IP3R deficit underlies loss of salivary fluid secretion in Sjogren's Syndrome.
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ABSTRACT:
SUBMITTER: Teos LY
PROVIDER: S-EPMC4568516 | biostudies-literature | 2015 Sep
REPOSITORIES: biostudies-literature
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IP3R deficit underlies loss of salivary fluid secretion in Sjögren's Syndrome.
Teos Leyla Y LY Zhang Yu Y Cotrim Ana P AP Swaim William W Won Jon H JH Ambrus Julian J Shen Long L Bebris Lolita L Grisius Margaret M Jang Shyh-Ing SI Yule David I DI Ambudkar Indu S IS Alevizos Ilias I
Scientific reports 20150914
The autoimmune exocrinopathy, Sjögren's syndrome (SS), is associated with secretory defects in patients, including individuals with mild lymphocytic infiltration and minimal glandular damage. The mechanism(s) underlying the secretory dysfunction is not known. We have used minor salivary gland biopsies from SS patients and healthy individuals to assess acinar cell function in morphologically intact glandular areas. We report that agonist-regulated intracellular Ca(2+) release, critically required ...[more]
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Project description:Not available
2009-04-02 | PRD000796 | Pride
Project description:Sjögren’s syndrome (SS) is a systemic autoimmune disease with a variety of presenting symptoms that may delay its diagnosis. We previously discovered a number of candidate salivary biomarkers for primary SS using both mass spectrometry and expression microarray analysis. In the current study, we aimed to verify these candidate biomarkers in independent patient populations and to evaluate their predictive values for primary SS detection.In total, 34 patients with primary SS, 34 patients with systemic lupus erythematosus (SLE), and 34 healthy individuals were enrolled for the validation studies. Salivary protein biomarkers were measured using either Western blotting or enzyme-linked immunosorbent assay, and the messenger RNA (mRNA) biomarkers were measured using quantitative polymerase chain reaction. Statistical analysis was performed using R software, version 2.9.Three protein biomarkers (cathepsin D [CPD], ?-enolase, and ß?-microglobulin [ß?m]) and 3 mRNA biomarkers (myeloid cell nuclear differentiation antigen [MNDA], guanylate binding protein 2 [GBP-2], and low-affinity IIIb receptor for the Fc fragment of IgG) were significantly elevated in patients with primary SS compared with both SLE patients and healthy controls. The combination of 3 protein biomarkers, CPD, ?-enolase, and ß?m, yielded a receiver operating characteristic (ROC) value of 0.99 in distinguishing primary SS from healthy controls. The combination of protein biomarkers ß?m and 2 mRNA biomarkers, MNDA and GBP-2, reached an ROC of 0.95 in discriminating primary SS from SLE.We have successfully verified a panel of protein and mRNA biomarkers that can discriminate primary SS from both SLE and healthy controls. If further validated in patients with primary SS and those with sicca symptoms but no autoimmune disease, these biomarkers may lead to a simple yet highly discriminatory clinical tool for diagnosis of primary SS.
| S-EPMC2995446 | biostudies-literature
Project description:To identify a panel of protein and messenger RNA (mRNA) biomarkers in human whole saliva (WS) that may be used in the detection of primary Sjögren's syndrome (SS).Mass spectrometry and expression microarray profiling were used to identify candidate protein and mRNA biomarkers of primary SS in WS samples. Validation of the discovered mRNA and protein biomarkers was also demonstrated using real-time quantitative polymerase chain reaction and immunoblotting techniques.Sixteen WS proteins were found to be down-regulated and 25 WS proteins were found to be up-regulated in primary SS patients compared with matched healthy control subjects. These proteins reflected the damage of glandular cells and inflammation of the oral cavity system in patients with primary SS. In addition, 16 WS peptides (10 up-regulated and 6 down-regulated in primary SS) were found at significantly different levels (P < 0.05) in primary SS patients and controls. Using stringent criteria (3-fold change; P < 0.0005), 27 mRNA in saliva samples were found to be significantly up-regulated in the primary SS patients. Strikingly, 19 of 27 genes that were found to be overexpressed were interferon-inducible or were related to lymphocyte filtration and antigen presentation known to be involved in the pathogenesis of primary SS.Our preliminary study has indicated that WS from patients with primary SS contains molecular signatures that reflect damaged glandular cells and an activated immune response in this autoimmune disease. These candidate proteomic and genomic biomarkers may improve the clinical detection of primary SS once they have been further validated. We also found that WS contains more informative proteins, peptides, and mRNA, as compared with gland-specific saliva, that can be used in generating candidate biomarkers for the detection of primary SS.
