Pathogenesis Of Sjögren's Syndrome Research Articles

Immune and non-immune mediators in the fibrosis pathogenesis of salivary gland in Sjögren's syndrome.

Sjögren's syndrome (SS) or Sjögren's disease (SjD) is a systemic autoimmune disease clinically manifested as sicca symptoms. This disease primarily impacts the functionality of exocrine glands, specifically the lacrimal and salivary glands (SG). SG fibrosis, an irreversible morphological change, is a severe consequence that occurs in the later stages of the disease due to sustained inflammation. However, the mechanism underlying SG fibrosis in SS remains under-investigated. Glandular fibrosis may arise from chronic sialadenitis, in which the interactions between infiltrating lymphocytes and epithelial cells potentially contributes to fibrotic pathogenesis. Thus, both immune and non-immune cells are closely involved in this process, while their interplays are not fully understood. The molecular mechanism of tissue fibrosis is partly associated with an imbalance of immune responses, in which the transforming growth factor-beta (TGF-β)-dependent epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling are recently investigated. In addition, viral infection has been implicated in the pathogenesis of SS. Viral-specific innate immune response could exacerbate the autoimmune progression, resulting in overt inflammation in SG. Notably, post-COVID patients exhibit typical SS symptoms and severe inflammatory sialadenitis, which are positively correlated with SG damage. In this review, we discuss the immune and non-immune risk factors in SG fibrosis and summarize the evidence to understand the mechanisms upon autoimmune progression in SS.

A Review of the Tear Film Biomarkers Used to Diagnose Sjogren's Syndrome.

This literature review looks at Sjogren's Syndrome (SS), a chronic autoimmune disorder affecting exocrine glands, particularly the lacrimal and salivary glands. SS manifests as ocular and oral dryness, with severe complications like visual dysfunction and corneal perforation, as well as systemic implications, such as interstitial lung disease and lymphoma. This review explores the use of tear film biomarkers to diagnose SS, emphasizing the significance of their identification in aiding clinical diagnosis and differentiation from other diseases. This study identified and analyzed 15 papers, encompassing 1142 patients and employing various tear sample collection methods. Tear biomarkers were categorized by function and explored in-depth. Categories include (1) antimicrobials, antivirals, and antifungals; (2) components of immune regulation; (3) components that regulate metabolic processes; and (4) inflammatory markers. Noteworthy findings include the potential diagnostic values of tear lysozyme, lactoferrin, dinucleoside polyphosphates, cathepsin, defensin, antibodies, epidermal fatty acid-binding protein, HLA-DR, ADAM10, aquaporin 5, and various miRNAs and mRNAs. Overall, our understanding of SS tear film composition is enhanced, providing valuable insights into the pathogenesis of SS and offering a foundation for future diagnostic and therapeutic advancements in autoimmune conditions affecting the ocular surface.

Subpopulation dynamics of T and B lymphocytes in Sjögren's syndrome: implications for disease activity and treatment.

Sjögren's syndrome (SS) is an autoimmune disorder primarily affecting the body's exocrine glands, particularly the salivary and lacrimal glands, which lead to severe symptoms of dry eyes and mouth. The pathogenesis of SS involves the production of autoantibodies by activated immune cells, and secretion of multiple cytokines, which collectively lead to tissue damage and functional impairment. In SS, the Immune interaction among T and B cells is particularly significant. Lymphocytic infiltration in the salivary glands is predominantly composed of CD4+ T cells, whose activation cause the death of glandular epithelial cells and subsequent tissue destruction. The excessive activity of T cells contributes significantly to the disease mechanism, with helper T cells (CD4+) differentiating into various subgroups including Th1/Th2, Th17, as well as Treg, each contributing to the pathological process through distinct cytokine secretion. In patients with SS, B cells are excessively activated, leading to substantial production of autoantibodies. These antibodies can attack self-tissues, especially the lacrimal and salivary glands, causing inflammation and tissue damage. Changes in B cell subpopulations in SS patients, such as increases in plasmablasts and plasma cells, correlate positively with serum autoantibody levels and disease progression. Therapies targeting T cells and B cells are extensively researched with the aim of alleviating symptoms and improving the quality of life for patients. Understanding how these cells promote disease development through various mechanisms, and further identifying novel T and B cell subgroups with functional characterization, will facilitate the development of more effective strategies to treat SS.

