SLECA: a single-cell atlas of systemic lupus erythematosus enabling rare cell discovery using graph transformer

Abstract

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease with complex immune and molecular dysregulation. While rare immune cell populations are increasingly recognized as critical drivers of disease pathogenesis and progression, the lack of sufficiently powered, comprehensive single-cell atlases has limited their systematic identification and characterization. To address this gap, we present SLECA, the first large-scale single-cell atlas of SLE, enabled by a novel graph-transformer framework for the interpretable discovery and analysis of disease-relevant rare cell populations. SLECA integrates 366 single-cell samples with standardized clinical and biological metadata, providing a comprehensive and analytically unified atlas of systemic lupus erythematosus. By enabling scalable integration and interpretable analysis, SLECA resolves 54 distinct cell types, including rare populations with critical disease relevance. Notably, we identify double-negative T cells (DNTs) as a disease-expanded population whose abundance correlates with clinical severity. Through in silico perturbation, we demonstrate that key transcription factors, specifically JUN and EGR1, can reprogram DNT cells toward conventional T-cell phenotypes, highlighting actionable regulatory vulnerabilities in SLE.