Spatial transcriptomic profiling identifies lacrimal-gland-epithelial cell-driven mechanisms underlying autoimmunity in Sjögren's disease.

INTRODUCTION: Sjögren's disease (SjD) is the second most prevalent rheumatic disease and is characterized by autoimmune pathology targeting the tear-producing lacrimal glands, leading to chronic ocular surface disease. Despite important advances, lacrimal gland pathology in SjD remains incompletely understood, limiting both diagnosis and treatment. METHODS: In this exploratory study, we used spatial transcriptomics to profile lacrimal glands from wild-type (C57Bl/6) mice and thrombospondin-1-deficient (TSP-1(-)/(-)) mice, a spontaneous model of SjD, to identify molecular signatures associated with the functional loss of major epithelial cell subtypes-acinar, ductal, and myoepithelial cells. RESULTS: Our analyses revealed gene expression patterns consistent with endoplasmic reticulum stress in acinar cells, mitochondrial dysfunction in ductal epithelial cells, secretory dysfunction in both acinar and ductal epithelial cells, and contractile impairment with profibrotic remodeling in myoepithelial cells in SjD lacrimal glands, highlighting potential early mechanisms and markers of glandular damage. Furthermore, in acinar epithelial cells, a significantly reduced expression of Pigr, which encodes the polymeric immunoglobulin receptor required for the transcytotic delivery of protective secretory IgA into tear fluid, correlated with reduced tear secretory IgA levels in SjD mice, consistent with their observed ocular surface disease. DISCUSSION: This finding supports the potential use of tear sIgA as a quantifiable biomarker of glandular dysfunction. By integrating spatial and cellular information, we uncovered a previously unrecognized spatial relationship between ductal epithelial cells and antigen-presenting cells in the lacrimal gland and identified a potential role for ductal epithelial cells as active drivers of inflammation by providing molecular and cellular cues that support periductal infiltrates rich in B cells and T follicular helper cells that form germinal centers and promote local autoantibody production. These findings together generate testable mechanistic hypotheses for each epithelial subtype and propose a framework for the therapeutic targeting of epithelial cells and multicellular interactions that underlie autoimmune lacrimal gland pathology in SjD.