Reconstruction of Sjögren's syndrome-like sialadenitis by a defined disease specific gut-reactive single TCR and an autoantibody

Lymphocytes such as CD4+ T cells and B cells mainly infiltrate the salivary glands; however, the precise roles and targets of autoreactive T cells and autoantibodies in the pathogenesis of Sjögren's Syndrome (SS) remain unclear. This study was designed to clarify the role of autoreactive T cells and autoantibodies at the single-cell level involved in the development of sialadenitis. Infiltrated CD4+ T and B cells in the salivary glands of a mouse model resembling SS were single-cell-sorted, and their T cell receptor (TCR) and B cell receptor (BCR) sequences were analyzed. The predominant TCR and BCR clonotypes were reconstituted in vitro, and their pathogenicity was evaluated by transferring reconstituted TCR-expressing CD4+ T cells into Rag2−/− mice and administering recombinant IgG in vivo. The reconstitution of Th17 cells expressing TCR (#G) in Rag2−/− mice resulted in the infiltration of T cells into the salivary glands and development of sialadenitis, while an autoantibody (IgGr22) was observed to promote the proliferation of pathogenic T cells. IgGr22 specifically recognizes double-stranded RNA (dsRNA) and induces the activation of dendritic cells, thereby enhancing the expression of IFN signature and inflammatory genes. TCR#G recognizes antigens related to the gut microbiota. Antibiotic treatment severely reduces the activation of TCR#G-expressing Th17 cells and suppresses sialadenitis development. These data suggest that the anti-dsRNA antibodies and, TCR recognizing the gut microbiota involved in the development of sialadenitis like SS. Thus, our model provides a novel strategy for defining the roles of autoreactive TCR and autoantibodies in the development and pathogenesis of SS.

PANoptosis Features, a Humanized NSG Murine Model of Sjogren's Syndrome.

Sjogren's syndrome (SS) is a complex systemic autoimmune disease. This study aims to elucidate a humanized NOD-PrkdcscidIl2rgem1/Smoc (NSG) murine model to better clarify the pathogenesis of SS. NSG female mice were adoptively transferred with 10 million peripheral blood mononuclear cells (PBMCs) through the tail vein from healthy controls (HCs), primary Sjogren's syndrome (pSS), and systemic lupus erythematosus (SLE) patients on D0. The mice were subcutaneously injected with C57/B6j submandibular gland (SG) protein or phosphate-buffered saline on D3, D17 and D31, respectively. NSG mice were successfully transplanted with human PBMCs. Compared with NSG-HC group, NSG-pSS and NSG-SLE mice exhibited a large number of lymphocytes infiltration in the SG, decreased salivary flow rate, lung involvement, decreased expression of genes related to salivary secretion, and the production of autoantibodies. Type I interferon-related genes were increased in the SG of NSG-pSS and NSG-SLE mice. The ratio of BAX/BCL2, BAX, cleaved caspase3, and TUNEL staining were increased in the SG of NSG-pSS and NSG-SLE mice. The expressions of p-MLKL and p-RIPK3 were increased in the SG of NSG-pSS and NSG-SLE mice. Increased expression of type I interferon-related genes, PANoptosis (apoptosis and necroptosis) were identified in the SG of this typical humanized NSG murine model of SS.

Weighted Gene Co-expression Network Analysis and Machine Learning Validation for Identifying Major Genes Related to Sjogren's Syndrome.

Sjogren's syndrome (SS) is an autoimmune disorder characterized by dry mouth and dry eyes. Its pathogenic mechanism is currently unclear. This study aims to integrate weighted gene co-expression network analysis (WGCNA) and machine learning to identify key genes associated with SS. We downloaded 3 publicly available datasets from the GEO database comprising the gene expression data of 231 SS and 78 control cases, including GSE84844, GSE48378 and GSE51092, and carried out WGCNA to elucidate differences in the abundant genes. Candidate biomarkers for SS were then identified using a LASSO regression model. Totally 6 machine-learning models were subsequently utilized for validating the biological significance of major genes according to their expression. Finally, immune cell infiltration of the SS tissue was assessed using the CIBERSORT algorithm. A weighted gene co-expression network was built to divide genes into 10 modules. Among them, blue and red modules were most closely associated with SS, and showed significant enrichment in type I interferon signaling, cellular response to type I interferon and response to virus, etc. Combined machine learning identified 5 hub genes, including OAS1, EIF2AK2, IFITM3, TOP2A and STAT1. Immune cell infiltration analysis showed that SS was associated with CD8+ T cell, CD4+ T cell, gamma delta T cell, NK cell and dendritic cell activation. WGCNA was combined with machine learning to uncover genes that may be involved in SS pathogenesis, which can be utilized for developing SS biomarkers and appropriate therapeutic targets.

