Deep immune profiling pinpoints cellular and molecular drivers of lupus immunopathology

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with an unknown etiology. To pinpoint new disease-relevant cell states and their molecular profiles, we performed an in-depth investigation of multimodal single-cell datasets comprising [~]2.1 million peripheral blood mononuclear cells from 346 donors. By resolving 123 fine-grained cell states across 27 cell types, we identified previously uncharacterized populations distinctively associated with clinical severity and treatment status, including GZMK+GZMH+HLA-DR+ effector memory CD8+ T cells (double-positive [DP] EMCD8) and FOXO1+ARHGAP15+ T cells. Through extensive statistical frameworks and multimodal approaches, we delineated their aberrant immune signaling networks, transcriptional regulators, key surface proteins, T cell receptor repertoires, and genetic/epigenetic landscapes, underscoring them as candidate drivers of SLE immunopathology. These findings provide new insights into therapeutic target discovery in SLE.