Pathogenesis Of Sjögren's Syndrome Research Articles

Molecular Mechanisms Linking Inflammation to Autoimmunity in Sjögren's Syndrome: Identification of New Targets.

Sjögren's syndrome (SS) is a systemic autoimmune rheumatic disorder characterized by the lymphocytic infiltration of exocrine glands and the production of autoantibodies to self-antigens. The involvement of the exocrine glands drives the pathognomonic manifestations of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) that define sicca syndrome. To date, the molecular mechanisms mediating pathological salivary gland dysfunction in SS remain to be elucidated, despite extensive studies investigating the underlying cause of this disease, hampering the development of novel therapeutic strategies. Many researchers have identified a multifactorial pathogenesis of SS, including environmental, genetic, neuroendocrine, and immune factors. In this review, we explore the latest developments in understanding the molecular mechanisms involved in the pathogenesis of SS, which have attracted increasing interest in recent years.

Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren's Syndrome.

Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n=958) or primary SS (n=911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P=2 × 10-9 ) and impaired function of the classical complement pathway (P=0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.

Targeting EZH2 prevents the occurrence and mitigates the development of Sjögren's syndrome in mice

ObjectiveWe analyzed RNA-SEQ data and found that EZH2 gene expression in salivary glands (SGs) of Sjögren's syndrome (SS) patients was up-regulated and correlated with pathological injury. In this study, we sought to determine if inhibiting EZH2 would ameliorate SS-like disease in NOD/Ltj (NOD) mice. MethodsWe analyzed RNA-SEQ data of SGs of patients with SS from data obtained from the GEO database to explore the correlation between EZH2 gene expression and the progression of SS. Inhibition of EZH2 in the NOD mice was achieved by intraperitoneal administration of GSK343 using both a preventative and a therapeutic model. The effects of GSK343 on SGs secretion and pathological damage, as well as the levels and functions of T cells, B cells, Myeloid-derived suppressor cells (MDSCs), and other immune cells were evaluated. ResultsThe expression levels of the gene encoding EZH2 in the SGs of SS patients were significantly higher than the non-SS sicca patients, and the expression levels were positively correlated with the severity of the SGs pathological damage. GSK343 treatment significantly increased the salivary flow rate and pathological damage of the SGs in the NOD mice compared to the control mice. In addition, GSK343 significantly inhibited the number and pro-inflammatory-factor secretion of CD4+ and CD8+ T cells and inhibited the increase in the Th1/Th2 cell ratio caused by SS. RNA-SEQ data also showed that EZH2 inhibited several inflammatory pathways during the pathogenesis of SS. ConclusionsEZH2 expression was up-regulated in the submandibular gland tissue of SS patients.Inhibition of EZH2 alleviated SS-like disease in NOD mice, suggesting that EZH2 might be a potential target for the clinical treatment of SS.

Reduced tear thrombospondin‐1/matrix metalloproteinase‐9 ratio can aid in detecting Sjögren's syndrome etiology in patients with dry eye

Differentiating patients with Sjögren's syndrome (SS)‐associated dry eye from non‐SS dry eye is critical for monitoring and appropriate management of possible sight‐ or life‐threatening extraglandular complications associated with SS. We tested whether reduced tear levels of immunoregulatory thrombospondin (TSP)‐1, which also inhibits matrix metalloproteinase (MMP)‐9, would reflect SS pathogenesis aiding the identification of patients with SS‐dry eye. Total of 61 participants, including healthy controls (n = 20), patients with non‐SS dry eye (n = 20) and SS‐dry eye (n = 21) were enrolled prospectively. Tear TSP‐1 and MMP‐9 levels were measured using a custom magnetic bead‐based multi‐plex assay in a masked manner. Analyte concentrations were assessed further according to ocular surface and tear film parameters. Relative to median tear TSP‐1 (308 ng/ml) and MMP‐9 (1.9 ng/ml) levels in the control group, significantly higher proportion of patients with SS‐dry eye than non‐SS had lower tear TSP‐1 levels (55% vs. 29%, odds ratio [OR] = 3, 95% confidence interval [CI] = 1.64 to 5.35, p < 0.05) and higher tear MMP‐9 levels (65% vs. 24%, OR = 5.8, 95% CI = 4.46 to 19.81, p < 0.05), respectively. The tear TSP‐1/MMP‐9 ratio was significantly reduced in patients with SS‐dry eye compared to non‐SS (B = −2.36, 95% CI = −3.94 to −0.0.79, p < 0.05), regardless of tear MMP‐9 levels. Patients with a lower ratio were 2.3 times more likely to have SS (OR = 0.28, 95% CI = 0.1 to 0.75, p < 0.05). This ratio showed significant inverse correlations with clinical parameters (conjunctival and corneal staining scores). Our results denote that tear TSP‐1/MMP‐9 ratio can be useful in identifying patients with dry eye with underlying SS and used as a screening test.

