Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren’s Syndrome

Abstract

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis. Currently, there is no effective cure for pSS and treatment options and targeted therapy approaches are limited due to a lack of our overall understanding of the disease etiology and its underlying pathology. To better elucidate the underlying molecular nature of this disease, we have performed RNA-sequencing to generate a comprehensive global gene expression profile of minor salivary glands from an ethnically diverse cohort of patients with pSS. Gene expression analysis has identified a number of pathways and networks that are relevant in pSS pathogenesis. Moreover, our detailed integrative analysis has revealed a primary Sjögren’s syndrome molecular signature that may represent important players acting as potential drivers of this disease. Finally, we have established that the global transcriptomic changes in pSS are likely to be attributed not only to various immune cell types within the salivary gland but also epithelial cells which are likely playing a contributing role. Overall, our comprehensive studies provide a database-enriched framework and resource for the identification and examination of key pathways, mediators, and new biomarkers important in the pathogenesis of this disease with the long-term goals of facilitating earlier diagnosis of pSS and to mitigate or abrogate the progression of this debilitating disease.

Differentially Expressed Gene Pathways in the Conjunctiva of Sjögren Syndrome Keratoconjunctivitis Sicca

“…Our results showing increased XBP-1 and STAT1 levels agree with the literature and with our previous publication that showed increased XBP-1 and GRP78 in the SS KCS conjunctiva compared to healthy controls (11). Increased levels of STAT1 have been previously reported in humans and animal models, also in the conjunctiva (13,14,62,109). XBP-1 (X-box binding protein-1) participates in ER stress and UPR, decreasing salivary gland protein secretion (110).…”

“…Two representatives Spearman correlation graphs are shown in Figure 5A : 1) CD74 , a critical step in MHC II pathway ( 75 ), inversely correlated with TBUT and positively with conjunctival staining score, 2) LAMP3 , a lysosomal protein involved in autophagy ( 76 ), which correlated with OSDI, TBUT, and conjunctival staining score. Increased levels of CD74 have been previously reported in minor salivary gland SS biopsies ( 62 , 77 ).…”

“…IRF7 is a transcription factor that mediates IFN-a signaling. IRF7 has been found elevated in the SS patients, where it is thought to mediate the IFN signature (35)(36)(37)(38)62).…”

Integrated Bioinformatics and Validation Reveal Potential Biomarkers Associated With Progression of Primary Sjögren’s Syndrome

“…Previous studies have extensively investigated molecular biomarkers of pSS over the last several decades; however, these studies were conducted based on only one kind of gland (3,8,(35)(36)(37). Considering the complexity of underlying pSS occurrence and development, it is essential for us to consider the expression of genes from all salivary glands in combination with clinical verification to identify more convincing biomarkers.…”

“…Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease of the primary exocrine glands characterized by specific pathological features (1,2). pSS often features immune-mediated destruction of exocrine tissues, such as salivary and lacrimal glands, resulting in the loss of saliva and tear production (3). Immunological abnormalities such as antinuclear antibodies (ANAs), antibodies against Ro/Sjögren's syndrome-related antigen A (SSA) and La/Sjögren's syndromerelated antigen B (SSB), and hypergammaglobulinemia are often detected in pSS patients by laboratory tests (4,5).…”