The epithelial cell in Sjögren's syndrome: from passive target to orchestrator of autoimmune reactivity

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by sicca symptoms, fatigue, multiorgan involvement, and an increased risk of B-cell lymphoma. Accumulating evidence over the past decades indicates that epithelial cells are not passive targets but active drivers of disease. Histopathologic and immunologic studies show lymphocytic infiltration around epithelial structures and aberrant epithelial expression of HLA-DR, co-stimulatory molecules, cytokines, chemokines, and autoantigens. Notably, patient-derived epithelial cells maintain these activated features in vitro, supporting intrinsic dysregulation. Functionally, epithelial cells can act as non-professional antigen-presenting cells, contributing to T-cell activation and local immune responses. Mechanistic pathways, including viral triggers, type I interferon signaling, autophagy, mitochondrial dysfunction, and innate immune activation, further support an epithelial-centered model. This review summarizes evidence for 'autoimmune epithelitis', examines related autoimmune paradigms, and discusses therapeutic strategies targeting both immune pathways and epithelial homeostasis.