Abstract
Sjogren’s syndrome (SS) is characterized by dysfunctional mucous membranes and dysregulated moisture-secreting glands resulting in various symptoms, including dry mouth and dry eyes. Here, we wanted to profile and compare the tear and saliva proteomes of SS patients to healthy controls. Tear and saliva samples were collected and subjected to an isotopic dimethylation labeling shotgun proteomics workflow to identify alterations in protein levels. In tear samples, we identified 83 upregulated and 112 downregulated proteins. Pathway enrichment analysis of the changing proteins by Metascape identified leukocyte transendothelial migration, neutrophil degranulation, and post-translation protein phosphorylation in tears of SS patients. In healthy controls’ tears, an enrichment for proteins related to glycolysis, amino acid metabolism and apoptotic signaling pathway were identified. In saliva, we identified 108 upregulated and 45 downregulated proteins. Altered pathways in SS patients’ saliva included cornification, sensory perception to taste and neutrophil degranulation. In healthy controls’ saliva, an enrichment for proteins related to JAK-STAT signaling after interleukin-12 stimulation, phagocytosis and glycolysis in senescence were identified. Dysregulated protease activity is implicated in the initiation of inflammation and immune cell recruitment in SS. We identified 20 proteases and protease inhibitors in tears and 18 in saliva which are differentially expressed between SS patients and healthy controls. Next, we quantified endogenous proteoglycan 4 (PRG4), a mucin-like glycoprotein, in tear wash and saliva samples via a bead-based immune assay. We identified decreased levels of PRG4 in SS patients’ tear wash compared to normal samples. Conversely, in saliva, we found elevated levels of PRG4 concentration and visualized PRG4 expression in human parotid gland via immunohistological staining. These findings will improve our mechanistic understanding of the disease and changes in SS patients’ protein expression will help identify new potential drug targets. PRG4 is among the promising targets, which we identified here, in saliva, for the first time.
Highlights
Sjogren’s syndrome (SS) is a chronic autoimmune disease that predominantly affects middle-aged women, with a high female to male ratio (9:1), and is characterized by both local and systemic inflammations, with exocrine glands being the primary site of disease manifestation (Virdee et al, 2017; Vivino, 2017; Mavragani and Moutsopoulos, 2020)
We describe changes in abundance of proteins as log2 fold change (SS tears over healthy controls), which means log2 values > 0 represent proteins that were upregulated in SS tears,
In the proteomics analysis (Supplementary Figure S1 and Supplementary Table S1), we identified 83 unique proteins that were upregulated in SS tears and 112 unique downregulated proteins
Summary
Sjogren’s syndrome (SS) is a chronic autoimmune disease that predominantly affects middle-aged women, with a high female to male ratio (9:1), and is characterized by both local and systemic inflammations, with exocrine glands (i.e., salivary, parotid and lacrimal glands) being the primary site of disease manifestation (Virdee et al, 2017; Vivino, 2017; Mavragani and Moutsopoulos, 2020). Lymphocyte infiltration and inflammation in salivary and lacrimal glands result in dryness of the mucosal surfaces, including the mouth (xerostomia) and eye (xerophthalmia), which are the key symptoms that lead to clinical suspicion of the disease occurring in more than 95% of the patients (RamosCasals et al, 2012; Brito-Zerón et al, 2016). Around 75% of infiltrating lymphocytes in the salivary glands of SS constitute T cells, which are mostly composed of CD4+ T cells (Fox et al, 1983; Verstappen et al, 2017) These cells can produce both Th1 and Th2 cytokines but are characterized by a shift in the favor of Th1 in the salivary gland in patients with SS (Mitsias et al, 2002). An overexpression of the cytokines IL4, IL17, and IFNγ have been associated with the pathogenesis of SS (Verstappen et al, 2017; López-Villalobos et al, 2021)
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