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Nguyen RD, Nortey J, Gebreegziabher E, Hinterwirth A, Zhong L, Chen C, Doan T, Lietman TM, Gonzales JA. A Distinguishable Peripheral Blood and Conjunctival Transcriptome and Gut Microbiome in Sjögren's Disease: A Pilot Study. Eye Contact Lens 2025:00140068-990000000-00284. [PMID: 40314468 DOI: 10.1097/icl.0000000000001186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 05/03/2025]
Abstract
OBJECTIVE To create a comprehensive multi-tissue molecular atlas of Sjögren's disease by using unbiased RNA sequencing to identify differentially expressed genes (DEGs) in peripheral blood and conjunctival transcriptomes, and to characterize the ocular surface and gut microbiome profiles in participants classified as Sjögren's versus non-Sjögren's disease. METHODS This exploratory study used high-throughput RNA sequencing to analyze peripheral blood, conjunctival swabs, and rectal swabs from participants (11 classified as Sjögren's disease and four classified as non-Sjögren's) to identify DEGs and microbial profiles that could distinguish these groups. RESULTS Differential gene expression analysis revealed upregulated type I interferon (IFI44L, OASL, USP18) and complement pathways (SERPING1) in peripheral blood, alongside activation of several novel pathways in the conjunctiva including intracellular vesicle trafficking (HIP1, GOLIM4, FIG4), immunometabolism (CERS5, HPRT1, ULK2), and cytoskeletal remodeling (MARK1, IQCB1) in Sjögren's disease. In addition, distinct gut microbiome compositions were observed in Sjögren's disease participants, characterized by an increased presence of Lactobacillus reuteri species. CONCLUSIONS Using unbiased RNA sequencing, we confirmed the role of type I interferon and complement pathways in the peripheral blood and identified novel molecular signatures in the conjunctiva of Sjögren's disease participants. These newly identified pathways-involved in intracellular vesicle trafficking, immunometabolism, and cytoskeletal remodeling-expand our understanding of disease mechanisms beyond traditional immune pathways. In addition, we found distinct gut microbial profiles in Sjögren's disease participants, although ocular surface microbiome showed no significant differences. Such findings may suggest possible new therapeutic targets and allow for Sjögren's disease patient stratification. However, validation in larger cohorts is needed to establish clinical significance and potential applications in Sjögren's disease.
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Affiliation(s)
- Robert D Nguyen
- Francis I. Proctor Foundation (R.D.N., J.N., E.G., A.H., L.Z., C.C., T.D., T.M.L., J.A.G.), University of California, San Francisco, CA; Department of Ophthalmology (T.D., T.M.L., J.A.G.), University of California, San Francisco, CA; Department of Ophthalmology (J.N.), Northwestern University, Chicago, IL
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Cavalcanti GV, de Oliveira FR, Bannitz RF, de Paula NA, Motta ACF, Rocha EM, Chiorini J, Ricz HMA, Garcia DM, Foss-Freitas MC, de Freitas LCC. Endoplasmic reticulum stress in the salivary glands of patients with primary Sjögren's syndrome, associated Sjögren's syndrome, and non-Sjögren's sicca syndrome: a comparative analysis and the influence of chloroquine. Adv Rheumatol 2025; 65:2. [PMID: 39780265 DOI: 10.1186/s42358-024-00430-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are adaptive mechanisms for conditions of high protein demand, marked by an accumulation of misfolded proteins in the endoplasmic reticulum (ER). Rheumatic autoimmune diseases (RAD) are known to be associated with chronic inflammation and an ERS state. However, the activation of UPR signaling pathways is not completely understood in Sjögren's disease (SD). This study evaluated the expression of ERS-related genes in glandular tissue of patients with primary SD (pSD), associated SD (aSD) with other autoimmune diseases, and non-Sjögren sicca syndrome (NSS). METHODS In a cross-sectional study, minor salivary gland biopsies were obtained from 44 patients with suspected SD and 13 healthy controls (HC). Patients were classified as pSD, aSD, or NSS based on clinical, serological, and histological assessment. Histopathological analysis and mRNA expression analysis of genes associated with ERS and UPR (PERK, XBP1, ATF-6, ATF-4, CANX, CALR, CHOP, and BIP) were performed on the samples. Differences between groups (pSD, aSD, NSS, and HC) were assessed. The influence of chloroquine (CQ) on the ER was also investigated. RESULTS Twenty-eight SD patients showed increased expression of PERK (p = 0.0117) and XBP1 (p = 0.0346), and reduced expression of ATF-6 (p = 0.0003) and CHOP (p = 0.0003), compared to the HC group. Increased expression of BIP (p < 0.0001), PERK (p = 0.0003), CALR (p < 0.0001), and CANX (p = 0.0111) was also observed in the SD group compared to the NSS group (n = 16). Patients receiving CQ (n = 16) showed a significant increase in ATF-6 (p = 0.0317) compared to patients not taking the medication (n = 29). CONCLUSIONS Altogether, the results suggest a greater activation of the ERS and UPR genes in patients with SD, especially in the pSD group. Antimalarial drugs, like CQ, used to treat RAD, may affect the ER function in exocrine glands.
