The Immune-Epithelial Interaction in the Pathogenesis of Primary Sjögren's Syndrome
Autoimmune disorders in humans are complex diseases that are often influenced by both genetic and environmental factors. Primary Sjögren’s Syndrome (SS), characterized primarily by salivary and ocular dryness, is one of most common autoimmune diseases that targets exocrine glands like the salivary gland (SG). Normal SG tissue consists of two main functional structures, acini and ducts, but in SS patients, SG histology also shows tightly packed foci of infiltrating immune cells, often described to be co-localized with ductal cells. However, there are no etiological mechanisms known for SS, party due to a lack of understanding of the cell-type-specific differences between SS patients and healthy controls. To address this need, laser microdissection (LMD) was applied to separate acini, ducts, and lymphocytic infiltrates from healthy and patient SGs biopsies, and gene expression profiles were assayed by RNA-Seq. A chemokine/receptor pair, CCL21 and CCR7, were identified to be upregulated in patients by differential expression analysis and confirmed with qPCR and immunohistochemistry. The LMD-RNA-Seq data were further subject to enrichment analysis against a larger RNA-Seq cohort of whole SG biopsies. Comparative analysis of the two datasets – LMD and whole SG RNA-Seq – showed the gains in sensitivity yielded by the LMD approach. Furthermore, one of the most significantly upregulated pathways in SS patients using whole SG data, IFN alpha/beta signaling, was only upregulated in patient acinar cells in the LMD dataset. Since IFN alpha/beta signaling is also upregulated due to viral infections, acinar cells were used in vitro to test the effect of a microRNA (miRNA) encoded by the Epstein-Barr Virus (EBV), found previously to be increased in SS patients. The miRNA, ebv-miR-BART13, selectively upregulated genes in the IFN alpha/beta pathway in acinar cell culture. Finally, the genes differentially expressed in LMD samples and the genes upregulated by BART13 both behave similarly in the larger whole SG dataset and correlate with focus score, adding further evidence for the link between EBV and SS.
Tandon, Mayank, "The Immune-Epithelial Interaction in the Pathogenesis of Primary Sjögren's Syndrome" (2017). ETD Collection for Thomas Jefferson University. AAI10634810.