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Salivary proteomic and genomic biomarkers for primary Sjogren's syndrome.

ABSTRACT: 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.

SUBMITTER: Hu S

PROVIDER: S-EPMC2856841 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Salivary proteomic and genomic biomarkers for primary Sjögren's syndrome.

Hu Shen S Wang Jianghua J Meijer Jiska J Ieong Sonya S Xie Yongming Y Yu Tianwei T Zhou Hui H Henry Sharon S Vissink Arjan A Pijpe Justin J Kallenberg Cees C Elashoff David D Loo Joseph A JA Wong David T DT

Arthritis and rheumatism 20071101 11

<h4>Objective</h4>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).<h4>Methods</h4>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 techniq ...[more]

PMID: 17968930

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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.

Project description:Objectives The aim of this study was to investigate serum biomarkers linked to primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD). Methods 69 pSS patients were consecutively enrolled and evaluated via quantitative ILD scoring based on high-resolution computed tomography (HRCT). Biomarkers of interest were assessed by multiplex enzyme-linked immunosorbent assays (ELISAs). Results Among consecutively enrolled patients with pSS, the presence of pSS–ILD was 50% based on the presence of radiographically defined interstitial lung abnormalities (ILA) meeting specified criteria for mild/moderate (ILA 2) or severe (ILA 3) disease. Age, immunoglobulin M (IgM), C-reactive protein (CRP), and serum levels of eotaxin/CCL11, Krebs von den Lungen-6 (KL-6), TNFα, and TGFα were significantly higher in the combined pSS–ILD group (ILA 2 + ILA 3) than in the pSS–no-ILD and pSS–indeterminate ILD groups (ILA 0 and ILA 1, respectively) in unadjusted analyses (p < 0.05 for all variables). A binary logistic regression model revealed that disease duration and KL-6 levels were associated with the presence of pSS–ILD (p < 0.05). Complementary least absolute shrinkage and selection operator (LASSO) modeling showed that age, KL-6, and TNF-α effectively differentiated pSS–ILD (ILA 2 + ILA3) from pSS without ILD (ILA 0 + ILA 1), with an area under the curve (AUC) of 0.883 (p value < 0.0001). Conclusions Patient age, disease duration, and serum levels of both KL-6 and TNFα were the most discriminating factors associated with the presence of ILD in our pSS patients. Higher levels of CRP, IgM, eotaxin, TGFα, and TNFα should also prompt the search for occult as well as clinically evident lung involvement based on statistically significant univariate associations with pSS–ILD. Clinical trial registration None. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-022-00828-3.

Project description:IntroductionPrimary Sjögren's syndrome (pSS) is an autoimmune disease characterized by inflammatory infiltration, and dysfunction of the salivary and lacrimal glands. This research aimed to explore the disease pathogenesis and improve the diagnosis and treatment of pSS by mining inflammation-associated biomarkers.MethodsFive pSS-related datasets were retrieved from the Gene Expression Omnibus (GEO) database. Inflammation-associated biomarkers were determined by the least absolute shrinkage and selection operator (LASSO) and support vector machines recursive feature elimination (SVM-RFE). Single sample gene set enrichment analysis (ssGSEA) was implemented to profile the infiltration levels of immune cells. Real-time quantitative PCR (RT-qPCR) verified the expression of biomarkers in clinical samples.ResultsFour genes (LY6E, EIF2AK2, IL15, and CXCL10) were screened as inflammation-associated biomarkers in pSS, the predictive performance of which were determined among three pSS-related datasets (AUC > 0.7). Functional enrichment results suggested that the biomarkers were involved in immune and inflammation-related pathways. Immune infiltration analysis revealed that biomarkers were notably connected with type 2 T helper cells, regulatory T cells which were significantly expressed between pSS and control. TESTOSTERONE and CYCLOSPORINE were predicted to take effect by targeting CXCL10 and IL15 in pSS, respectively.ConclusionFour inflammation-associated biomarkers (LY6E, EIF2AK2, IL15, and CXCL10) were explored, and the underlying regulatory mechanisms and targeted drugs associated with these biomarkers were preliminarily investigated according to a series of bioinformatics methods based on the online datasets of pSS, which provided a reference for understanding the pathogenesis of pSS. Key Points • Inflammation-associated biomarkers (LY6E, EIF2AK2, IL15, and CXCL10) were firstly identified in Sjögren's syndrome based on LASSO and SVM-RFE analyses. • CXCL10, EIF2AK2 and LY6E were prominently positively correlated with immature B cells, while IL15 were significantly negatively correlated with memory B cells in Sjögren's syndrome. • LY6E, EIF2AK2, IL15, and CXCL10 were significantly more highly expressed in clinical Sjögren's syndrome samples compared to healthy control samples, which was consistent with the analysis results of the GEO database. •LY6E, EIF2AK2, IL15, and CXCL10 might be used as the biomarkers for the treatment and diagnosis of Sjögren's syndrome.

Project description:Objective: Salivary gland ultrasound (SGUS) is emerging as a valid tool in the management of primary Sjögren's syndrome (pSS). This study aimed to investigate whether pSS patients with normal-appearing or pathological SGUS findings showed different clinical, laboratory, and pathologic pSS-related features, and to compare the results by using two different SGUS scores. Methods: Consecutive pSS patients, according to the ACR-EULAR classification criteria, were evaluated. Salivary glands were scored using the early 1992 score by De Vita et al. and the latest 2019 OMERACT score, both being semiquantitative 0-3 scoring systems focused on ultrasonographic parenchymal inhomogeneity (grades 0 and 1, normal-appearing; grades 2 and 3, pathological). The patients were then divided into two groups: "SGUS normal-appearing" if all the salivary glands had normal-appearing parenchyma (grade 0 or 1), or "SGUS pathological" if the grade was 2 or 3 in at least one salivary gland. The associations between SGUS and pSS-related clinical, laboratory, and pathological features were then investigated in the two groups. Results: One hundred pSS patients were evaluated, the mean age (±SD) was 60.9 ± 12.0 years, and mean disease duration was 11.7 ± 7.2 years. Twenty-nine out of 100 (29%) patients were in the "SGUS normal-appearing" group and 71/100 (71%) were in the "SGUS pathological" group. A normal-appearing SGUS was significantly associated with the absence of anti-La/SSB antibodies (p < 0.001) and normal unstimulated salivary flow rate (p = 0.02) by both univariate and multivariate analyses. By univariate analysis, a normal-appearing SGUS was significantly associated also with the absence of rheumatoid factor (p = 0.002) and of serum monoclonal component (p = 0.003), ESSDAI < 5 (p = 0.03), and with a negative lip biopsy (p = 0.029). No associations were found with other items, including anti-Ro/SSA (p = 0.145), Schirmer's test (p = 0.793), ESSPRI (p = 0.47), and demographic data. No differences in these results were observed by using the two SGUS scoring systems. Conclusion: The SGUS allowed the identification of different phenotypes of pSS, and different SGUS scores focused on salivary gland inhomogeneity may be effective to this end.

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Salivary proteomic and genomic biomarkers for primary Sjogren's syndrome.

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Salivary proteomic and genomic biomarkers for primary Sjögren's syndrome.

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