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Affiliation(s)
- Graziela Vieira Cavalcanti
- Department of Ophthalmology, Otolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
- Ophthalmology, Otolaryngology, Head and Neck Surgery Department, Ribeirão Preto Medical School, University of São Paulo, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto, SP, 14.040-900, Brazil.
| | - Fabiola Reis de Oliveira
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Rafael Ferraz Bannitz
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Natalia Aparecida de Paula
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Ana Carolina Fragoso Motta
- Department of Stomatology, Public Health and Forensic Dentistry, Ribeirão Preto School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Eduardo Melani Rocha
- Department of Ophthalmology, Otolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - John Chiorini
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Hilton Marcos Alves Ricz
- Department of Ophthalmology, Otolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Denny Marcos Garcia
- Department of Ophthalmology, Otolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Maria Cristina Foss-Freitas
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, and Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, USA
| | - Luiz Carlos Conti de Freitas
- Department of Ophthalmology, Otolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
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Zhou J, Xu Y, Wang H, Chen C, Wang K. Unveiling the mystery: Investigating the debate surrounding mitochondrial DNA copy number and Sjögren syndrome using Mendelian randomization analysis. Medicine (Baltimore) 2024; 103:e40908. [PMID: 39686495 PMCID: PMC11651504 DOI: 10.1097/md.0000000000040908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Numerous studies have investigated the relationship between mitochondrial DNA (mtDNA) copy number and Sjögren syndrome (SS). However, the conclusions remain inconclusive, with conflicting findings. The genome-wide association study summary statistics for mtDNA copy number were obtained from 2 sources: a cohort of 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the UK Biobank, and a dataset of 395,718 UK Biobank participants. Additionally, we obtained 2 sets of genome-wide association study summary statistics for SS through datasets from FinnGen and the UK Biobank, involving a total of 809,836 participants. Furthermore, we conducted a two-sample bidirectional Mendelian randomization analysis, primarily utilizing the inverse variance weighted method, complemented by 4 other validation methods, to explore the association between mtDNA copy number and SS. Following our comprehensive investigation, no discernible causal relationship was identified between mtDNA copy number and SS in either the training or validation cohorts (inverse variance weighted, P > .05). Similarly, the reverse Mendelian randomization analysis yielded negative results (inverse variance weighted, P > .05). Furthermore, all analyses indicated an absence of horizontal pleiotropy or heterogeneity. Our analysis revealed no causal relationship between mtDNA copy number and SS.
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Affiliation(s)
- Jie Zhou
- The Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Yixin Xu
- The Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Haitao Wang
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Chao Chen
- The Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - Kun Wang
- The Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
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Cai Y, Zhang Y, Wang S, Changyong E. MiR-23b-3p alleviates Sjögren's syndrome by targeting SOX6 and inhibiting the NF-κB signaling. Mol Immunol 2024; 172:68-75. [PMID: 38901181 DOI: 10.1016/j.molimm.2024.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/20/2024] [Accepted: 06/01/2024] [Indexed: 06/22/2024]
Abstract
OBJECTIVE MicroRNA-23b-3p has been demonstrated to act as a safeguard against several autoimmune diseases. However, its role in Sjögren's syndrome (SS) remains unclear. METHODS In order to investigate its role in SS, we administered agomiR-23b-3p or agomiR-NC to non-obese diabetic (NOD) mice via tail vein weekly for 6 weeks. The study examined the saliva flow rate, histological changes in submandibular glands, and levels of autoantibodies. Additionally, the levels of several cytokines, cell apoptosis, and NF-κB signaling were evaluated. The protective effect of miR-23b-3p was confirmed in a cell model. RESULTS The results demonstrated that miR-23b-3p overexpression improved salivary flow rates, inhibited lymphocyte infiltration, reduced cytokine levels, and suppressed cell apoptosis in NOD mice. Moreover, NF-κB signaling was inactivated following miR-23b-3p overexpression. In a cellular model of SS, overexpression of miR-23b-3p protected submandibular gland epithelial cells exposed to IFN-γ against apoptosis and inflammation by targeting SOX6. CONCLUSIONS The study concludes that miR-23b-3p alleviates SS by targeting SOX6 and inhibiting the NF-κB signaling pathway. The miR-23b-3p/SOX6 axis represents a promising avenue for the development of novel therapeutic strategies for SS.
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Affiliation(s)
- Yan Cai
- Department of Oral and Maxillofacial Radiology, Hospital of Stomatology, Jilin University, Changchun, Jilin Province, PR China
| | - Yi Zhang
- Department of Orthodontics, Hospital of Stomatology, Jilin University, Changchun, Jilin Province, PR China
| | - Sihan Wang
- Department of Orthodontics, Hospital of Stomatology, Jilin University, Changchun, Jilin Province, PR China
| | - E Changyong
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, PR China.
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Chu WX, Ding C, Du ZH, Wei P, Wang YX, Ge XJ, Yu GY. SHED-exos promote saliva secretion by suppressing p-ERK1/2-mediated apoptosis in glandular cells. Oral Dis 2024; 30:3066-3080. [PMID: 37849447 DOI: 10.1111/odi.14776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 09/19/2023] [Accepted: 10/09/2023] [Indexed: 10/19/2023]
Abstract
OBJECTIVES Confirm that stem cells from human exfoliated deciduous teeth-derived exosomes (SHED-exos) can limit inflammation-triggered epithelial cell apoptosis and explore the molecular mechanism. METHODS SHED-exos were injected into the submandibular glands (SMGs) of non-obese diabetic (NOD) mice, an animal model of Sjögren's syndrome (SS). Cell death was evaluated by western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling staining. RESULTS SHED-exos treatment promoted the saliva flow rates of NOD mice, accompanied by decreased cleaved caspase-3 levels and apoptotic cell numbers in SMGs. SHED-exos inhibited autophagy, pyroptosis, NETosis, ferroptosis, necroptosis and oxeiptosis marker expression in SS-damaged glands. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis of exosomal miRNAs suggested that the rat sarcoma virus (RAS)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway might play an important role. In vivo, the expression of Kirsten RAS, Harvey RAS, MEK1/2 and p-ERK1/2 was upregulated in SMGs, and this change was blocked by SHED-exos treatment. In vitro, SHED-exos suppressed p-ERK1/2 activation and increased cleaved caspase-3 and apoptotic cell numbers, which were induced by IFN-γ. CONCLUSION SHED-exos suppress epithelial cell death, which is responsible for promoting salivary secretion. SHED-exos inhibited inflammation-triggered epithelial cell apoptosis by suppressing p-ERK1/2 activation, which is involved in these effects.
