Decoding autoimmune disease with single-cell immune repertoire and transcriptome sequencing: mechanisms and therapeutic opportunities.

Autoimmune diseases result from a breakdown of immune tolerance, driving the aberrant activation and clonal expansion of self-reactive T and B cells. Progress has been limited by the inability to link clonal identity to functional states at single-cell resolution. Single-cell T- and B-cell receptor sequencing (scTCR/BCR-seq) now bridges this gap by simultaneously recovering paired TCR (α/β) and BCR (heavy/light) chains and gene-expression profiles, enabling direct coupling of clonotypes to cellular function and tissue trafficking. This shift from population-level averaging to clonal-resolution analysis, particularly when integrated with multi-omics, has yielded substantial insights. Mechanistically, scTCR/BCR-seq identifies tissue-homing, putatively pathogenic clones and resolves somatic hypermutation, class-switch recombination, and T-B cell interaction networks, thereby delineating the clonal basis of disease heterogeneity. Clinically, it enables tracking of clonal dynamics to inform prognosis and to predict responses to therapies such as anti-CD20 or BAFF-targeted agents. For therapeutic development, reconstructing autoantibodies from BCR clones and mapping epitopes through TCR analysis provide a foundation for antigen-specific tolerance strategies. This review synthesizes scTCR/BCR-seq methodologies and systematically charts these advances and discusses current challenges and future directions toward precision subtyping, biomarker development, and novel immunotherapies in autoimmune disease.