Chemokines and lymphocyte homing in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4β7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-β, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-β receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.

Integrated analysis of m6A regulator-mediated RNA methylation modification patterns and immune characteristics in Sjögren's syndrome

The epigenetic modifier N6-methyladenosine (m6A), recognized as the most prevalent internal modification in messenger RNA (mRNA), has recently emerged as a pivotal player in immune regulation. Its dysregulation has been implicated in the pathogenesis of various autoimmune conditions. However, the implications of m6A modification within the immune microenvironment of Sjögren's syndrome (SS), a chronic autoimmune disorder characterized by exocrine gland dysfunction, remain unexplored. Herein, we leverage an integrative analysis combining public database resources and novel sequencing data to investigate the expression profiles of m6A regulatory genes in SS. Our cohort comprised 220 patients diagnosed with SS and 62 healthy individuals, enabling a comprehensive evaluation of peripheral blood at the transcriptomic level. We report a significant association between SS and altered expression of key m6A regulators, with these changes closely tied to the activation of CD4+ T cells. Employing a random forest (RF) algorithm, we identified crucial genes contributing to the disease phenotype, which facilitated the development of a robust diagnostic model via multivariate logistic regression analysis. Further, unsupervised clustering revealed two distinct m6A modification patterns, which were significantly associated with variations in immunocyte infiltration, immune response activity, and biological function enrichment in SS. Subsequently, we proceeded with a screening process aimed at identifying genes that were differentially expressed (DEGs) between the two groups distinguished by m6A modification. Leveraging these DEGs, we employed weight gene co-expression network analysis (WGCNA) to uncover sets of genes that exhibited strong co-variance and hub genes that were closely linked to m6A modification. Through rigorous analysis, we identified three critical m6A regulators - METTL3, ALKBH5, and YTHDF1 - alongside two m6A-related hub genes, COMMD8 and SRP9. These elements collectively underscore a complex but discernible pattern of m6A modification that appears to be integrally linked with SS's pathogenesis. Our findings not only illuminate the significant correlation between m6A modification and the immune microenvironment in SS but also lay the groundwork for a deeper understanding of m6A regulatory mechanisms. More importantly, the identification of these key regulators and hub genes opens new avenues for the diagnosis and treatment of SS, presenting potential targets for therapeutic intervention.

The role of cytokines from salivary gland epithelial cells in the immunopathology of Sjögren's syndrome.

In the pathogenesis and progression of Sjögren's syndrome (SS), hematopoietic cells in the peripheral circulation, tissue-resident immune cells, and parenchymal cells of salivary gland tissues (such as epithelial cells, endothelial cells, fibroblasts, etc.) all play crucial roles. These diverse cells form intricate networks and interact with each other, leading to tissue destruction and persistent chronic inflammation, ultimately causing irreversible damage in glandular function. Among these, salivary gland epithelial cells (SGECs) consistently hold a key position, characterized by their functions in expressing co-stimulatory and antigen-presenting molecules and secreting pro-inflammatory cytokines and chemokines. Moreover, SGECs actively engage in and facilitate the development of specific pathological structures within the salivary gland, such as lymphoepithelial lesions (LELs) and tertiary lymphoid structures (TLSs), thereby substantially elevating the risk of mucosa-associated lymphoid tissue (MALT) lymphoma. Overall, SGECs are recognized for their essential and irreplaceable contributions to the pathogenesis of SS. This review article initially delves into the anatomical composition of salivary gland epithelial cells, subsequently focusing on elucidating the different cytokines derived from SGECs, encompassing chemokines, pro-inflammatory cytokines, anti-inflammatory cytokines, pro-survival cytokines, and damage-associated molecular patterns (DAMPs), to explore their key roles in the pathogenesis of SS.

Rapamycin can alleviate the submandibular gland pathology of Sjögren's syndrome by limiting the activation of cGAS-STING signaling pathway.