| S-EPMC2856841 | biostudies-literature
Project description:ObjectiveSjögren's syndrome (SS) is a complex multisystem autoimmune disease that results in progressive destruction of the exocrine glands. The purpose of this study was to characterize epigenetic changes in affected gland tissue and describe the relationship of these changes to known inflammatory processes.MethodsA genome-wide DNA methylation study was performed on human labial salivary gland (LSG) biopsy samples obtained from 28 female members of the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry. Gland tissue was methylotyped using the Illumina HumanMethylation450 BeadChip platform, followed by rigorous probe-filtering and data-normalization procedures.ResultsA genome-wide case-control study of 26 of the 28 subjects revealed 7,820 differentially methylated positions (DMPs) associated with disease status, including 5,699 hypomethylated and 2,121 hypermethylated DMPs. Further analysis identified 57 genes that were enriched for DMPs in their respective promoters; many are involved in immune response, including 2 previously established SS genetic risk loci. Bioinformatics analysis highlighted an extended region of hypomethylation surrounding PSMB8 and TAP1, consistent with an increased frequency of antigen-presenting cells in LSG tissue from the SS cases. Transcription factor motif enrichment analysis revealed the specific nature of the genome-wide methylation differences, demonstrating colocalization of SS-associated DMPs with stress- and immune response-related motifs.ConclusionOur findings underscore the utility of CpG methylotyping as an independent probe of active disease processes in SS, offering unique insights into the composition of disease-relevant tissue. Methylation profiling implicated several genes and pathways previously thought to be involved in disease-related processes, as well as a number of new candidates.
| S-EPMC5132022 | biostudies-literature
Project description:We aimed to evaluate the changes over time in salivary gland (SG) abnormalities by ultrasound (US) in patients with primary Sjögren's syndrome (pSS). Patients with pSS (n = 70) and idiopathic sicca syndrome (n = 18) underwent baseline salivary gland ultrasound (SGUS) scans, and follow-up scans two years later. The semi-quantitative SGUS score (0-48) and intraglandular power Doppler signal (PDS) were assessed. We found that in the pSS group, the SGUS scores for total SGs and bilateral parotid glands significantly increased after the median 23.4-months follow-up. SGUS scores either worsened, improved, or were stable in 18.6%, 2.9%, and 78.6% of patients with pSS, respectively. The median changes from baseline in SGUS scores for total and parotid glands were +1.0 and +0.5, respectively. None of the SGUS scores changed significantly in the controls. The variables of homogeneity and hypoechoic showed a statistically significant progression of SGUS scores. In pSS patients, the baseline and follow-up PDS scores were significantly higher in the "worsening" group than in the "no change/improvement" group. Overall, the structural abnormalities in major SGs assessed using SGUS remained stable in patients with pSS. At the 2-year follow-up, SGUS scores worsened in 18.6% of patients with pSS. Intra-glandular hypervascularity was associated with the worsening of SG abnormalities.
