Comprehensive Immune Repertoires of T Cell Receptor and B Cell Receptor Identify Key Immune Features Associated With Disease Activity of Systemic Lupus Erythematosus

ABSTRACT

We integrated immune repertoire sequencing (CD4+ and CD8+ T cell receptor [TCR], B cell receptor [BCR]) and transcriptional profiling to characterize the peripheral immune landscape in 32 active systemic lupus erythematosus (SLE) patients, 30 stable SLE patients, and 35 healthy donors. CD4+ and CD8+ TCR α‐ and β‐chain repertoires in SLE patients showed lower diversity, reduced similarity, and more heterogeneous V–J usage, with CD8+ TCR profiles exhibiting relatively consistent stepwise changes across healthy, stable, and active groups. CD8+ T‐cell transcriptomics revealed activity‐associated upregulation of CD38 , S100A11 , IFITM3 , and LAG3 . In addition, BCR immunoglobulin heavy chain (IGH) repertoire analysis showed isotype‐specific remodeling in SLE, characterized by contracted IgM/IgD repertoires, increased IgA isotype ratio and richness, and enhanced IgG diversity. Active SLE showed further increased IgG richness with rare‐clone enrichment and higher IgM diversity. Among the TCR, BCR, and CD8+ T‐cell transcriptomic features evaluated, IGH‐derived metrics, particularly IgG‐ and IgA‐associated features, showed apparent within‐cohort discrimination between active and stable SLE. Genetic algorithm‐based label‐guided feature selection followed by hierarchical clustering revealed a multi‐omics pattern associated with disease activity within the current cohort. Our study characterized peripheral immune repertoire and transcriptional alterations in SLE and highlighted their value for characterizing disease activity.