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Affiliation(s)
- Wei-Xia Chu
- Department of Periodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, P.R. China
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, P.R. China
| | - Chong Ding
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, P.R. China
| | - Zhi-Hao Du
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China
| | - Pan Wei
- Department of Oral Medicine, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, P.R. China
| | - Yi-Xiang Wang
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, P.R. China
| | - Xue-Jun Ge
- Department of Periodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, P.R. China
| | - Guang-Yan Yu
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China
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Pastva O, Klein K. Long Non-Coding RNAs in Sjögren's Disease. Int J Mol Sci 2024; 25:5162. [PMID: 38791207 PMCID: PMC11121283 DOI: 10.3390/ijms25105162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/25/2024] [Accepted: 04/28/2024] [Indexed: 05/26/2024] Open
Abstract
Sjögren's disease (SjD) is a heterogeneous autoimmune disease characterized by severe dryness of mucosal surfaces, particularly the mouth and eyes; fatigue; and chronic pain. Chronic inflammation of the salivary and lacrimal glands, auto-antibody formation, and extra-glandular manifestations occur in subsets of patients with SjD. An aberrant expression of long, non-coding RNAs (lncRNAs) has been described in many autoimmune diseases, including SjD. Here, we review the current literature on lncRNAs in SjD and their role in regulating X chromosome inactivation, immune modulatory functions, and their potential as biomarkers.
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Affiliation(s)
- Ondřej Pastva
- Department of Rheumatology and Immunology, Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
| | - Kerstin Klein
- Department of Rheumatology and Immunology, Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
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Yang Y, Zhang H, Xiao X, Guo M. PANoptosis Features, a Humanized NSG Murine Model of Sjogren's Syndrome. DNA Cell Biol 2024; 43:207-218. [PMID: 38635961 DOI: 10.1089/dna.2023.0374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024] Open
Abstract
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.
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Affiliation(s)
- Yiying Yang
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, China
- Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
- Postdoctoral Research Station of Biology, School of Basic Medicine Science, Central South University, Changsha, China
| | - Huali Zhang
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, China
- Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, China
- Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, China
| | - Xiaoyu Xiao
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Muyao Guo
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
- Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, China
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Fu C, Qin X, Shao W, Zhang J, Zhang T, Yang J, Ding C, Song Y, Ge X, Wu G, Bikker FJ, Jiang N. Carbon quantum dots as immune modulatory therapy in a Sjögren's syndrome mouse model. Oral Dis 2024; 30:1183-1197. [PMID: 37125663 DOI: 10.1111/odi.14603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/30/2023] [Accepted: 04/13/2023] [Indexed: 05/02/2023]
Abstract
OBJECTIVES The objective of the study was to evaluate the therapeutic effects of carbon quantum dots (CQDs) in immunomodulation on non-obese diabetic (NOD) mice, as the model for Sjögren's syndrome (SS). METHODS Carbon quantum dots were generated from Setaria viridis via a hydrothermal process. Their toxic effects were tested by cell viability and blood chemistry analysis, meanwhile therapeutic effects were investigated in NOD mice in the aspects of saliva flow, histology, and immune cell distribution. RESULTS Carbon quantum dots, with rich surface chemistry and unique optical properties, showed non-cytotoxicity in vitro or no damage in vivo. Intravenously applied CQDs alleviated inflammation in the submandibular glands in NOD mice after 6-week treatments. The inflammatory area index and focus score were significantly decreased in CQD-treated mice. Besides, the levels of anti-SSA and anti-SSB were decreased in the presence of CQDs. The stimulated saliva flow rates and weight of submandibular glands were significantly increased in CQD-treated mice by reducing the apoptosis of cells. The CD3+ and CD4+ T cells distributed around the ducts of submandibular glands were significantly decreased, while the percentage of Foxp3+ cells was higher in CQD-treated mice than that in the control group. CONCLUSIONS Our findings suggest that CQDs may ameliorate the dysregulated immune processes in NOD mice.
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Affiliation(s)
- Cuicui Fu
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU), Amsterdam, The Netherlands
- Central Laboratory, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Xiaoyun Qin
- School of Material and Chemical Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Wenlong Shao
- School of Material and Chemical Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Jin Zhang
- School of Material and Chemical Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Ting Zhang
- Laboratory of Biomimetic Nanomaterials, Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Jiaqi Yang
- Central Laboratory, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
- Department of Endodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Chong Ding
- Central Laboratory, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Yeqing Song
- Central Laboratory, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Xuejun Ge
- Department of Endodontics, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, China
| | - Gang Wu
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), Amsterdam Movement Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Floris J Bikker
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU), Amsterdam, The Netherlands
| | - Nan Jiang
- Central Laboratory, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing, China
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Zhou J, Pathak JL, Liu Q, Hu S, Cao T, Watanabe N, Huo Y, Li J. Modes and Mechanisms of Salivary Gland Epithelial Cell Death in Sjogren's Syndrome. Adv Biol (Weinh) 2023; 7:e2300173. [PMID: 37409392 DOI: 10.1002/adbi.202300173] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/16/2023] [Indexed: 07/07/2023]
Abstract
Sjogren's syndrome is an autoimmune disease in middle and old-aged women with a dry mucosal surface, which is caused by the dysfunction of secretory glands, such as the oral cavity, eyeballs, and pharynx. Pathologically, Sjogren's syndrome are characterized by lymphocyte infiltration into the exocrine glands and epithelial cell destruction caused by autoantibodies Ro/SSA and La/SSB. At present, the exact pathogenesis of Sjogren's syndrome is unclear. Evidence suggests epithelial cell death and the subsequent dysfunction of salivary glands as the main causes of xerostomia. This review summarizes the modes of salivary gland epithelial cell death and their role in Sjogren's syndrome progression. The molecular mechanisms involved in salivary gland epithelial cell death during Sjogren's syndrome as potential leads to treating the disease are also discussed.