| S-EPMC7141294 | biostudies-literature
Project description:Key events in the pathogenesis of Sjӧgren syndrome (SS) include the change of salivary gland epithelial cells into antigen-presenting cell-like phenotypes and focal lymphocytic sialadenitis (FLS). However, what triggers these features in SS is unknown. Dysbiosis of the gut and oral microbiomes is a potential environmental factor in SS, but its connection to the etiopathogenesis of SS remains unclear. This study aimed to characterize the oral microbiota in SS and to investigate its potential role in the pathogenesis of SS. Oral bacterial communities were collected by whole mouthwash from control subjects (14 without oral dryness and 11 with dryness) and primary SS patients (8 without oral dryness and 17 with dryness) and were analyzed by pyrosequencing. The SS oral microbiota was characterized by an increased bacterial load and Shannon diversity. Through comparisons of control and SS in combined samples and then separately in non-dry and dry conditions, SS-associated taxa independent of dryness were identified. Three SS-associated species and 2 control species were selected and used to challenge human submandibular gland tumor (HSG) cells. Among the selected SS-associated bacterial species, Prevotella melaninogenica uniquely upregulated the expression of MHC molecules, CD80, and IFNλ in HSG cells. Concomitantly, P. melaninogenica efficiently invaded HSG cells. Sections of labial salivary gland (LSG) biopsies from 8 non-SS subjects and 15 SS patients were subjected to in situ hybridization using universal and P. melaninogenica-specific probes. Ductal cells and the areas of infiltration were heavily infected with bacteria in the LSGs with FLS. Collectively, dysbiotic oral microbiota may initiate the deregulation of SGECs and the IFN signature through bacterial invasion into ductal cells. These findings may provide new insights into the etiopathogenesis of SS.
| S-EPMC7092996 | biostudies-literature
Project description:ObjectiveA major characteristic of the autoimmune disease primary Sjögren's syndrome (SS) is salivary gland (SG) hypofunction. The inability of resident SG stem cells (SGSCs) to maintain homeostasis and saliva production has never been explained and limits our comprehension of mechanisms underlying primary SS. The present study was undertaken to investigate the role of salivary gland stem cells in hyposalivation in primary SS.MethodsSGSCs were isolated from parotid biopsy samples from controls and patients classified as having primary SS or incomplete primary SS, according to the American College of Rheumatology/European League Against Rheumatism criteria. Self-renewal and differentiation assays were used to determine SGSC regenerative potential, RNA was extracted for sequencing analysis, single telomere length analysis was conducted to determine telomere length, and frozen tissue samples were used for immunohistochemical analysis.ResultsSGSCs isolated from primary SS parotid gland biopsy samples were regeneratively inferior to healthy control specimens. We demonstrated that SGSCs from samples from patients with primary SS are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNA sequencing, and immunostaining. We further found that SGSCs exposed to primary SS-associated proinflammatory cytokines we induced to proliferate, express senescence-associated genes, and subsequently differentiate into intercalated duct cells. We also localized p16+ senescent cells to the intercalated ducts in primary SS SG tissue, suggesting a block in SGSC differentiation into acinar cells.ConclusionThis study represents the first characterization of SGSCs in primary SS, and also the first demonstration of a linkage between an autoimmune disease and a parenchymal premature-aging phenotype. The knowledge garnered in this study indicates that disease-modifying antirheumatic drugs used to treat primary SS are not likely to restore saliva production, and should be supplemented with fresh SGSCs to recover saliva production.
| S-EPMC6607019 | biostudies-literature
Project description:BACKGROUND:Gross cystic disease fluid protein-15(GCDFP-15)/prolactin-inducible protein (PIP) is a secretory acinar glycoprotein of 14 KDa which we have recently described as significantly lower in salivary samples of patients with primary Sjögren's syndrome (pSS) in comparison to healthy volunteers by proteomic analysis. AIMS OF THE STUDY:(1) to validate our previous data on the decrease of GCDFP-15/PIP protein in a larger number of subjects with pSS (2) to integrate the proteomic results with complementary immunoassays in order better clarify the pathophysiological relevance of GCDFP-15/PIP in pSS exocrinopathy (3) to assess both the glandular expression of the GCDFP-15/PIP and the levels of glandular GCDFP-15/PIP mRNA in the patients' minor salivary gland (MSG) biopsies