Spatiotemporal orchestration of the salivary gland immune microenvironment in Sjögren’s disease: a multidimensional framework of epithelial licensing, lymphoid neogenesis, and stromal remodeling

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and progressive secretory dysfunction. Although the major molecular abnormalities in SjD, including prominent type I interferon activation and abnormal B-cell responses, are now better defined, these findings have not consistently translated into effective disease-modifying therapy. A persistent gap therefore remains between biological target engagement and clinical benefit. This review argues that this gap may partly reflect a mismatch between current pathological models of SjD and the way clinical trials are designed. Conventional frameworks often treat SjD as a relatively homogeneous inflammatory disease and rely heavily on systemic disease-activity measures. Such approaches may underrepresent the spatiotemporal evolution of the salivary gland microenvironment and the heterogeneity of treatment responses across tissue states. Drawing on recent evidence, including single-cell RNA sequencing, spatial transcriptomics, and longitudinal histological studies, we propose a tissue-centered interpretive framework for SjD. This framework highlights three partially overlapping dimensions: epithelial activation states linked to nucleic-acid-sensing and interferon-related programs; lymphoid organization and B-cell-supportive niches associated with IFN-BAFF and Tfh/Tph-related activity; and later structural remodeling associated with fibrosis, impaired regeneration, and reduced functional reversibility. These dimensions are used here as interpretive constructs rather than as validated clinical staging categories. On this basis, precision medicine in SjD may need to move beyond a uniform anti-inflammatory strategy toward mechanism-based stratification anchored in tissue state and disease stage. Biomarkers such as salivary gland ultrasonography, TLS-related features, and microenvironment-linked molecular readouts may help refine patient stratification, endpoint selection, and clinical trial design, although these applications still require prospective validation.