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Affiliation(s)
- Jiannan Zhou
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Janak Lal Pathak
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Qianwen Liu
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Shilin Hu
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Tingting Cao
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
| | - Nobumoto Watanabe
- Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, 351-0198, Japan
| | - Yongliang Huo
- Experimental Animal Center, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China
| | - Jiang Li
- Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, China
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Yu J, Wang S, Yang J, Huang W, Tang B, Peng W, Tian J. Exploring the mechanisms of action of Zengye decoction (ZYD) against Sjogren's syndrome (SS) using network pharmacology and animal experiment. PHARMACEUTICAL BIOLOGY 2023; 61:1286-1297. [PMID: 37606264 PMCID: PMC10446814 DOI: 10.1080/13880209.2023.2248188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 08/05/2023] [Accepted: 08/09/2023] [Indexed: 08/23/2023]
Abstract
CONTEXT Zengye decoction (ZYD) has been considered to have a curative effect on Sjogren's syndrome (SS). However, its therapeutic mechanisms remain obscure. OBJECTIVES This research explores the mechanisms of ZYD against SS. MATERIALS AND METHODS The active compounds and targets of ZYD were searched in the TCMSP and BATMAN-TCM databases. SS-related targets were obtained from the GeneCards database. The GO and KEGG enrichment analyses elucidated the molecular mechanisms. Animal experiments were performed using 8 C57BL/6 mice that served as the control group (physiological saline treatment) and 16 NOD mice randomly divided into the model group (physiological saline treatment) and the ZYD group (ZYD treatment) for 8 weeks to verify the therapeutic effects of ZYD on SS. RESULTS Twenty-nine active compounds with 313 targets of ZYD and 1038 SS-related targets were screened. Thirty-two common targets were identified. β-Sitosterol and stigmasterol might be important components. GO analysis suggested that the action of ZYD against SS mainly involved oxidative stress, apoptotic processes, and tumor necrosis factor receptor superfamily binding, etc. KEGG analysis indicated the most significant signaling pathway was apoptosis-multiple species. Animal experiments showed that ZYD improved lymphocytic infiltration of the submandibular glands (SMGs), reduced the serum levels of TNF-α, IL-1β, IL-6, and IL-17, upregulated the expression of Bcl-2, and downregulated the expression of Bax and Caspase-3 in the model mice. DISCUSSION AND CONCLUSION ZYD has anti-inflammatory and anti-apoptotic effects on SS, which provides a theoretical basis for the treatment of SS with ZYD.
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Affiliation(s)
- Jiake Yu
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shuying Wang
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jie Yang
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wuxinrui Huang
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Beikang Tang
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Weijun Peng
- Department of Integrated Traditional Chinese and Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jing Tian
- Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Wang S, Yu J, Yang J, Ge Y, Tian J. Effects of iguratimod on inflammatory factors and apoptosis of submandibular gland epithelial cells in NOD mice. Sci Rep 2023; 13:18205. [PMID: 37875724 PMCID: PMC10597989 DOI: 10.1038/s41598-023-45529-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 10/20/2023] [Indexed: 10/26/2023] Open
Abstract
Non-obese diabetic (NOD) mice were taken as primary Sjögren's syndrome (pSS) model mice to examine the therapeutic impact of iguratimod (IGU) on inflammatory factors levels and apoptosis of submandibular epithelial cells, and provide experimental basis for the treatment of pSS by iguratimod. Twenty-four NOD murine models were divided into the model, high-dose (IGU 30 mg/kg) and low-dose (IGU 10 mg/kg) groups, eight mice per group. The normal control group comprised eight C57B/L mice. From 8 weeks of age, the NOD mice were administered IGU by intragastric gavage administration every day for 8 weeks; their water consumption, saliva secretion, submandibular gland, and spleen indices were measured. The levels of serum inflammatory factor (IL-1β, TNF-α, IL-6, and IL-17) were evaluated, and Bax, caspase-3, and Bcl-2 levels were detected. The histological alterations in the submandibular glands were discovered. IGU can reduce the water intake of NOD mice (p < 0.01), increase the saliva secretion and the submandibular gland index (p < 0.01); reduce the spleen index and the serum inflammatory factors (p < 0.01); improve the pathological tissue damage and cell apoptosis of the submandibular gland (p < 0.05). IGU can reduce the expression levels of inflammatory mediators in the serum and the extent of lymphocyte infiltration and apoptosis in submandibular gland epithelial cells. It can also regulate apoptosis-related protein expression, thereby improving the secretory function of exocrine glands.
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Affiliation(s)
- Shuying Wang
- Affiliated Nanhua Hospital, University of South China, Hengyang, 421000, Hunan, China
| | - Jiake Yu
- Department of Rheumatology and Immunology, The 2nd Xiangya Hospital of Central South University, Changsha, 410000, Hunan, China
| | - Jie Yang
- Department of Rheumatology and Immunology, The 2nd Xiangya Hospital of Central South University, Changsha, 410000, Hunan, China
| | - Yan Ge
- Department of Rheumatology and Immunology, The 2nd Xiangya Hospital of Central South University, Changsha, 410000, Hunan, China
| | - Jing Tian
- Department of Rheumatology and Immunology, The 2nd Xiangya Hospital of Central South University, Changsha, 410000, Hunan, China.
