Intratracheal Poly(I:C) Exposure Accelerates the Immunological Disorder of Salivary Glands in Sjogren's-Like NOD/ShiLtJ Mice.
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SUBMITTER: Hu P
PROVIDER: S-EPMC8076562 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundBone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment.MethodsWhole BM cells were lysed and soluble intracellular contents ("BM Soup") were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice.Results bm souprestored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice.ConclusionBM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment.
| S-EPMC3906116 | 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:The C57BL/6.NOD-Aec1Aec2 mouse is considered a highly appropriate model of Sjögren's Syndrome (SS), a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the development and onset of observed clinical manifestations. More recently, studies carried out in the C57BL/6.IL14α transgenic mouse have indicated that the marginal zone B (MZB) cell population is responsible for development of SS disease, reflecting recent observations that MZB cells are present in the salivary glands of SS patients and most likely initiate the subsequent loss of exocrine functions. Although MZB cells are difficult to study in vivo and in vitro, we have carried out an ex vivo investigation that uses temporal global RNA transcriptomic analyses to profile differentially expressed genes known to be associated with cell migration. Results indicate a temporal upregulation of specific chemokine, chemokine receptor, and Rho-GTPase genes in the salivary glands of C57BL/6.NOD-Aec1Aec2 mice that correlate with the early appearance of periductal lymphocyte infiltrations. Using the power of transcriptomic analyses to better define the genetic profile of lymphocytic emigration into the salivary glands of SS mice, new insights into the underlying mechanisms of SS disease development and onset begin to come into focus, thereby establishing a foundation for further in-depth and novel investigations of the covert and early overt phases of SS disease at the cellular level.
| S-EPMC8267620 | biostudies-literature
Project description:Angiogenesis has been proposed to play a role in the inflammation observed in Sjögren's Syndrome (SS). However, no studies have validated the degree of angiogenesis in salivary glands with SS. Therefore, the goal of this study was to determine the presence and localization of angiogenesis and lymphangiogenesis in salivary glands with SS. We used frozen tissue sections from human minor salivary glands (hMSG) with and without SS in our analyses. To investigate signs of angiogenesis, hMSG tissue lysates were used to detect levels of the pro-angiogenic protein vascular endothelial growth factor (VEGF) by western blot analyses. Additionally, we labeled blood vessels using antibodies specific to platelet endothelial cell adhesion molecule-1 (PECAM-1) and von Willebrand Factor (vWF) to determine blood vessel organization and volume fraction using fluorescence microscopy. Lymphatic vessel organization and volume fraction were determined using antibodies specific to lymphatic vessel endothelial hyaluronan receptor (LYVE-1). Our results suggest that expression levels of VEGF are decreased in hMSG with SS as compared with controls. Interestingly, there were no significant differences in blood or lymphatic vessel organization or volume fraction between hMSG with and without SS, suggesting that angiogenesis and lymphangiogenesis have little impact on the progression of SS.
| S-EPMC4409942 | biostudies-literature
Project description:Recent studies have demonstrated that the oral microbiome in patients with Sjögren's syndrome (SS) is significantly different from that in healthy individuals. However, the potential role of the oral microbiome in SS pathogenesis has not been determined. In this study, stimulated intraductal saliva samples were collected from the parotid glands (PGs) of 23 SS and nine non-SS subjects through PG lavage and subjected to 16S ribosomal RNA amplicon sequencing. The correlation between the oral microbiome and clinical features, such as biological markers, clinical manifestations, and functional and radiological characteristics was investigated. The salivary microbial composition was examined using bioinformatic analysis to identify potential diagnostic biomarkers for SS. Oral microbial composition was significantly different between the anti-SSA-positive and SSA-negative groups. The microbial diversity in SS subjects was lower than that in non-SS sicca subjects. Furthermore, SS subjects with sialectasis exhibited decreased microbial diversity and Firmicutes abundance. The abundance of Bacteroidetes was positively correlated with the salivary flow rate. Bioinformatics analysis revealed several potential microbial biomarkers for SS at the genus level, such as decreased Lactobacillus abundance or increased Streptococcus abundance. These results suggest that microbiota composition is correlated with the clinical features of SS, especially the ductal structures and salivary flow, and that the oral microbiome is a potential diagnostic biomarker for SS.
