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

Abstract

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.

Key findings

• ▸Gene expression patterns in acinar cells are consistent with endoplasmic reticulum stress.
• ▸Ductal epithelial cells exhibit signs of mitochondrial dysfunction.
• ▸Secretory dysfunction is observed as a key mechanism underlying autoimmunity in the lacrimal gland.

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Identifiers

DOI

10.3389/fimmu.2026.1759347

Journal

Frontiers in Immunology

Year

2026