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Kor A, Yalçın M, Erten Ş, Maraş Y, Oğuz EF, Doğan İ, Atalar E, Başer S, Erel Ö. 14-3-3η Proteins as a Diagnostic Marker, Disease Activation Indicator, and Lymphoma Predictor in Patients with Primary Sjögren Syndrome. ARCHIVES OF IRANIAN MEDICINE 2023; 26:582-591. [PMID: 38310415 PMCID: PMC10862092 DOI: 10.34172/aim.2023.85] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 07/03/2023] [Indexed: 02/05/2024]
Abstract
BACKGROUND Primary Sjögren syndrome (PSS) is a chronic, autoimmune, and lymphoproliferative disease of the connective tissue. In patients with PSS, the risk of developing B-cell non-Hodgkin lymphoma (NHL) increases dramatically, with a prevalence of approximately 5%. The 14-3-3 protein isoforms are phospho-serin/phospho-threonine binding proteins associated with many malignant diseases. This study aimed to evaluate the relationship between disease activity parameters and markers predicting lymphoma development in patients with PSS and 14-3-3η proteins. METHODS This study was designed as an analytical case-control study. A total of 57 PSS patients and 54 healthy volunteers were included in the study. The European League Against Rheumatism (EULAR) Sjögren syndrome disease activity index (ESSDAI) was used to assess systemic disease activity in PSS. Receiver operating characteristic (ROC) analysis was used to test the diagnostic accuracy measures of the analytical results. Multivariable linear regression analysis was used to evaluate the effects of independent variables on the 14-3-3η protein. RESULTS The 14-3-3η protein serum levels were found to be significantly higher in PSS (2.72 [2.04-4.07]) than healthy controls (1.73 [1.41-2.43]) (P<0.0001). A significant relationship was found between 14-3-3η protein levels and ESSDAI group (β=0.385, 95%CI=0.318-1.651, P=0.005), hypocomplementemia (C3 or C4) (β=0.223, 95% CI=0.09-1.983, P=0.048) and purpura (β=0.252, 95% CI=0.335-4.903, P=0.022), which are accepted as lymphoma predictors. A significant correlation was found between PSS disease activity score ESSDAI and 14-33η protein (β=0.496, 95% CI=0.079-0.244, P=0.0002). CONCLUSION 14-3-3η proteins are potential candidates for diagnostic marker, marker of disease activity, and predictor of lymphoma in PSS patients.
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Affiliation(s)
- Ahmet Kor
- Department of Rheumatology, Aksaray Education and Research Hospital, Aksaray, Turkey
| | - Merve Yalçın
- Department of Internal Medicine, Ankara Bilkent City Hospital, Ministry of Health, Ankara, Turkey
| | - Şükran Erten
- Department of Rheumatology, Faculty of Medicine Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Yüksel Maraş
- Department of Rheumatology, Ankara Bilkent City Hospital, Health Sciences University, Ankara, Turkey
| | - Esra Fırat Oğuz
- Department of Medical Biochemistry, Ankara Bilkent City Hospital, Ministry of Health, Ankara, Turkey
| | - İsmail Doğan
- Department of Rheumatology, Faculty of Medicine Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Ebru Atalar
- Department of Rheumatology, Ankara Bilkent City Hospital, Ministry of Health, Ankara, Turkey
| | - Salih Başer
- Department of Internal Medicine, Faculty of Medicine Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Özcan Erel
- Department of Medical Biochemistry, Faculty of Medicine Ankara Bilkent City Hospital, Ankara Yıldırım Beyazıt University, Ankara, Turkey
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Nakamura H, Tanaka T, Zheng C, Afione SA, Warner BM, Noguchi M, Atsumi T, Chiorini JA. Lysosome-Associated Membrane Protein 3 Induces Lysosome-Dependent Cell Death by Impairing Autophagic Caspase 8 Degradation in the Salivary Glands of Individuals With Sjögren's Disease. Arthritis Rheumatol 2023; 75:1586-1598. [PMID: 37096570 PMCID: PMC11132095 DOI: 10.1002/art.42540] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/03/2023] [Accepted: 04/10/2023] [Indexed: 04/26/2023]
Abstract
OBJECTIVE Lysosome-associated membrane protein 3 (LAMP3) overexpression is implicated in the development and progression of Sjögren's disease (SjD) by inducing lysosomal membrane permeabilization (LMP) and apoptotic cell death in salivary gland epithelium. The aim of this study was to clarify the molecular details of LAMP3-induced lysosome-dependent cell death and to test lysosomal biogenesis as a therapeutic intervention. METHODS Human labial minor salivary gland biopsies were analyzed using immunofluorescence staining for LAMP3 expression levels and galectin-3 puncta formation, a marker of LMP. Expression level of caspase 8, an initiator of LMP, was determined by Western blotting in cell culture. Galectin-3 puncta formation and apoptosis were evaluated in cell cultures and a mouse model treated with glucagon-like peptide 1 receptor (GLP-1R) agonists, a known promoter of lysosomal biogenesis. RESULTS Galectin-3 puncta formation was more frequent in the salivary glands of SjD patients compared to control glands. The proportion of galectin-3 puncta-positive cells was positively correlated with LAMP3 expression levels in the glands. LAMP3 overexpression increased caspase 8 expression, and knockdown of caspase 8 decreased galectin-3 puncta formation and apoptosis in LAMP3-overexpressing cells. Inhibition of autophagy increased caspase 8 expression, while restoration of lysosomal function using GLP-1R agonists decreased caspase 8 expression, which reduced galectin-3 puncta formation and apoptosis in both LAMP3-overexpressing cells and mice. CONCLUSION LAMP3 overexpression induced lysosomal dysfunction, resulting in lysosome-dependent cell death via impaired autophagic caspase 8 degradation, and restoring lysosomal function using GLP-1R agonists could prevent this. These findings suggested that LAMP3-induced lysosomal dysfunction is central to disease development and is a target for therapeutic intervention in SjD.
