Project description:The IFN type I signature is present in over half of primary Sjögren’s syndrome (pSS) patients and associated with higher disease-activity and autoantibody presence. Plasmacytoid dendritic cells (pDCs) are considered to be the source of enhanced IFN type I expression. The objective of this study was to unravel the molecular pathways underlying IFN type I bioactivity in pDCs of pSS patients. We used microarray gene expression analysis to detail the programme of gene expression underlying IFN type I bioactivity in pDCs of primary Sjogrens' Syndrome patients.
Project description:Objective. A variety of chemokines contribute the pathogenesis of Sjögren’s syndrome (SS). However, the comprehensive analysis as for clinically potent ckemokines in SS has not been performed. In this study, focusing on CXC chemokines, we investigated the precise molecular mechanism and the clinical significance through chemokine and its receptor in the autoimmune lesions of primary SS. Methods. Gene expression profiles in the lip salivary glands (LSGs) from pSS patients and controls were analyzed using DNA microarray. Expression of chemokines and their receptor of biopsy samples of pSS pathients and controls were detected by immunofluorescence analysis. In addition, in vitro experiments using human salivary gland ductal and acinar cell lines were performed to analyze the expression of chemokines and signaling pathwaycytokines by qRT-PCR, ELISA, and Western blot analysis. Results. Gene expression profiles and immunohistochemical analysis revealed that IFN-γ-induced CXCL9 and CXCL10 were significantly increased in LSGs of pSS patients. In vitro experiments revealed that the protein expression of CXCL10 in ductal and acinar cells was differentially regulated by IFN-γ or TNF-α via NF-κB or JAK/STAT pathway. Moreover, CXCR3 expression was detected mainly in CD68+ macrophages, CD123+ plasmacytoid dendritic cells (pDCs), and in a few CD3+ T cells. Finally, Spearman's rank analysis revealed a negative correlation between the existence of CXCR3+ cells and pathological grading in LSG tissues of pSS patients (r: -0.019, p<0.01). Conclusion. These results suggest that CXCL10/CXCR3 axis plays in a key role in autoimmune response by interaction between immune cells and target cells in the pathogenesis of pSS.
Project description:Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease with complex etiopathogenesis. Here we use Affymetrix U133 plus 2.0 microarray gene expression data from human parotid tissue. Parotid gland tissues were harvested from 17 pSS and 14 14 non-pSS sicca patients and 18 controls. The data were used in the following article: Nazmul-Hossain ANM, Pollard RPE, Kroese FGM, Vissink A, Kallenberg CGM, Spijkervet FKL, Bootsma H, Michie SA, Gorr SU, Peck AB, Cai C, Zhou H, Horvath S, Wong DTW (2012) Systems Analysis of Primary Sjögren’s Syndrome Pathogenesis in Salivary Glands: Comparative Pathways and Molecular Events in Humans and a Mouse Model. Parotid gland tissues were harvested from 17 pSS and 14 non-pSS sicca patients and 18 controls.
Project description:To study the difference of gene expression profile in minor salivary glands of female patients with primary Sjögren’s syndrome (pSS) and healthy volunteers
Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. Conventional dendritic cells (cDCs)-2 play a critical role in T and B cell activation, leading to germinal centre formation and autoantibody production. To understand the mechanisms underlying cDC2 dysregulation in pSS we performed RNA-sequencing analysis and functional validation on circulating cDC2s from pSS, non-Sjögren’s sicca (nSS) patients and healthy controls (HC). Two independent cohorts were established to identify reproducible dysregulated signatures, which included the interferon (IFN), toll-like receptors (TLR) signaling and antigen processing and presentation pathways. We confirm by flow cytometry that pSS-cDC2s were less efficient to degrade BSA but more efficient to uptake BSA both linked with the presence of anti-SSA antibodies. As the majority of the SSA+ pSS patients exhibit an IFN-signature, we tested whether IFNα priming would influence cDC2s antigen-uptake and processing. IFNα priming increased cDC2s uptake capacity, but not antigen processing. Additionally, pSS-cDC2s showed an increased uptake capacity of apoptotic salivary gland epithelial cells. Finally, pSS-cDC2s increased the proliferation of HC CD4+ T cells and the expression of CXCR3 and CXCR5 on the proliferating HC CD4+ T cells, contributing to T cell migration into the inflamed salivary glands. Here we provide the first in-depth molecular characterization of pSS-cDC2s and show that the transcriptomic and functional alterations observed in pSS-cDC2s are linked to IFN-signature. In view of its role in pSS immunopathology, delineating the molecular networks that drive cDC2s holds promise for targeting these cells in pSS.
Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by infiltration of the exocrine glands and prominent B cell hyperactivity. Considering the key role of monocytes in promoting B cell hyperactivity, we performed RNA-sequencing analysis of CD14+ monocytes from patients with pSS, non-Sjögren’s sicca (nSS), and healthy controls (HC). We demonstrated that the transcriptomic profile of pSS patients is enriched in intermediate and non-classical monocyte profiles, and confirmed the increased frequency of non-classical monocytes in pSS patients by flow-cytometry analysis. Weighted gene co-expression network analysis identified four molecular signatures in monocytes from pSS patients, functionally annotated for processes related with translation, IFN-signaling, and toll like receptor signaling. Systemic and local inflammatory features significantly correlated with the expression of these signatures. Furthermore, genes highly associated with clinical features in pSS were identified as hub-genes for each signature. Unsupervised hierarchical cluster analysis of the hub-genes identified four clusters of nSS and pSS patients, each with distinct inflammatory and transcriptomic profiles. One cluster showed a significantly higher percentage of pSS patients with higher prevalence of anti-SSA autoantibodies, interferon score, and erythrocyte sedimentation rate compared to the other clusters. Finally, we showed that the identified transcriptomic differences in pSS monocytes were induced in monocytes of healthy controls by exposure to serum of pSS patients. Representative hub-genes of all four signatures were partially inhibited by interferon-a/b receptor blockade, indicating that the circulating inflammatory mediators, including type I interferons have a significant contribution to the altered transcriptional profile of pSS-monocytes. Our study suggests that targeting key circulating inflammatory mediators, such as type I interferons, could offer new insights into the important pathways and mechanisms driving pSS, and holds promise for halting immunopathology in Sjögren’s Syndrome.
Project description:Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease with complex etiopathogenesis. Here we use Affymetrix U133 plus 2.0 microarray gene expression data from human parotid tissue. Parotid gland tissues were harvested from 17 pSS and 14 14 non-pSS sicca patients and 18 controls. The data were used in the following article: Nazmul-Hossain ANM, Pollard RPE, Kroese FGM, Vissink A, Kallenberg CGM, Spijkervet FKL, Bootsma H, Michie SA, Gorr SU, Peck AB, Cai C, Zhou H, Horvath S, Wong DTW (2012) Systems Analysis of Primary Sjögren’s Syndrome Pathogenesis in Salivary Glands: Comparative Pathways and Molecular Events in Humans and a Mouse Model.
Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and prominent B cell hyperactivity. B cells are crucial in the pathophysiology of pSS through several mechanisms, including cytokine production, exocrine gland destruction, and autoantibody secretion. Considering the central role of B cells we performed RNA-sequencing analysis of circulating CD19+ B cells from patients with pSS, non-Sjögren’s sicca (nSS), and healthy controls (HC).
Project description:To reveal the role of DNA methylation in peripheral monocytes (Mo) of primary Sjögren’s syndrome (pSS) patients, monocyte DNAs from 11 pSS patients and 5 matched controls were analyzed by methylation microarray. In total, we identified 1977 hypomethylated and 842 hypermethylated differentially methylated positions (DMPs) in Mo from pSS patients compared to healthy controls.
