Tlr9 expression protects against Tlr7-dependent exocrine gland and systemic disease manifestations in primary Sjögren’s disease in a sex-biased manner
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ABSTRACT:
PROVIDER: PRJNA1237810 | ENA |
REPOSITORIES: ENA
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Project description:Primary Sjogren’s disease (pSD) is a systemic autoimmune disease. Currently, the causes of pSD remain unknown, and no curative therapies are available. Prior studies by our group showed Tlr7 activation was an important driver of pSD in females. Since Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would exacerbate disease in a Tlr7-dependent manner. To this end, we generated pSD mice that lacked systemic expression of either Tlr9 (NOD.B10 Tlr9-/-) or both Tlr7 and Tlr9 (NOD.B10 Tlr-DKO). The objective of this study was to determine if Tlr9 mediated sex-biased disease and whether this was dependent on the expression of Tlr7.
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Project description:Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease characterized by typical autoantibody production and lymphocytic-mediated exocrine gland damage. Interstitial lung disease (ILD) is a common complication of pSS and can be associated with a poor prognosis. However, the pathogenesis of ILD in pSS is still unclear. In this study, we used RNA sequencing to investigate the gene-expression profile of the minor salivary glands (MSGs) from 36 patients with ILD-pSS and 128 patients with non-ILD-pSS. In the remarkably enriched chemokine-mediated signaling pathway, CXCR2 was found to be significantly elevated in both MSG and plasma from pSS patients with versus without ILD (p < 0.001). Furthermore, the CXCR2 expression level in MSG and plasma was significantly associated with the diffusing capacity of the lungs for carbon monoxide, erythrocyte sedimentation rate, and EULAR Sjögren’s Syndrome Disease Activity Index in ILD-pSS. Therefore, with its potential role in ILD progression in patients with pSS and its strong association with clinical manifestations of the disease, CXCR2 may serve as a useful index for disease activity in ILD associated with pSS.
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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).
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Project description:Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune disease characterized by exocrine glands damage and extraglandular manifestations. To identify potential biomarkers for the early diagnosis of pSS and further investigate the potential mechanisms in progression of the disease, we combined our previous RNA- sequencing study and four microarrays data to conduct integrative transcriptome analyses in salivary glands (SGs) between the pSS and non-pSS. Differential gene expression analysis, gene co-expression network analysis and pathway analysis were conducted to detect hub gene, which was subsequently validated in peripheral blood. Correlation analysis, single-gene Gene Set Enrichment Analysis (GSEA) and receiver operating characteristic (ROC) curve were applied to investigate the role of ICOS in pSS and its classification capacity for pSS.
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Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by chronic inflammation of exocrine tissue, resulting in loss of tears and saliva. Patients also experience many extra-glandular disease manifestations. Treatment for pSS is palliative, and there are currently no treatments available that target disease etiology. Previous studies in our lab demonstrated that Myd88 is crucial for pSS pathogenesis in the NOD.B10Sn-H2b (NOD.B10) pSS mouse model, although the way in which Myd88-dependent pathways become activated in disease remains unknown. Based on its importance in other autoimmune diseases, we hypothesized that TLR7 activation accelerates pSS pathogenesis. We administered the TLR7 agonist Imiquimod (Imq) or sham treatment to pre-disease NOD.B10 females for 6 weeks. Parallel experiments were performed in age and sex-matched C57BL/10 controls. Imq-treated pSS animals exhibited cervical lymphadenopathy, splenomegaly, and expansion of TLR7-expressing B cells. Robust lymphocytic infiltration of exocrine tissues, kidney and lung was observed in pSS mice following treatment with Imq. TLR7 agonism also induced salivary hypofunction in pSS mice, which is a hallmark of disease. Anti-nuclear autoantibodies, including Ro (SSA) and La (SSB) were increased in pSS mice following Imq administration. Cervical lymph nodes from Imq-treated NOD.B10 animals demonstrated an increase in the percentage of activated/memory CD4+ T cells. Finally, aged-associated B cells (ABCs) were expanded in the spleens of Imq-treated pSS mice. Thus, activation of TLR7 accelerates local and systemic disease and promotes expansion of the ABC subset in pSS.
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Project description:Sjögren’s disease (SjD) is a systemic autoimmune disorder primarily affecting the exocrine glands and characterized by dry mouth and dry eye, the presence of anti-SSA and/or anti-SSB autoantibodies in blood serum, and chronic lymphocytic infiltration of salivary and lacrimal glands (i.e., sialadenitis and dacryoadenitis, respectively). The interleukin-14α transgenic (IL-14αTG) mouse model of SjD recapitulates many aspects of human SjD, including progressive sialadenitis, loss of salivary gland function, and development of B cell lymphoma. We performed Visium V1 3' spatial transcriptomic analysis of fresh frozen submandibular and sublingual glands from a 12-month-old IL-14αTG Sjögren’s-like mouse and age-matched C57BL/6 control mouse.