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Affiliation(s)
- Hiroyuki Nakamura
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Tsutomu Tanaka
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Changyu Zheng
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Sandra A Afione
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Blake M. Warner
- Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Masayuki Noguchi
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - John A. Chiorini
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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Blinova VG, Vasilyev VI, Rodionova EB, Zhdanov DD. The Role of Regulatory T Cells in the Onset and Progression of Primary Sjögren's Syndrome. Cells 2023; 12:1359. [PMID: 37408193 DOI: 10.3390/cells12101359] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 07/07/2023] Open
Abstract
Regulatory T cells (Tregs) play a key role in maintaining immune balance and regulating the loss of self-tolerance mechanisms in various autoimmune diseases, including primary Sjögren's syndrome (pSS). With the development of pSS primarily in the exocrine glands, lymphocytic infiltration occurs in the early stages, mainly due to activated CD4+ T cells. Subsequently, in the absence of rational therapy, patients develop ectopic lymphoid structures and lymphomas. While the suppression of autoactivated CD4+ T cells is involved in the pathological process, the main role belongs to Tregs, making them a target for research and possible regenerative therapy. However, the available information about their role in the onset and progression of this disease seems unsystematized and, in certain aspects, controversial. In our review, we aimed to organize the data on the role of Tregs in the pathogenesis of pSS, as well as to discuss possible strategies of cell therapy for this disease. This review provides information on the differentiation, activation, and suppressive functions of Tregs and the role of the FoxP3 protein in these processes. It also highlights data on various subpopulations of Tregs in pSS, their proportion in the peripheral blood and minor salivary glands of patients as well as their role in the development of ectopic lymphoid structures. Our data emphasize the need for further research on Tregs and highlight their potential use as a cell-based therapy.
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Affiliation(s)
- Varvara G Blinova
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
| | - Vladimir I Vasilyev
- Joint and Heart Treatment Center, Nizhnyaya Krasnoselskaya St. 4, 107140 Moscow, Russia
| | | | - Dmitry D Zhdanov
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
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Rosso P, Fico E, Colafrancesco S, Bellizzi MG, Priori R, Cerbelli B, Leopizzi M, Giordano C, Greco A, Tirassa P, Severini C, Fusconi M. Involvement of Substance P (SP) and Its Related NK1 Receptor in Primary Sjögren's Syndrome (pSS) Pathogenesis. Cells 2023; 12:1347. [PMID: 37408182 DOI: 10.3390/cells12101347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 05/01/2023] [Indexed: 07/07/2023] Open
Abstract
Primary Sjögren's Syndrome (pSS) is a systemic autoimmune disease that primarily attacks the lacrimal and salivary glands, resulting in impaired secretory function characterized by xerostomia and xerophthalmia. Patients with pSS have been shown to have impaired salivary gland innervation and altered circulating levels of neuropeptides thought to be a cause of decreased salivation, including substance P (SP). Using Western blot analysis and immunofluorescence studies, we examined the expression levels of SP and its preferred G protein-coupled TK Receptor 1 (NK1R) and apoptosis markers in biopsies of the minor salivary gland (MSG) from pSS patients compared with patients with idiopathic sicca syndrome. We confirmed a quantitative decrease in the amount of SP in the MSG of pSS patients and demonstrated a significant increase in NK1R levels compared with sicca subjects, indicating the involvement of SP fibers and NK1R in the impaired salivary secretion observed in pSS patients. Moreover, the increase in apoptosis (PARP-1 cleavage) in pSS patients was shown to be related to JNK phosphorylation. Since there is no satisfactory therapy for the treatment of secretory hypofunction in pSS patients, the SP pathway may be a new potential diagnostic tool or therapeutic target.
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Affiliation(s)
- Pamela Rosso
- Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Elena Fico
- Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Serena Colafrancesco
- Department of Internal Medicine and Medical Specialties, Rheumatology Unit, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Mario Giuseppe Bellizzi
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Roberta Priori
- Division of Rheumatology, Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University, Viale del Policlinico 155, 00185 Rome, Italy
| | - Bruna Cerbelli
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, 00185 Rome, Italy
| | - Martina Leopizzi
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, 00185 Rome, Italy
| | - Carla Giordano
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Antonio Greco
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Paola Tirassa
- Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Cinzia Severini
- Institute of Biochemistry and Cell Biology, National Research Council (IBBC-CNR), Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
| | - Massimo Fusconi
- Department of Sense Organs, Sapienza University of Rome, Viale del Policlinico 155, 00185 Rome, Italy
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Rivière E, Chivasso C, Pascaud J, Bechara R, Ly B, Delporte C, Mariette X, Nocturne G. Hyperosmolar environment and salivary gland epithelial cells increase extra-cellular matrix remodeling and lymphocytic infiltration in Sjögren's syndrome. Clin Exp Immunol 2023; 212:39-51. [PMID: 36759947 PMCID: PMC10081106 DOI: 10.1093/cei/uxad020] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/11/2023] [Accepted: 02/09/2023] [Indexed: 02/11/2023] Open
Abstract
Salivary gland epithelial cells (SGECs) play an active role in primary Sjogren's syndrome (pSS) pathogenesis. Quantitative and qualitative abnormalities of saliva might expose SGECs to chronic hyperosmolarity. We aimed to decipher the links between hyperosmolar stimulation of SGECs and lymphocytic infiltration of the salivary glands (SG) observed in pSS. RNAseq was performed on NS-SV-AC cells stimulated with hyperosmolar media containing NaCl (100 mM) or sucrose (200 mM), or with iso-osmolar (Iso) medium. RNAseq was performed on primary cultured SGECs from pSS and controls, in the presence or not of B cells. Hyperosmolar stimulation of NS-SV-AC-cells identified an upregulation of interferon-induced (MX1, IFIT2) and MMPs genes. Enrichment analysis revealed an over-representation of fibrosis pathway. In parallel, RNAseq of SGECs comparing pSS to controls identified an over-representation of a pathway involving MMPs. Given the unexpected upregulation of collagen (COL3A1, COL1A2) and ADAMTS genes in pSS SGECs, we hypothesized that SGECs might undergo epithelial-mesenchymal transition. ZEB2 was upregulated and SLUG was down regulated in SGECs from pSS versus controls. MMP24 and ZEB2 were higher in SGECs from pSS with a focus score ≥1 versus <1. Lastly, SGECs cocultured with B cells expressed higher levels of COL1A2. These results suggest the existence of a vicious circle. Alteration of SGECs in pSS participates in the establishment of a hyperosmolar microenvironment, which in turn promotes SGECs transcriptomic modifications. These modifications include extracellular matrix remodeling and promote SG lymphocytic infiltration.