in order to verify whether the observed reduction of GCDFP-15/PIP in saliva may be related to a decrease in the protein production. PATIENTS AND METHODS:A total of 123 salivary samples from patients affected by pSS, no-SS sicca syndrome and sex- age-matched healthy volunteers were analyzed by different proteomic techniques (SELDI-TOF-MS, 2DE, MALDI-TOF-MS). The expression of GCDFP-15/PIP was then validated by western blot analysis. Real Time PCR and immunohistochemistry for GCDFP-15/PIP in the minor salivary glands (MSG) biopsies were then carried out. RESULTS:By using complementary proteomic analysis we found that a putative peak of 16547 m/z was among the best independent biomarkers for pSS able to discriminate between patients and healthy controls with a sensitivity of 96 % and a specificity of 70%, with a global cross validated error of 29%. We identified the peak as the GCDFP-15/PIP protein and verified that the intensity of GCDFP-15/PIP was significantly lower in pSS patients when compared to both no-SS sicca subjects and healthy controls (p<0.0001). GCDFP-15/PIP expression also correlated with both the salivary flow rate (r=0.312, p=0.023) and MSG biopsies focus score (r=-0.377, p=0.04). Finally, immunohistochemistry confirmed that GCDFP-15/PIP staining was faint in mucus acini and Real Time PCR showed that GCDFP-15/PIP mRNA was significantly lower in pSS patients when compared to both no-SS sicca subjects and healthy controls (p=0.023) thus supporting the hypothesis that the observed reduction of GCDFP-15/PIP in pSS saliva may be related to a decrease in the protein production. CONCLUSION:In this study by different complementary-omic techniques we confirmed the potential role of GCDFP-15/PIP as a novel biomarker for pSS. This finding might also be functionally important as GCDFP-15/PIP has previously been shown to bind to Aquaporin 5 (AQP5), a salivary gland water channel, critical to saliva formation that is known to be downregulated in pSS. It is likely that exploring the GCDFP-15/PIP/AQP5 axis will help better understand the mechanism of salivary gland dysfunction in pSS.
| S-EPMC3884953 | biostudies-literature
Project description:Sjögren's syndrome (SjS) is a chronic autoimmune epithelitis in which cell apoptosis promotes the formation of inflammatory lesions. We used immunohistochemistry and TUNEL to assay B cell infiltration and apoptosis in salivary gland tissue from 16-week-old NOD/LtJ mice with SjS. In co-cultures of primary salivary glandepithelial cells (SGECs) and spleen B cells, we assessed SGEC viability and apoptosis using CCK8 assays and flow cytometry. ELISAs were employed to assess cytokine levels in culture medium. Leptin protein, leptin receptor (OB-R), pro- and anti-apoptotic proteins, and Jak2/Stat3/ERK signaling molecules were analyzed using western blotting. B cell infiltration and salivary gland apoptosis were increased in salivary tissue from mice with SjS. Leptin treatment had no effect on cell viability or apoptosis among B cells and primary SGECs. B cell and SGEC co-culture systems showed that leptin increased apoptosis induced by B lymphocytes, reduced SGEC cell viability, and promoted IL-4 secretion from B cells. This suggests Leptin/OB-R signaling stimulates B cells-induced SGEC apoptosis via IL-4 secretion and OB-R-Jak2-Stat3 activation.
| S-EPMC5609933 | biostudies-literature
Project description:BackgroundActivated T and B cells participate in the development and progression of Sjögren's syndrome (SS). Metformin, a first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS.MethodsMetformin or vehicle was administered orally to the mice for 9?weeks. The salivary flow rate was measured at 11, 13, 15, 17, and 20?weeks. Histological analysis of the salivary glands from vehicle- and metformin-treated mice was conducted. CD4+ T and B cell differentiation in the peripheral blood and/or spleen was determined by flow cytometry. Serum total IgG, IgG1, and IgG2a levels were determined by enzyme-linked immunosorbent assay.ResultsMetformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-?, IL-17 mRNA, and protein levels in the salivary glands. Metformin reduced the Th17 and Th1 cell populations and increased the regulatory T cell population in the peripheral blood and spleen and modulated the balance between Tfh and follicular regulatory T cells. In addition, metformin reduced B cell differentiation into germinal center B cells, decreased the serum immunoglobulin G level, and maintained the balance between IL-10- and IL-17-producing B cells.ConclusionMetformin suppresses effector T cells, induces regulatory T cells, and regulates B cell differentiation in an animal model of SS. In addition, metformin ameliorates salivary gland inflammation and hypofunction, suggesting that it has potential for the treatment of SS.
| S-EPMC6549273 | biostudies-literature