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Project description:Sjögren’s disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis and decreased expression of membrane proteins involved in secretory function, such as Na-K-Cl cotransporter-1 (NKCC1), in salivary and lacrimal glands. Although the pathogenic mechanism triggering SjD is not well understood, overexpression of lysosome-associated membrane protein 3 (LAMP3) is associated with the disease in a subset of SjD patients and the development of SjD-like phenotype in mice. In this study, histological analysis of minor salivary glands of SjD patients suggested that LAMP3-containing material is being ejected from cells. Follow-on in vitro experiments with cells exposed to larger extracellular vesicles (LEVs) derived from LAMP3-overexpressing cells showed increased apoptosis and decreased NKCC1 expression. Proteomics identified LAMP3 as a major component of LEVs derived from LAMP3-overexpressing cells. Live-cell imaging visualized release and uptake of LAMP3-containing LEVs from LAMP3-overexpressing cells to naïve cells. Furthermore, experiments with recombinant LAMP3 protein alone or complexed with Xfect protein transfection reagent demonstrated that internalization of LAMP3 was required for apoptosis in a caspase-dependent pathway. Taken together, we identified a new role for extracellular LAMP3 in cell-to-cell communication via LEVs, which provides further support for targeting LAMP3 as a therapeutic approach in SjD.
2023-03-10 | PXD036774 | Pride
Project description:Primary Sjögren’s syndrome (SS or autoimmune epithelitis) is a relatively common autoimmune disorder that is primarily characterized by chronic lymphoepithelial inflammatory reactions in the exocrine glands, mainly the salivary and lachrymal glands. It may extend from disease confined to the exocrine glands (organ-specific exocrinopathy) to various extraglandular manifestations (systemic disease) and the development of B-cell lymphoma. Several studies from our laboratory had provided evidence for the strong implication of ductal salivary gland epithelial cells (SGEC) in the pathogenesis of Sjögren’s syndrome (SS), including the development of salivary gland infiltrating lesions and of adverse systemic clinical complications, such as the development of B-cell lymphoma. In fact, the comparative assessment of non-neoplastic SGEC lines derived from SS patients and disease controls had indicated that the ductal epithelia of SS patients manifest an “intrinsically activated” status that is associated with distinct aberrant phenotypic and functional features encountered in “inflamed” cells. Herein, using microarray analysis, we sought to comparatively analyze the constitutive gene expression in long-term cultured non-neoplastic SGEC lines derived from non-SS sicca control individuals and from SS patients. The study aimed to reveal the genes that are differentially expressed between SGEC lines derived from SS patients and controls, as well as between SGEC lines derived from SS patients with moderate lymphocytic infiltrations (focus score<2; SS-Group-1) and SS patients with severe lymphocytic infiltrations (focus score ≥2; SS-Group-2). The transcriptome profiling analysis presented herein lends further support to the intrinsic activation status of patients’ ductal epithelia and its association with distinct proinflammatory and metabolism-related gene signatures, which occur primarily among patients with heavy tissue infiltrates and high risk for lymphoma development.
2017-04-11 | GSE97614 | GEO
Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by reduced activity of the exocrine glands (principally the salivary and lacrimal glands) due to chronic lymphocytic infiltration. pSS has been closely associated with an enhanced risk of mucosa-associated lymphoid tissue (MALT) lymphoma. However, the dynamic epigenetic changes in gland cells accompanied with this pathogenesis are not fully understood. In present study, the labial gland (LG) and parotid gland (PG) tissues from two pSS patients with lymphoma were harvested including LG with negative antinuclear antibodies (ANA) and LG with positive ANA at the first diagnosis of pSS, as well as PG with and without lymphoma tissues at the second diagnosis of MALT. RNA-seq of these tissues were studied. This data is benefit to advanced understanding the dynamic development of MALT from pSS, emphasizing the importance of epigenetic alterations in regulating transcription during the pathologic process.
2021-04-17 | E-MTAB-10339 | biostudies-arrayexpress
Project description:Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by reduced activity of the exocrine glands (principally the salivary and lacrimal glands) due to chronic lymphocytic infiltration. pSS has been closely associated with an enhanced risk of mucosa-associated lymphoid tissue (MALT) lymphoma. However, the dynamic epigenetic changes in gland cells accompanied with this pathogenesis are not fully understood. In present study, the labial gland (LG) and parotid gland (PG) tissues from two pSS patients with lymphoma were harvested including LG with negative anti-SSA/SSB and LG with positive anti-SSA/SSB at the first diagnosis of pSS, as well as PG with and without lymphoma tissues at the second diagnosis of MALT. ChIP-seq of H3K4/9/27/36/79me3 were performed. This data is benefit to advanced understanding the dynamic development of MALT from pSS, emphasizing the importance of epigenetic alterations in regulating transcription during the pathologic process.
2021-04-17 | E-MTAB-10340 | biostudies-arrayexpress