factors, supporting a role for disease-specific immunovascular mechanisms. Autoantibodies targeting endothelin receptor A (ETAR) and endothelin receptor B (ETBR) have been implicated in vascular injury in other autoimmune diseases, but their clinical and functional relevance in SLE remains unclear. We tested whether ET receptor autoantibodies associate with endothelial activation and directly stimulate ET receptor signalling in SLE. METHODS: Plasma anti-ETAR and anti-ETBR autoantibodies and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in a pilot cohort of women with SLE and non-SLE controls and in an independent validation cohort stratified by SLE and hypertension (HTN) status. Multivariable models adjusted for demographic variables, blood pressure and medication use. Mechanistic studies were performed in primary human renal endothelial cells (HRECs) using live-cell calcium (Ca2+) imaging, ET receptor antagonists and receptor-directed blocking peptides. RESULTS: Anti-ETAR and anti-ETBR autoantibodies were elevated in SLE across both cohorts, with the highest level observed in SLE with HTN. Anti-ETAR demonstrated the strongest association with sVCAM-1 and independently identified women with the highest endothelial activation burden beyond clinical covariates and anti-double-stranded DNA. In primary HRECs, SLE-derived IgG induced Ca2+ flux that was attenuated by ET receptor antagonism. Blockade of the ETAR extracellular loop 2 domain reduced IgG-mediated Ca2+signalling, supporting a non-canonical mechanism of endothelial ETAR activation. CONCLUSIONS: Anti-ETAR autoantibodies associate with immunovascular risk and endothelial activation in SLE and directly stimulate endothelial signalling through a non-canonical ETAR-dependent mechanism. These findings support the use of anti-ETAR autoantibodies as clinically relevant biomarkers and potential novel contributors to vascular dysfunction in SLE.

Mare endometrosis is a chronic degenerative condition of the endometrium, primarily characterized by fibrosis, involving interactions among fibroblasts, immune cells, and epithelial cells regulated by cytokines and growth factors. T helper (Th)1 and Th2 cells seem to play a pivotal role in fibrosis. However, their roles in equine endometrial fibrosis remain unknown. This study explores Th1 and Th2 cell distribution across different stages of endometrium histopathological Kenney and Doig categories; and evaluated their secretome effects on non-fibrotic endometrium derived fibroblast functional characteristics, extracellular matrix (ECM)-associated mRNA transcription, and transcriptomic profiles. Th1 and Th2 cells, along with cytokines (IFN-γ, IL-4, IL-13) and their receptors, were present in mare endometria at all endometrium stages. Th1 secretome influenced genes enriched in metabolism, cell cycle, and ECM-related pathways, while Th2 secretome regulated genes enriched in tissue remodeling and signaling pathways, suggesting their role in the development of fibrosis in the endometrosis progression.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-20152-0.

Chimeric antigen receptor (CAR) T cells have become an established immunotherapy with promising results for the treatment of hematological malignancies. However, modulation of the targeted antigen’s surface level in cancer cells affects the quality and safety of CAR-T cell therapy. Here we present an engineered yeast-based antigen system for simulation of cancer cells with precise regulation of surface-antigen densities, providing a tool for controlled activation of CAR T cells and systematic assessment of antigen density effects. This Synthetic Cellular Advanced Signal Adapter (SCASA) system uses G protein-coupled receptor signaling to control cancer antigen densities on the yeast surface and provides a customizable platform allowing selectable signal inputs and modular pathway engineering for precise output fine-tuning. In relation to CD19+ cancers, we demonstrate synthetic cellular communication between CD19-displaying yeast and human CAR T cells as well as applications in high-throughput characterization of different CAR designs. We show that yeast is an alternative to conventional technologies (e.g. microbeads) and can provide higher activation control of clinically derived CAR T cells in vitro, relative to cancer cells. In summary, we present a customizable yeast-based platform for high-throughput characterization of CAR-T cell functionality and show potential applications within therapeutic T cells in clinical settings. Chimeric antigen receptor T (CAR-T) cell therapy uses engineered donor T cells to recognize and eliminate cancer cells through cognate antigen-dependent activation. Here authors develop an alternative to bead-based or cancer-cell-induced CAR-T cell activation by presenting the antigen on the surface of engineered yeast cells, which allows precise regulation of antigen density.