Single-cell landscape of immune cells in multiple autoimmune diseases

Autoimmune pathologies arise from dysregulated immune activation, yet conserved molecular programs across autoimmune contexts remain incompletely characterized. Here, we analyzed integrative single-cell RNA sequencing data of over 1.3 million cells from 239 samples spanning six autoimmune diseases, revealing disease-specific and cell type-specific transcriptional programs. Systematic immune profiling identified 41 functionally annotated gene clusters (GCs) with cross-disease activation. We identified a cytotoxic <i>CD8</i> ⁺ T cell-enriched gene cluster (GC40) that drives enhanced cytotoxic function and clonal expansion across four autoimmune diseases. In parallel, we identified a secretory granule lumen-associated GC08 that is highly expressed in <i>CD14</i> ⁺ monocytes and promotes plasma cell activation through upregulation of TNFSF13B secretion. Furthermore, we leveraged a disease classifier to discriminate autoimmune disease types and healthy states. Our study provides both a resource and a predictive framework at the single-cell level, supporting future targeted therapies for autoimmune diseases.