Linares-Blanco, J.; Schäfer, P. S. L.; Zimmermann, L.; Melo Ferreira, R.; Toro-Dominguez, D.; Carmona-Saez, P.; Tanevski, J.; Alarcon Riquelme, M. E.; Eadon, M. T.; Ramirez Flores, R. O.; Saez-Rodriguez, J.

Systemic lupus erythematosus (SLE) shows marked clinical and molecular heterogeneity, yet patient stratification often relies on gene expression signatures lacking multicellular context. Here we construct a transcriptional patient map of SLE by analyzing 1,167 total samples (783 SLE, 384 healthy controls) across different resolutions, including single-cell and bulk blood as well as spatially resolved kidney tissue transcriptomes. Using an unsupervised approach we inferred patient-level transcriptomic immune programs from two independent single-cell RNA sequencing cohorts of peripheral blood mononuclear cells (PBMCs), capturing both differences between SLE and health as well as within-SLE heterogeneity. Specifically, we identified four conserved programs comprising two multicellular inflammatory programs driven by interferon and TNF/NFkB activity across immune cells, and two cell type-specific programs reflecting CD8 T cell cytotoxicity and a CD4 T cell naive-to-effector state. Functional analysis of these programs revealed a rewiring of both cell-to-cell interactions and task allocation across cell types during disease activation. In addition, mapping these programs onto an external longitudinal blood transcriptomic cohort predicted flare risk and identified candidate blood protein biomarkers detectable by proteomics. Finally, we showed that these blood programs were enriched in immune-infiltrated glomerular regions from kidney biopsies of individuals with lupus nephritis using spatially resolved transcriptomic data, thereby linking systemic immune programs to local tissue pathology.