Exploration of the pathogenesis of Sjögren's syndrome via DNA methylation and transcriptome analyses.

Sjögren's syndrome (SS), a systemic autoimmune disorder, is characterized by dry mouth and eyes. However, SS pathogenesis is poorly understood. We performed bioinformatics analysis to investigate the potential targets and molecular pathogenesis of SS. Gene expression profiles (GSE157159) and methylation data (GSE110007) associated with SS patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially methylated positions (DMPs) and differentially expressed genes (DEGs) were identified by the R package limma. The potential biological functions of DEGs were determined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Key DMPs were selected by overlap and the shrunken centroid algorithm, and corresponding genes were identified as hub genes, with their diagnostic value assessed by receiver operating characteristic (ROC) curves. The potential molecular mechanisms of hub genes were analyzed by protein-protein interaction (PPI) networks and single-gene gene set enrichment analysis (GSEA). Peripheral blood mononuclear cells (PBMCs) were collected from control and SS patients atThe Affiliated Hospital of Southwest Medical Universityand Dazhou Central Hospital. The mRNA levels of hub genes were verified by quantitative real-time polymerase chain reaction (qRT-PCR). We identified 788 DMPs and 2457 DEGs between the two groups. Functional enrichment analysis suggested that the DEGs were significantly enriched in T cell activation, leukocyte cell-cell adhesion, and cytokine-cytokine receptor interaction. TSS200, TSS1500, and 1stExon were identified as highly enriched areas of differentially methylated promoter CpG islands (DMCIs). In total, 61 differentially methylated genes (DMGs) were identified by the overlap of 2457 DEGs and 507 genes related to DMPs (DMPGs), of which 21 genes located near TSS200, TSS1500, and 1stExon were selected. Then, three key DMPs and the corresponding hub genes (RUNX3, HLA-DPA1, and CD6) were screened by the shrunken centroid algorithm and calculated to have areas under the ROC curve of 1.000, 0.931, and 0.986, respectively, indicating good diagnostic value. The GSEA results suggested that all three hub genes were highly associated with the immune response. Finally, positive mRNA expression of the three hub genes in clinical SS samples was verified by qRT-PCR, consistent with the GSE157159 data. The identification of three hub genes provides novel insight into molecular mechanisms and therapeutic targets for SS. Key Points • Hub genes were screened by DNA methylation and transcriptome analyses. • The relative expression of hub genes in peripheral blood samples was verified by qRT-PCR. • HLA-DPA1 was correlated with the pathogenic mechanism of SS.

Umbilical cord mesenchymal stem cells alleviate Sjögren's syndrome and related pulmonary inflammation through regulating Vγ4+ IL-17+ T cells.

