Gene expression alterations in salivary gland epithelia of Sj\xf6gren\u2019s syndrome patients are associated with clinical and histopathological manifestations

Ariana Dela Cruz,Stefano Monti,Kathrine Skarstein,Taylor L Reynolds,Xaralabos Varelas,Janicke L Jensen,Vinay Kartha,Maria A Kukuruzinska,Rongjuan Mi,Andrew Tilston-Lunel,Michael Mingueneau

doi:10.1038/s41598-021-90569-w

Ariana Dela Cruz, Stefano Monti + Show 9 more

Open Access

https://doi.org/10.1038/s41598-021-90569-w

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Abstract

Sjögren’s syndrome (SS) is a complex autoimmune disease associated with lymphocytic infiltration and secretory dysfunction of salivary and lacrimal glands. Although the etiology of SS remains unclear, evidence suggests that epithelial damage of the glands elicits immune and fibrotic responses in SS. To define molecular changes underlying epithelial tissue damage in SS, we laser capture microdissected (LCM) labial salivary gland epithelia from 8 SS and 8 non-SS controls for analysis by RNA sequencing (RNAseq). Computational interrogation of gene expression signatures revealed that, in addition to a division of SS and non-SS samples, there was a potential intermediate state overlapping clustering of SS and non-SS samples. Differential expression analysis uncovered signaling events likely associated with distinct SS pathogenesis. Notable signals included the enrichment of IFN-γ and JAK/STAT-regulated genes, and the induction of genes encoding secreted factors, such as LTF, BMP3, and MMP7, implicated in immune responses, matrix remodeling and tissue destruction. Identification of gene expression signatures of salivary epithelia associated with mixed clinical and histopathological characteristics suggests that SS pathology may be defined by distinct molecular subtypes. We conclude that gene expression changes arising in the damaged salivary epithelia may offer novel insights into the signals contributing to SS development and progression.

Highlights

Sjögren’s syndrome (SS) is a complex autoimmune disease associated with lymphocytic infiltration and secretory dysfunction of salivary and lacrimal glands
Our studies provide evidence that damage to salivary gland epithelia is associated with changes in gene expression signatures that provide insights into deregulated pathways and cellular processes which may underlie predisposition to, and early onset of, SS
Sixteen samples of labial salivary glands were obtained from female patients who presented with sicca symptoms to the Department of Otolayngology/Head and Neck Surgery at Haukeland University Hospital, Bergen

Summary

Introduction

Sjögren’s syndrome (SS) is a complex autoimmune disease associated with lymphocytic infiltration and secretory dysfunction of salivary and lacrimal glands. Genes involved in NF-κB signaling and CXCR5 chemokine production were shown to be u pregulated[9,17] These studies provided a strong support for the role of innate immunity, as well as adaptive immune mechanisms, in the pathogenesis of pSS. Our studies provide evidence that damage to salivary gland epithelia is associated with changes in gene expression signatures that provide insights into deregulated pathways and cellular processes which may underlie predisposition to, and early onset of, SS. These findings provide support for the theory that alterations in gene expression arising in the salivary epithelia contribute to the etiology of SS.

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