Sjögren's Syndrome (SS) is also known as autoimmune exocrine gland disease. Previous studies have confirmed that adaptive immunity plays an important role in the development of this disease. But less is known about the role of the innate immune system. To identify the core pathways, and local infiltrated immune cells in the local immune microenvironment of SS. We verified the activation of these core genes and core signaling pathways in SS model mice by in vivo experiment and transcriptome sequencing. Finally, we identified 6 core genes EPSTI1, IFI44L, MX1, CXCL10, IFIT3, and IFI44. All the 6 genes had good diagnostic value. Based on multi-omics sequencing results and experimental studies, we found that cGAS-STING signaling pathway is most relevant to the pathogenesis of SS. By in vivo experiments, we verified that autophagy is the key brake to limit the activation of cGAS-STING signaling pathway. Maladaptive activation of autophagy and cGAS-STING signaling pathway are central contributors to the SG pathogenesis of pSS patient. Regulating autophagy by rapamycin may be a possible treatment for Sjögren's syndrome in the future.

Application of omics in Sjögren's syndrome.

The pathogenesis, diagnosis, and treatment of Sjögren's syndrome (SS) face many challenges, and there is an urgent need to develop new technologies to improve our understanding of SS. By searching the literature published domestically and internationally in the past 20 years, this artical reviewed the research of various omics techniques in SS. Omics technology provided valuable insights into the pathogenesis, early diagnosis, condition and efficacy evaluation of SS. It is helpful to reveal the pathogenesis of the disease and explore new treatment schemes, which will open a new era for the study of SS. At present, omics research has made some gratifying achievements, but there are still many uncertainties. Therefore, in the future, we should improve research techniques, standardize the collection of samples, and adopt a combination of multi-omics techniques to jointly study the pathogenesis of SS and provide new schemes for its treatment.

Identification of key genes in salivary gland in Sjögren's syndrome complicated with Hashimoto thyroiditis: Common pathogenesis and potential diagnostic markers.

The coexistence of Sjögren's syndrome (SS) and Hashimoto thyroiditis (HT) has been confirmed, but the common mechanism of its co-occurrence remains unknown. This study aims to further explore the underlying mechanism and biomarkers for the co-occurrence of SS and HT. The Gene Expression Omnibus databases were used to obtain gene expression profiles for SS (GSE127952 and GSE23117) and HT (GSE29315 and GSE138198). Following identifying SS and HT's shared differentially expressed genes, functional annotation, protein-protein interaction network creation, and module assembly were performed to discover hub genes. H&E staining and immunohistochemistry were performed to validate the expression of the hub genes in salivary glands. Finally, the receiver operating characteristic (ROC) curve was utilized to assess the discrimination of the hub genes as biomarkers in predicting SS, this study applied CIBERSORTx to analyze the immune infiltration in SS and HT in addition. A total of 48 common differentially expressed genes (48 upregulated genes and 0 downregulated genes) were chosen for further investigation. We analyzed the expression and function of PTPRC, CD69, IKZF1, and lymphocyte cytosolic protein 2 via H&E, immunohistochemistry, and ROC analysis. The 4 hub genes were mainly enriched in the T-cell receptor signaling pathway. We then evaluated and verified the diagnosis value of 4 hub genes in clinical minor labial gland biopsy of SS with HT, SS without HT, and non-SS. ROC analysis revealed that the 4 hub genes had a strong diagnostic value. Our study showed the common pathogenesis of SS and HT. These hub genes and diagnostic models may put forward some new insights for diagnosing and treating SS complicated with HT.

Insights into Microbiota in Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a heterogeneous chronic autoimmune disorder with multiple clinical manifestations that can develop into non-Hodgkin's lymphoma in mucosa-associated lymphoid tissue. The pathogenesis of Sjögren's syndrome (SS) is not completely understood, but it is assumed that pathogenesis of SS is multifactorial. The microbiota plays a notable role in the development of autoimmune disorders, including Sjögren's syndrome. Molecular mimicry, metabolite changes and epithelial tolerance breakdown are pathways that might help to clarify the potential contribution of the microbiota to SS pathogenesis. This review aims to provide an overview of recent studies describing microbiota changes and microbiota mechanisms associated with Sjögren's syndrome. Data on the microbiota in SS from PubMed, Web of Science, Scopus and the Cochrane Library databases are summarized. Overall, the microbiota makes a major contribution to the development of Sjögren's syndrome and progression. Future microbiota studies should improve the management of this heterogeneous autoimmune disease.

Identification of the shared mechanisms and common biomarkers between Sjögren's syndrome and atherosclerosis using integrated bioinformatics analysis.