BackgroundSince gamma delta (γδ) T cells are involved in various autoimmune diseases, we aimed to verify whether γδ T cells participate in the pathogenesis of Sjögren’s syndrome (SS) and related pulmonary inflammation, and also aimed to evaluate the effects of umbilical cord mesenchymal stem cells (MSCs) on SS-related pulmonary inflammation and the γδ T cells.MethodsThe saliva flow rates of female non-obese diabetic (NOD/Ltj) mice were measured. Histopathologic analysis was performed in salivary glands (SG) and lung tissues. The levels of γδ T cells and their subsets in the peripheral blood, spleen, and lung were examined by flow cytometry. The purified γδ T cells were adoptively transferred into NOD/Ltj mice. MSC transplantation was performed in 8-week-old NOD/Ltj mice.ResultsThe results showed lymphocytic infiltration in SG and lacrimal glands (LG), and reduction of saliva flow rates in 8-week NOD/Ltj mice. The levels of γδ T cells decreased in peripheral blood, but increased in the lung of 8- and 12-week-old NOD/Ltj mice. The proportions and numbers of Vγ4+ T cells and Vγ4+ IL-17A+ T cells increased in the lung, but decreased in peripheral blood of 8-week-old NOD/Ltj mice. Notably, transfer of γδ T cells decreased the rate of saliva flow, as well as aggravated the pathological changes in the lung. The transplantation of MSCs increased saliva flow rate and alleviated pathological injury in the SG and lung. The frequencies of Vγ4+ T cells and Vγ4+ IL-17A+ T cells in the lung and spleen significantly decreased after MSC treatment. Our results demonstrated that γδ T cells and Vγ4+ T cells contribute to the pathogenesis of SS and SS-related pulmonary inflammation. In addition, MSCs relieved SS and SS-related pulmonary inflammation through suppressing Vγ4+ IL-17A+ T cells.ConclusionsPeripheral Vγ4+ T cells infiltrate into the lung in SS mice, and aggravate the symptoms of SS and SS-related pulmonary inflammation by secreting IL-17A. Meanwhile, lymphocyte infiltration could be reversed by MSC transplantation, which indicates the potential of MSCs in the treatment of SS and SS-related pulmonary inflammation patients.

Maladaptive Autophagy in the Pathogenesis of Autoimmune Epithelitis in Sjögren's Syndrome.

Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjögren's syndrome (SS); however, the mechanisms sustaining SGEC activation in primary SS remain unclear. We undertook this study to determine the role of autophagy in the survival and activation of SGECs in primary SS. Primary SGECs isolated from the minor SGs of patients with primary SS or sicca syndrome were evaluated by flow cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic flux, light chain 3 IIB [LC3-IIB], p62, LC3-IIB+/lysosome-associated membrane protein 1 [LAMP-1] staining), apoptosis (annexin V/propidium iodide [PI], caspase 3), and activation (intercellular adhesion molecule, vascular cell adhesion molecule). Focus score and germinal center presence were assessed in the SGs from the same patients to assess correlation with histologic severity. Human SG (HSG) cells were stimulated in vitro with peripheral blood mononuclear cells (PBMCs) and serum from primary SS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation. SGECs from primary SS patients (n=24) exhibited increased autophagy (autophagic flux [P=0.001]; LC3-IIB [P=0.02]; p62 [P=0.064]; and as indicated by LC3-IIB/LAMP-1+ staining), increased expression of antiapoptotic molecules (Bcl-2 [P=0.006]), and reduced apoptosis (annexin V/PI [P=0.002]; caspase 3 [P=0.057]), compared to samples from patients with sicca syndrome (n=16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from primary SS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy. In primary SS SGECs, inflammation induces autophagy and prosurvival mechanisms, which promote SGEC activation and mirror histologic severity. These findings indicate that autophagy is a central contributor to the pathogenesis of primary SS and a new therapeutic target.

Pharmacological Inhibition of Glutaminase 1 Normalized the Metabolic State and CD4+ T Cell Response in Sjogren's Syndrome.

Previous studies have shown that abnormal metabolic reprogramming in CD4+ T cells could explain the occurrence of several autoimmune disorders, including Sjogren's syndrome (SS). However, therapeutic targets of the abnormal metabolism of CD4+ T cells remain to be explored. Here, we report that glutaminase 1 (Gls1), a pivotal factor in glutaminolysis, might be involved in the pathogenesis of SS. The expression of Gls1 was upregulated in infiltrated labial CD4+ T cells and circulating CD4+ T cells of SS patients. Inhibiting Gls1 with BPTES significantly abolished the proliferation rate, as indicated by EdU, CFSE, and Western blot analyses. Additionally, BPTES downregulated the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) values of activated CD4+ T cells from SS mice. In vivo, we injected different doses of BPTES into SS-like NOD/Ltj mice and found that 10 mg/kg BPTES significantly restored the salivary flow rate. Histological and qRT–PCR analyses showed that this concentration of BPTES attenuated lymphocytic infiltration and the numbers of PCNA-positive cells and CD4+ T cells. The proportions of IFNγ-producing cells and IL-17A-producing cells and the expression of several proinflammatory cytokines, including IFNγ and IL-17A, were also affected in the salivary glands of SS-like mice. Cytokine production in circulating serum was analyzed and showed that BPTES downregulated the effector functions of Th17 cells and Th1 cells. Collectively, these results indicate a positive relationship between Gls1 and SS development. Pharmacological inhibition of Gls1 with BPTES could normalize the effector functions of CD4+ T cells and effectively attenuate the symptoms of SS.

