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

Sjogrens disease (SjD) is a second most prevalent rheumatic disease involving autoimmune pathology of tear-producing lacrimal glands that leads to a common clinical manifestation of chronic ocular surface disease. Despite advances in understanding of SjD, lacrimal gland pathology remains incompletely understood limiting diagnosis and treatment. Here we analyze spatial transcriptomic profile of lacrimal glands from wild-type (C57Bl/6) mice and Thrombospondin (TSP)-1-/- mice, a spontaneous mouse model of SjD. We uncover molecular mechanisms underlying functional loss of major epithelial cell subtypes - acinar, duct and myoepithelial cells. We identify potential early mechanisms and markers of glandular damage. By integrating spatial and cellular profiles, we uncover the presence of antigen presenting cells in the proximity of duct epithelial cells that were not described previously in lacrimal glands. We further identify role of epithelial cells as active participants in promoting or sustaining inflammation. Our findings help reveal potential molecular and cellular cues that drive periductal infiltrates containing B cells and Tfh cells that form germinal centers to facilitate local autoantibody production. Overall, our study can provide a framework for therapeutic targeting of epithelial cell types and multicellular interactions underlying autoimmune pathology. Significance StatementTears produced by lacrimal glands are critical for protecting the eye surface by preventing tissue dryness and maintaining normal vision. Disruption of this function due to autoimmune inflammation in Sjogrens Disease compromises the protection of the eye surface causing dryness, a condition with a potential for sight-threatening complications like infections and ulcers. Understanding cellular and molecular interactions that lead to functional loss and autoimmune inflammation of the lacrimal gland is critical for developing effective therapies. We have analyzed transcriptional profile of glandular cells in a tissue section where their morphology and interactions with surrounding cells is preserved. By comparing glands from normal and mice with Sjogrens disease we identify molecular mechanisms that can form the basis for new therapies.