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by exocrine and extra-glandular symptoms. The literature indicates that SS is an independent risk factor for atherosclerosis (AS); however, its pathophysiological mechanism remains undetermined. This investigation aimed to elucidate the crosstalk genes and pathways influencing the pathophysiology of SS and AS via bioinformatic analysis of microarray data. Microarray datasets of SS (GSE40611) and AS (GSE28829) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were acquired using R software's "limma" packages, and the functions of common DEGs were determined using Gene Ontology and Kyoto Encyclopedia analyses. The protein-protein interaction (PPI) was established using the STRING database. The hub genes were assessed via cytoHubba plug-in and validated by external validation datasets (GSE84844 for SS; GSE43292 for AS). Gene set enrichment analysis (GSEA) and immune infiltration of hub genes were also conducted. Eight 8 hub genes were identified using the intersection of four topological algorithms in the PPI network. Four genes (CTSS, IRF8, CYBB, and PTPRC) were then verified as important cross-talk genes between AS and SS with an area under the curve (AUC) ≥0.7. Furthermore, the immune infiltration analysis revealed that lymphocytes and macrophages are essentially linked with the pathogenesis of AS and SS. Moreover, the shared genes were enriched in multiple metabolisms and autoimmune disease-related pathways, as evidenced by GSEA analyses. This is the first study to explore the common mechanism between SS and AS. Four key genes, including CTSS, CYBB, IRF8, and PTPRC, were associated with the pathogenesis of SS and AS. These hub genes and their correlation with immune cells could be a potential diagnostic and therapeutic target.

Identification of Fangji Huangqi Tang as a potential herbal formula for Sjogren syndrome treatment via network pharmacology and experimental validation.

Fangji Huangqi Tang (FHT) is a well-known Chinese herbal formula that is prescribed as treatment for rheumatoid diseases. In this study, we aimed to investigate the potential therapeutic targets, efficacy, and safety of FHT in the treatment of Sjogren's syndrome (SS). The Gene Expression Omnibus (GEO) database was used to screen differentially expressed genes (DEGs) in SS. Further, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological functions of the DEGs. Subsequently, an FHT-herb-active compound-target network was constructed to identify the relationship between the active compounds in FHT and the related targets. Then, enrichment analysis involving the DEGs and protein-protein interaction (PPI) network analysis were performed to analyze the biological functions of potential targets and screen hub genes. Further, molecular docking was employed to verify the binding affinity between the active compounds and the hub targets, and in vivo experiments involving NOD/LtJ mice were conducted to verify the therapeutic effects of FHT on SS-like symptoms. Finally, inhibition of PIK3CK/Akt pathway by FHT was validated by WB and rt-qPCR. A total of 1836 DEGs were identified in SS based on the GSE159574 dataset, and 114 targets of the active compounds in FHT were screened. Further, via network pharmacology analysis and molecular docking, six active compounds and five hub targets were obtained, and enrichment analysis showed that the anti-SS effect of FHT was predominantly associated with immune cells, such as T cells and neutrophils. In vivo, FHT effectively reduced lymphocyte infiltration foci, increased saliva flow rate, and inhibited increases in the levels of SS-related autoantibodies (anti-SSA and anti-SSB). Furthermore, the biosafety of FHT was verified via the serological examination of liver and kidney function. WB and rt-qPCR analysis confirmed that FHT could inhibit the expression of PIK3CG and the activation of PIK3CG/Akt pathway. Via network pharmacological analysis, molecular docking, and in vivo verification, we demonstrated the multicomponent and multitarget characteristics of FHT in SS treatment, thereby providing novel insights into the pathogenesis of SS and the therapeutic targets of FHT for SS.

Lessons from Animal Models in Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a connective tissue disease characterized by a wide spectrum of clinical features, extending from a benign glandular disease to an aggressive systemic disorder and/or lymphoma. The pathogenesis of Sjögren's syndrome (SS) is not completely understood, but it is assumed that pathogenesis of SS is multifactorial. The studies based on the animal models of SS provided significant insight in SS disease pathogenesis and management. The aim of this review is to summarize current studies on animal models with primary SS-like symptoms and discuss the impact of these studies on better understanding pathogenesis and management of Sjögren's syndrome. Databases PubMed, Web of Science, Scopus and Cochrane library were searched for summarizing studies on animal models in SS. Available data demonstrate that animal models are highly important for our understanding of SS disease.

Tear Cytokine Levels in Sicca Syndrome-Related Dry Eye: A Meta-Analysis.