Qing Zao Fang (QZF) Alleviates the Inflammatory Microenvironment of the Submandibular Gland in Sjögren's Syndrome Based on the PI3K/Akt/HIF-1α/VEGF Signaling Pathway.

Sjögren's syndrome (SS) which could lead to a disorder of our immune system is a chronic autoimmune disease characterized by invading exocrine glands such as salivary glands and lacrimal glands and other exocrine glands. Its common symptom is dry mouth and dry eyes, often accompanied by a large number of lymphocyte infiltrations and can involve other organs to cause complex clinical manifestations. In this study, we aimed at investigating the effect of QZF in SS, identifying the molecular mechanism in modulating autoimmune response, and determining the important roles of these factors' function as a modulator in the pathogenesis of SS. The NOD mice were utilized to establish the rats' model of Sjögren's syndrome. After 10 weeks' hydroxychloroquine and QZF in different dose interference, submandibular gland tissue was collected. The therapeutic effect of QZF on SS rats was identified, and the results suggest the comparable potential to hydroxychloroquine. In submandibular gland tissue, interleukin- (IL-) 17 was significantly lower in high-dose QZF than that in SS rats and the focal lymphocytes were highly attenuated. Moreover, we found that PI3K/Akt signals were activated and the downstream HIF-1α/VEGF signals were enhanced in SS rats whose protein expression could be inhibited by QZF treatment. In addition, QZF could modulate autophagy in submandibular gland tissue and then inhibit the inflammation response and therefore facilitate the tissue repair.

Why Should We Consider Potential Roles of Oral Bacteria in the Pathogenesis of Sjögren Syndrome?

Sjögren syndrome (SS) is a chronic autoimmune disorder that primarily targets the salivary and lacrimal glands. The pathology of these exocrine glands is characterized by periductal focal lymphocytic infiltrates, and both T cell-mediated tissue injury and autoantibodies that interfere with the secretion process underlie glandular hypofunction. In addition to these adaptive mechanisms, multiple innate immune pathways are dysregulated, particularly in the salivary gland epithelium. Our understanding of the pathogenetic mechanisms of SS has substantially improved during the past decade. In contrast to viral infection, bacterial infection has never been considered in the pathogenesis of SS. In this review, oral dysbiosis associated with SS and evidence for bacterial infection of the salivary glands in SS were reviewed. In addition, the potential contributions of bacterial infection to innate activation of ductal epithelial cells, plasmacytoid dendritic cells, and B cells and to the breach of tolerance via bystander activation of autoreactive T cells and molecular mimicry were discussed. The added roles of bacteria may extend our understanding of the pathogenetic mechanisms and therapeutic approaches for this autoimmune exocrinopathy.

One year in review 2021: Sjögren's syndrome.

Sjögren's syndrome (SS) is a multifactorial systemic autoimmune disease of unknown aetiology characterised by a wide spectrum of different clinical manifestations and scattered complications. Recently, great efforts have been made to elucidate mechanisms involved in the pathogenesis of the disease in order to identify exploitable therapeutic targets in SS. Similarly, novel insights have enabled to better define disease phenotypes and different outcomes. Ultimately, the discovery of new potential therapeutic targets and a better stratification of patients are paving new avenues for novel treatment options and treat-to-target therapeutic approach. In this review, we will provide a critical digest of the recent literature published in 2020 on SS pathogenesis, clinical manifestations and novel treatment options.