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Affiliation(s)
- Elodie Rivière
- Université Paris-Saclay, INSERM UMR 1184, Autoimmune disease laboratory, Center for immunology of viral infections and autoimmune diseases, Le Kremlin Bicêtre, France
- Rheumatology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Clara Chivasso
- Laboratory of Pathophysiological and Nutritional Biochemistry, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Juliette Pascaud
- Université Paris-Saclay, INSERM UMR 1184, Autoimmune disease laboratory, Center for immunology of viral infections and autoimmune diseases, Le Kremlin Bicêtre, France
| | - Rami Bechara
- Université Paris-Saclay, INSERM UMR 1184, Autoimmune disease laboratory, Center for immunology of viral infections and autoimmune diseases, Le Kremlin Bicêtre, France
| | - Bineta Ly
- Université Paris-Saclay, INSERM UMR 1184, Autoimmune disease laboratory, Center for immunology of viral infections and autoimmune diseases, Le Kremlin Bicêtre, France
| | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Xavier Mariette
- Université Paris-Saclay, INSERM UMR 1184, Autoimmune disease laboratory, Center for immunology of viral infections and autoimmune diseases, Le Kremlin Bicêtre, France
- Rheumatology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Gaetane Nocturne
- Université Paris-Saclay, INSERM UMR 1184, Autoimmune disease laboratory, Center for immunology of viral infections and autoimmune diseases, Le Kremlin Bicêtre, France
- Rheumatology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Le Kremlin Bicêtre, France
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Nakamura H, Tanaka T, Ji Y, Zheng C, Afione SA, Warner BM, Oliveira FR, Motta ACF, Rocha EM, Noguchi M, Atsumi T, Chiorini JA. Salivary gland LAMP3 mRNA expression is a possible predictive marker in the response to hydroxychloroquine in Sjögren's disease. PLoS One 2023; 18:e0282227. [PMID: 36821638 PMCID: PMC9949663 DOI: 10.1371/journal.pone.0282227] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 02/10/2023] [Indexed: 02/24/2023] Open
Abstract
Hydroxychloroquine (HCQ) is a lysosomotropic agent that is commonly used for treating Sjögren's disease (SjD). However, its efficacy is controversial because of the divergent response to the drug among patients. In a subgroup of SjD patients, lysosome-associated membrane protein 3 (LAMP3) is elevated in expression in the salivary glands and promotes lysosomal dysregulation and lysosome-dependent apoptotic cell death. In this study, chloroquine (CQ) and its derivative HCQ were tested for their ability to prevent LAMP3-induced apoptosis, in vitro and on a mouse model of SjD. In addition, efficacy of HCQ treatment was retrospectively compared between high LAMP3 mRNA expression in minor salivary glands and those with LAMP3 mRNA levels comparable with healthy controls. Study results show that CQ treatment stabilized the lysosomal membrane in LAMP3-overexpressing cells via deactivation of cathepsin B, resulting in decreased apoptotic cell death. In mice with established SjD-like phenotype, HCQ treatment also significantly decreased apoptotic cell death and ameliorated salivary gland hypofunction. Retrospective analysis of SjD patients found that HCQ tended to be more effective in improving disease activity index, symptom severity and hypergammaglobulinemia in patients with high LAMP3 expression compared those with normal LAMP3 expression. Taken together, these findings suggested that by determining salivary gland LAMP3 mRNA level, a patient's response to HCQ treatment could be predicted. This finding may provide a novel strategy for guiding the development of more personalized medicine for SjD.
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Affiliation(s)
- Hiroyuki Nakamura
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America
| | - Tsutomu Tanaka
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America
| | - Youngmi Ji
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America
| | - Changyu Zheng
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America
| | - Sandra A. Afione
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America
| | - Blake M. Warner
- Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America
| | - Fabiola Reis Oliveira
- Department of Clinical Medicine, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Ana Carolina F. Motta
- Department of Stomatology, Public Health and Forensic Dentistry, School of Dentistry of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Eduardo M. Rocha
- Department of Ophthalmology, Otorhinolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Masayuki Noguchi
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - John A. Chiorini
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States of America
- * E-mail:
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18
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Tanaka T, Nakamura H, Tran DT, Warner BM, Wang Y, Atsumi T, Noguchi M, Chiorini JA. LAMP3 transfer via extracellular particles induces apoptosis in Sjögren's disease. Sci Rep 2023; 13:2595. [PMID: 36788255 PMCID: PMC9929273 DOI: 10.1038/s41598-023-28857-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 01/25/2023] [Indexed: 02/16/2023] Open
Abstract
Sjögren's disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis 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 extracellular particles (EPs) derived from LAMP3-overexpressing cells showed increased apoptosis. Proteomics identified LAMP3 as a major component of EPs derived from LAMP3-overexpressing cells. Live-cell imaging visualized release and uptake of LAMP3-containing EPs 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 EPs, which provides further support for targeting LAMP3 as a therapeutic approach in SjD.