Sjogren's syndrome (SS) is an autoimmune disease that affects exocrine glands, mainly salivary and lacrimal glands. Several studies have investigated cytokine profiles in tears in order to understand the pathogenesis of SS and find additional diagnostic markers. This systematic review and meta-analysis aimed to analyze cytokines in tears of SS patients. A systematic literature search of the Cochrane, Medline via PubMed, Scopus, and Web of Science databases was conducted using key terms related to "Sjögren's syndrome" and "tears" combined with "biomarker", "cytokines", "interleukin", and "chemokines", following PRISMA guidelines. Article selection was subjected to certain eligibility criteria. A total of 17 articles (from 1998 and 2022) were selected for the quantitative and qualitative analysis. When compared to controls, concentrations of IFN-γ, TNF-α, IL-1α, IL-1 Ra, IL-4, IL-6, IL-8, IL-10, IL-17, IL-21 and IL-22 were consistently higher; however, IL-23 was significantly lower in patients with SS compared to the controls. Tear levels of some cytokines were significantly elevated among SS groups compared to control groups. Therefore, these cytokines could be potential biomarkers of SS. However, standardization of sample collection and analytical methods is necessary in order to translate these findings into clinical practice.

Pathogenesis and treatment of Sjogren's syndrome: Review and update.

Sjogren's syndrome (SS) is a chronic autoimmune disease accompanied by multiple lesions. The main manifestations include dryness of the mouth and eyes, along with systemic complications (e.g., pulmonary disease, kidney injury, and lymphoma). In this review, we highlight that IFNs, Th17 cell-related cytokines (IL-17 and IL-23), and B cell-related cytokines (TNF and BAFF) are crucial for the pathogenesis of SS. We also summarize the advances in experimental treatment strategies, including targeting Treg/Th17, mesenchymal stem cell treatment, targeting BAFF, inhibiting JAK pathway, etal. Similar to that of SLE, RA, and MS, biotherapeutic strategies of SS consist of neutralizing antibodies and inflammation-related receptor blockers targeting proinflammatory signaling pathways. However, clinical research on SS therapy is comparatively rare. Moreover, the differences in the curative effects of immunotherapies among SS and other autoimmune diseases are not fully understood. We emphasize that targeted drugs, low-side-effect drugs, and combination therapies should be the focus of future research.

NLRP3 Gene Polymorphisms in Rheumatoid Arthritis and Primary Sjogren's Syndrome Patients.

Aim: The activation of NLRP3 inflammasome leads to the stimulation of cytokines and is significantly involved in the pathogenesis and progression of autoimmune diseases. The purpose of this study is to examine the associations of NLRP3 gene polymorphisms with rheumatoid arthritis (RA) and primary Sjogren's syndrome (SS) patients. Methods: A total of 239 patients with RA, 285 patients with primary SS, and 170 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood mononuclear cells, and gene polymorphisms were genotyped through the TaqMan assay. Antinuclear antibody (ANA), anti-Ro, and anti-CCP antibodies were detected using immunofluorescence immunoassay. Results: The T allele of rs4612666 CT elevated the susceptibility to RA disease. The RF titer during diagnosis of RA was significantly high in RA patients with the A allele of rs12079994 G/A polymorphism. The titer of anti-CCP during diagnosis of RA was high in the absence of the C allele of rs10754558 C/G polymorphisms in RA patients. Antinuclear antibody and anti-CCP were positively associated with the A allele of rs12079994 G/A polymorphism in primary SS. The C allele of rs4612666 C/T was negatively associated with ANA in primary SS. Conclusions: The results have shown that NLRP3 gene polymorphisms may play a role in the pathogenesis of RA and primary SS.

Nucleic acid-sensing toll-like receptors: Important players in Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease that affects the salivary and lacrimal glands, as well as other organ systems like the lungs, kidneys and nervous system. SS can occur alone or in combination with another autoimmune disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. The etiology of SS is unknown but recent studies have revealed the implication of the activation of innate immune receptors, including Toll-like receptors (TLRs), mainly through the detection of endogenous nucleic acids, in the pathogenesis of systemic autoimmune diseases. Studies on SS mouse models suggest that TLRs and especially TLR7 that detects single-stranded RNA of microbial or endogenous origin can drive the development of SS and findings in SS patients corroborate those in mouse models. In this review, we will give an overview of the function and signaling of nucleic acid-sensing TLRs, the interplay of TLR7 with TLR8 and TLR9 in the context of autoimmunity, summarize the evidence for the critical role of TLR7 in the pathogenesis of SS and present a possible connection between SARS-CoV-2 and SS.