Untargeted serum metabolomics and potential biomarkers for Sjögren's syndrome.

At present, the pathogenesis of Sjögren's syndrome (SS) remains unclear. This research aimed to identify differential metabolites that contribute to SS diagnosis and discover the disturbed metabolic pathways. Recent advances in mass spectrometry have allowed the identification of hundreds of unique metabolic signatures and the exploration of altered metabolite profiles in disease. In this study, 505 candidates including healthy controls (HCs) and SS patients were recruited and the serum samples were collected. A non-targeted gas chromatography-mass spectrometry (GC-MS) serum metabolomics method was used to explore the changes in serum metabolites. We found SS patients and HCs can be distinguished by 21 significant metabolites. The levels of alanine, tryptophan, glycolic acid, pelargonic acid, cis-1-2-dihydro-1-2-naphthalenediol, diglycerol, capric acid, turanose, behenic acid, dehydroabietic acid, stearic acid, linoleic acid, heptadecanoic acid, valine, and lactic acid were increased in serum samples from SS patients, whereas levels of catechol, anabasine, 3-6-anhydro-D-galactose, beta-gentiobiose, 2-ketoisocaproic acid and ethanolamine were decreased. The significantly changed pathways included the following: Linoleic acid metabolism; unsaturated fatty acid biosynthesis; aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; glycerolipid metabolism; selenocompound metabolism; galactose metabolism; alanine, aspartate and glutamate metabolism; glyoxylate and dicarboxylate metabolism; glycerophospholipid metabolism; and valine, leucine and isoleucine degradation. These findings enhance the informative capacity of biochemical analyses through the identification of serum biomarkers and the analysis of metabolic pathways and contribute to an improved understanding of the pathogenesis of SS.

LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization

ABSTRACT Sjögren syndrome (SS) is a chronic and progressive autoimmune disease characterized by dry mouth and dry eyes, and characteristic autoantibodies. Evidence of altered macroautophagy/autophagy and apoptosis has been associated with SS, but a mechanistic understanding of the gene expression changes associated with these abnormal processes has not been realized. Recently, increased LAMP3 (lysosomal associated membrane protein 3) expression was found in a subset of SS patients and was associated with increased apoptosis and autoantigen accumulation and release. To better understand how LAMP3 expression might modulate apoptosis, cell biology, and biochemical studies were used to examine the effect of LAMP3 expression in minor salivary gland cells. LAMP3 expression resulted in degradation of LAMP1 increasing lysosomal membrane permeabilization and relocalization of cathepsins to the cytoplasm, resulting in destabilizing autophagic flux and caspase activation. These findings highlight the central role of LAMP3 expression in the pathogenesis of SS.

Plasmacytoid dendritic cells promote the pathogenesis of Sjögren's syndrome

Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) and promote pathogenesis of multiple autoimmune diseases. Autoimmune Sjögren's syndrome (SS) primarily affects salivary and lacrimal glands, causing their inflammation, destruction and dysfunction. pDCs and type I IFN activity are elevated in salivary glands of SS patients, and this study seeks to elucidate the in vivo actions of pDCs in SS pathogenesis using the non-obese diabetic (NOD) mouse model. We confirmed the type I IFN-dependency of SS development in female NOD mice and elevation of pDC-type I IFN in their submandibular glands (SMGs). We administered a pDC-depleting anti-BST2/CD317 antibody to female NOD mice from 4 to 7 weeks of age at the early stage of SS, and assessed SS pathologies at age 10 weeks, the time of disease onset. Depletion of pDCs impeded the development of SMG inflammation and secretory dysfunction. It drastically reduced the amount of type I IFN mRNA and the number of total leukocytes, and T- and B lymphocytes in SMGs. Gene expression analyses showed that pDC depletion markedly diminished SMG expression of IL-7, BAFF, TNF-α, IFN-γ, CXCL9, CXCL11, CD40, CD40L, Lt-α, Lt-β and NOS2. Hence, pDCs critically contribute to the development and onset of SS-like salivary gland exocrinopathy.

