Mapping the B-cell axis in Sjögren's disease: repertoire, microenvironment, and potential routes to precision treatment.

Sjögren's disease (SjD) is a chronic autoimmune disorder in which sustained B-cell activation drives glandular injury and systemic complications. Epithelial stress and interferon tone amplify B-cell activating factor (BAFF)-dependent survival, skewing selection toward autoreactive clones in both glands and blood. In addition, single-cell B-cell receptor analyses have uncovered interferon-high endotypes with tissue-imprinted oligoclonality and biased isotype and light-chain usage. Within salivary glands, ectopic germinal centers and FcRL4⁺ B cells act as local 'training sites,' integrating Tfh/Tph help, CXCL13 cues, and BAFF/APRIL-NF-κB signaling to sustain plasmablast differentiation. Extrafollicular trajectories - double-negative and age-associated B cells - expand in IFN/TLR7 and IL-21 milieus, while regulatory B-cell restraint is diminished. Emerging data also implicate glycolysis and mTORC1-GLUT1 metabolism in sustaining B-cell hyperactivation. Chronic B-cell receptor signaling and clonal evolution provide a bridge to lymphoma risk. In this review, we outline how these converging pathways define molecular endotypes and propose a precision framework linking them to targeted therapy in SjD.