| S-EPMC9114876 | biostudies-literature
Project description:PurposeTo investigate salivary gland ultrasonography (SGUS) findings in primary Sjögren's syndrome (pSS) patients positive for the anti-centromere antibody (ACA) and compare these with those in ACA-negative pSS patients.MethodsWe analyzed demographic, clinical, laboratory, and SGUS data of pSS patients who fulfilled the 2002 American-European Consensus Group classification criteria for pSS. SGUS findings of four major salivary glands (bilateral parotid and submandibular glands) were scored in five categories and compared between ACA-positive and ACA-negative pSS patients. Linear regression analysis was performed to elucidate the factors associated with SGUS score.ResultsIn total, 121 pSS patients were enrolled (19, ACA-positive). The ACA-positive patients were older (67.0 vs 58.0 years, P = 0.028), whereas anti-Ro/SSA and anti-La/SSB positivity was more prevalent in the ACA-negative group (89.2% vs 21.1%, P < 0.001, and 47.1% vs 10.5%, P = 0.007, respectively). The total SGUS and hypoechoic area scores were lower in ACA-positive patients (16.0 vs 23.0, P = 0.027, and 4.0 vs 7.0, P = 0.004, respectively). In univariate regression analysis, being positive for unstimulated salivary flow rate (USFR < 1.5 ml/15 min), anti-Ro/SSA, and rheumatoid factor were positively associated whereas ACA positivity was negatively associated with the SGUS score. In multivariate regression analysis, being positive for USFR, anti-Ro/SSA, and rheumatoid factor showed significant association with the SGUS score.ConclusionsACA-positive pSS patients showed a lower SGUS score than ACA-negative patients, which was especially prominent in the hypoechoic area component.
| S-EPMC8565722 | biostudies-literature
Project description: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.
| S-EPMC7821166 | biostudies-literature
Project description:A generally accepted hypothesis for the initial activation of an immune or autoimmune response argues that alarmins are released from injured, dying and/or activated immune cells, and these products complex with receptors that activate signal transduction pathways and recruit immune cells to the site of injury where the recruited cells are stimulated to initiate immune and/or cellular repair responses. While there are multiple diverse families of alarmins such as interleukins (IL), heat-shock proteins (HSP), Toll-like receptors (TLR), plus individual molecular entities such as Galectin-3, Calreticulin, Thymosin, alpha-Defensin-1, RAGE, and Interferon-1, one phylogenetically conserved family are the Annexin proteins known to promote an extensive range of biomolecular and cellular products that can directly and indirectly regulate inflammation and immune activities. For the present report, we examined the temporal expression profiles of the 12 mammalian annexin genes (Anxa1-11 and Anxa13), applying our temporal genome-wide transcriptome analyses of ex vivo salivary and lacrimal glands from our C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren's Syndrome (SS), a human autoimmune disease characterized primarily by severe dry mouth and dry eye symptoms. Results indicate that annexin genes Anax1-7 and -11 exhibited upregulated expressions and the initial timing for these upregulations occurred as early as 8 weeks of age and prior to any covert signs of a SS-like disease. While the profiles of the two glands were similar, they were not identical, suggesting the possibility that the SS-like disease may not be uniform in the two glands. Nevertheless, this early pre-clinical and concomitant upregulated expression of this specific set of alarmins within the immune-targeted organs represents a potential target for identifying the pre-clinical stage in human SS as well, a fact that would clearly impact future interventions and therapeutic strategies.
| S-EPMC9570365 | biostudies-literature
Project description:BackgroundLow-level, chronic viral infections have been suspect in the development of select autoimmune diseases, including primary Sjögren's syndrome (pSS). Multiple studies have shown stimulation of antiviral response pathways in pSS tissues suggestive of a viral infection. Yet, with this data in hand, a causal link between a viral infection and development of pSS had not been identified. Therefore, a study was designed to further define the viral landscape within pSS-affected salivary gland tissue to identify potential viral-mediated triggers in the pathogenesis of this autoimmune disease.MethodsA viral microarray was utilized to measure viral transcripts present in salivary gland tissue from patients diagnosed with pSS compared to healthy controls. Murine models of salivary gland localized HDV antigen expression were developed to evaluate the capacity of a chronic HDV signature to trigger the development of a pSS-like phenotype.ResultsThrough this analysis, two distinct viral profiles were identified, including the increased presence of hepatitis delta virus (HDV) in 50% of pSS patients evaluated. Presence of HDV antigen and sequence were confirmed in minor salivary gland tissue. Patients with elevated HDV levels in salivary gland tissue were negative for detectible hepatitis B virus (HBV) surface antigen and antibodies to HBV or HDV. Expression of HDV antigens in vivo resulted in reduced stimulated saliva flow, increase in focal lymphocytic infiltrates, and development of autoantibodies.ConclusionIdentification of HDV in pSS patients and induction of a complete pSS-like phenotype in vivo provides further support of a viral-mediated etiopathology in the development of pSS.
| S-EPMC4902173 | biostudies-literature