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

Sjögren syndrome (SS) is an autoimmune condition that targets the salivary and lacrimal glands, with cardinal clinical signs of dry eye (keratoconjunctivitis sicca, KCS) and dry mouth. The conjunctiva of SS patients is often infiltrated by immune cells that participate in the induction and maintenance of local inflammation. The purpose of this study was to investigate immune-related molecular pathways activated in the conjunctiva of SS patients. Female SS patients (n=7) and controls (n=19) completed a series of oral, ocular surface exams. Symptom severity scores were evaluated using validated questionnaires (OSDI and SANDE). All patients fulfilled the ACR/EULAR criteria for SS and the criteria for KCS. Fluorescein and lissamine green dye staining evaluated tear-break-up time (TBUT), corneal and conjunctival disease, respectively. Impression cytology of the temporal bulbar conjunctiva was performed to collect cells lysed and subjected to gene expression analysis using the NanoString Immunology Panel. 53/594 differentially expressed genes (DEGs) were observed between SS and healthy controls; 49 DEGs were upregulated, and 4 were downregulated (TRAF5, TGFBI, KLRAP1, and CMKLRI). The top 10 DEGs in descending order were BST2, IFITM1, LAMP3, CXCL1, IL19, CFB, LY96, MX1, IL4R, CDKN1A. Twenty pathways had a global significance score greater or equal to 2. Spearman correlations showed that 29/49 upregulated DEGs correlated with either TBUT (inverse) or OSDI or conjunctival staining score (positive correlations). Venn diagrams identified that 26/29 DEGs correlated with TBUT, 5/26 DEGs correlated with OSDI, and 16/26 correlated with conjunctival staining scores. Five upregulated DEGs (CFB, CFI, IL1R1, IL2RG, IL4R) were uniquely negatively correlated with TBUT. These data indicate that the conjunctiva of SS patients exhibits a phenotype of immune activation, although some genes could be inhibitory. Some of the DEGs and pathways overlap with previous DEGs in salivary gland biopsies, but new DEGs were identified, and some of these correlated with symptoms and signs of dry eye. Our results indicate that gene analysis of conjunctiva imprints is a powerful tool to understand the pathogenesis of SS and develop new therapeutic targets.

Protective effects of miR-155-5p silencing on IFN-γ-induced apoptosis and inflammation in salivary gland epithelial cells.

Previous studies have demonstrated that microRNAs (miRNAs/miRs) serve a vital role in the pathogenesis of Sjögren's syndrome (SS). The present study aimed to investigate the role of miR-155-5p in SS and determine its underlying molecular mechanism. An inflammatory lesion model was established by stimulating salivary gland epithelial cells (SGECs) with interferon-γ (IFN-γ). The apoptosis of SGECs was measured by using flow cytometry. Levels of proinflammatory factors were detected by reverse transcription-quantitative PCR and ELISA, respectively. Immunofluorescence was used for p65 staining. Dual-luciferase reporter assay was performed to verify the interaction between miR-155-5p and arrestin β2 (ARRB2). The protein levels in the NF-κB signaling pathway were assessed by western blotting. The results of the present study demonstrated that treatment with IFN-γ increased miR-155-5p expression, in addition to inducing apoptosis and inflammation in SGECs. Furthermore, overexpression of miR-155-5p promoted IFN-γ-induced apoptosis and inflammation in SGECs. Overexpression of miR-155-5p also increased Bax protein expression, enzyme activities of caspase 3 and caspase 9, release of inflammatory cytokines interleukin-6 and tumor necrosis factor-α, and decreased Bcl-2 protein expression in IFN-γ-treated SGECs. By contrast, all of the effects aforementioned were reversed following miR-155-5p knockdown. These results demonstrated that miR-155-5p activated the NF-κB signaling pathway, where treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate, reversed the effects of miR-155-5p overexpression on the inflammatory factors in IFN-γ-induced SGECs. miR-155-5p was demonstrated to target ARRB2 and negatively regulated its expression levels, such that overexpression of ARRB2 reversed the effects of miR-155-5p overexpression on the inflammatory response, apoptosis and the NF-κB signaling pathway in IFN-γ-treated SGECs. Collectively, results from the present study suggest that miR-155-5p may activate the NF-κB signaling pathway by negatively regulating ARRB2 to promote salivary gland damage during SS pathogenesis. This suggests that miR-155-5p may serve to be a potential target for the treatment of SS.

Intratracheal Poly(I:C) Exposure Accelerates the Immunological Disorder of Salivary Glands in Sjogren's-Like NOD/ShiLtJ Mice.

Evidences have suggested that Sjogren's syndrome (SS) is associated with viral infection. The aim of this study was to investigate the involvement of respiratory viral poly(I:C) in the pathogenesis of SS and potential mechanisms using a SS-like NOD/ShiLtJ (NOD) mouse model. 5-week female NOD mice were intratracheally administered poly(I:C) every other day for 5 times to mimic viral infection. Pilocarpine induced saliva secretion was determined every 8 days. Submandibular glands (SMG) and lungs were harvested for the detection of pathological changes. We found that intratracheal administration of poly(I:C) significantly advanced and enhanced the reduction of saliva flow rate in NOD mice. Furthermore, poly(I:C) treatment aggravated the histopathological lesions and inflammatory cells infiltration in SMG. Accompanied by elevated expression of IFN cytokines and IL-33, Th1 activation was enhanced in SMG of poly(I:C)-treated NOD mice, but Th17 cells activation was unchanged among the groups. In addition, intratracheal poly(I:C) exposure promoted the expression of IL-33 and increased T cells proportion in the lung, which were consistent with the change in SMG. Therefore, intratracheal poly(I:C) exposure aggravated the immunological and function disorder of SMG in NOD mice.

Pathology of salivary gland dysfunction and restoration of function.

In this review, the author shows that simultaneous multiple disorders caused by reactivation of Epstein-Barr virus can lead to salivary gland disorders as part of Sjogren's syndrome (SS). Therefore, clinicians must differentiate SS from other diseases when diagnosing and treating salivary gland disorders. In particular, the author explains how microbial infection in SS overcomes immunological tolerance, leading to pathological changes, and how cytokine overexpression and endocrine disrupters contribute to glandular tissue injury. Also, the author suggests that involvement of reactive oxygen species is a common pathogenesis of salivary gland disorders and SS, so regulation of oxidative stress is an effective treatment for both. The results of clinical studies on restoring salivary gland function and regenerating salivary glands with tissue stem cells may provide clues on elucidating the cause of SS.

Periodontal conditions in patients with Sjögren's syndrome: A meta-analysis

Sjögren's syndrome (SS) is a chronic autoimmune rheumatic disease characterized by a progressive lymphocytic infiltration of salivary glands, resulting in xerostomia and other oral diseases. The pathogenesis and mechanisms of SS on periodontal tissues are not well understood. Furthermore, results of two systemic reviews and meta-analyses in which compared periodontal parameters of patients with SS to healthy subjects were different. To determine whether periodontal conditions in SS were different from healthy controls, we re-examined the issue with a random-effect model, avoiding recruiting active controls and inadequate data conversion. Outcome measures included probing pocket depth (PPD), clinical attachment loss (CAL), plaque index (PI), and gingival index (GI). Recruited individuals comprised 198 patients with SS and 180 subjects for healthy controls. Quantitative analysis revealed higher PI (WMD = 0.76, 95% CI: 0.30, 1.23) and GI (WMD of total = 0.50, 95% CI: 0.01, 0.98) in SS patients who were not categorized into primary or secondary types of SS. PPD and CAL in SS patients was comparable with control subjects. However, heterogeneity was observed among included studies. Thus, results from this and previous analyses should be interpretated carefully, and a well-designed observational study regarding this issue should be conducted.

Treatment of Sjogren's Syndrome with Liver Depression

Liu Chunying is a famous old Chinese medicine doctor for more than 30 years. He has rich experience in the understanding and treatment of Sjogren's syndrome (SS). Liu Shi systematically discusses the etiology and pathogenesis of SS from the angle of liver depression. In the treatment, it is emphasized that "Muyu Da Zhi" is the first, with the addition and subtraction of the disease, to provide a new idea for the treatment of Sjogren's syndrome from liver depression, and to attach a test case.