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Affiliation(s)
- Tsutomu Tanaka
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Hiroyuki Nakamura
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Duy T Tran
- NIDCR Imaging Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Blake M Warner
- Salivary Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Yan Wang
- Mass Spectrometry Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masayuki Noguchi
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - John A Chiorini
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.
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Liu Y, Tan YQ, Zhou G. Melatonin: a potential therapeutic approach for the management of primary Sjögren's syndrome. Immunol Res 2023; 71:373-387. [PMID: 36715831 DOI: 10.1007/s12026-023-09360-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 01/03/2023] [Indexed: 01/31/2023]
Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disease that primarily affects the exocrine glands and is mainly characterized by sicca symptoms of the eyes and mouth. Approximately 30-50% of pSS patients develop systemic multi-organ disorders including malignant lymphoma. The etiology of pSS is not well understood; growing evidence suggests that uncontrolled immune/inflammatory responses, excessive oxidative stress, defected apoptosis, dysregulated autophagy, exosomes, and exogenous virus infections may participate in the pathogenesis of pSS. There is no ideal therapeutic method for pSS; the management of pSS is mainly palliative, which aims to alleviate sicca symptoms. Melatonin, as the main secretory product of the pineal gland, has been evidenced to show various physiological functions, including effects of immunoregulation, capability of antioxidation, moderation of autophagy, suppressive activities of apoptosis, regulative capacity of exosomes, properties of anti-infection, and improvement of sleep. The beneficial effects of melatonin have been already validated in some autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). However, our previous research firstly revealed that melatonin might inhibit pathogenic responses of peripheral Th17 and double-negative (DN) T cells in pSS. More importantly, melatonin administration alleviated the development of pSS in animal models with reduced infiltrating lymphocytes, improved functional activity of salivary gland, and decreased production of inflammatory factors as well as autoantibodies. Owing to the important biological properties reported in melatonin are characteristics closely related to the treatment of pSS; the potential role and underlying mechanisms of melatonin in the administration of pSS are certainly worth further investigations. Consequently, the aim of this review is to give a deep insight to the therapeutic potency of melatonin for pSS.
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Affiliation(s)
- Yi Liu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ya-Qin Tan
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Oral Medicine, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, China
| | - Gang Zhou
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China. .,Department of Oral Medicine, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, China.
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Nakamura H, Tanaka T, Zheng C, Afione SA, Warner BM, Noguchi M, Atsumi T, Chiorini JA. Correction of LAMP3-associated salivary gland hypofunction by aquaporin gene therapy. Sci Rep 2022; 12:18570. [PMID: 36329045 PMCID: PMC9633788 DOI: 10.1038/s41598-022-21374-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022] Open
Abstract
Sjögren's disease (SjD) is a chronic autoimmune sialadenitis resulting in salivary gland hypofunction with dry mouth symptom. Previous studies showed that lysosome-associated membrane protein 3 (LAMP3) overexpression is involved in the development of salivary gland hypofunction associated with SjD. However, the molecular mechanisms are still unclear, and no effective treatment exists to reverse gland function in SjD. Analysis on salivary gland samples from SjD patients showed that salivary gland hypofunction was associated with decreased expression of sodium-potassium-chloride cotransporter-1 (NKCC1) and aquaporin 5 (AQP5), which are membrane proteins involved in salivation. Further studies revealed that LAMP3 overexpression decreased their expression levels by promoting endolysosomal degradation. Additionally, we found that LAMP3 overexpression enhanced gene transfer by increasing internalization of adeno-associated virus serotype 2 (AAV2) via the promoted endolysosomal pathway. Retrograde cannulation of AAV2 vectors encoding AQP1 gene (AAV2-AQP1) into salivary glands induced glandular AQP1 expression sufficient to restore salivary flow in LAMP3-overexpressing mice. LAMP3 could play a critical role in the development of salivary gland hypofunction in SjD by promoting endolysosomal degradation of NKCC1 and AQP5. But it also could enhance AAV2-mediated gene transfer to restore fluid movement through induction of AQP1 expression. These findings suggested that AAV2-AQP1 gene therapy is useful in reversing salivary gland function in SjD patients.
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Affiliation(s)
- Hiroyuki Nakamura
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Tsutomu Tanaka
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Changyu Zheng
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Sandra A Afione
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA
| | - Blake M Warner
- Salivary Disorder Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Masayuki Noguchi
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - John A Chiorini
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Bethesda, MD, 20892, USA.
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Sisto M, Ribatti D, Lisi S. Molecular Mechanisms Linking Inflammation to Autoimmunity in Sjögren's Syndrome: Identification of New Targets. Int J Mol Sci 2022; 23:13229. [PMID: 36362017 PMCID: PMC9658723 DOI: 10.3390/ijms232113229] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/26/2022] [Accepted: 10/26/2022] [Indexed: 10/15/2023] Open
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune rheumatic disorder characterized by the lymphocytic infiltration of exocrine glands and the production of autoantibodies to self-antigens. The involvement of the exocrine glands drives the pathognomonic manifestations of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) that define sicca syndrome. To date, the molecular mechanisms mediating pathological salivary gland dysfunction in SS remain to be elucidated, despite extensive studies investigating the underlying cause of this disease, hampering the development of novel therapeutic strategies. Many researchers have identified a multifactorial pathogenesis of SS, including environmental, genetic, neuroendocrine, and immune factors. In this review, we explore the latest developments in understanding the molecular mechanisms involved in the pathogenesis of SS, which have attracted increasing interest in recent years.
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Affiliation(s)
- Margherita Sisto
- Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari “Aldo Moro”, Piazza Giulio Cesare 1, I-70124 Bari, Italy
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22
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Cytotoxic CD8 + T cells may be drivers of tissue destruction in Sjögren's syndrome. Sci Rep 2022; 12:15427. [PMID: 36104369 PMCID: PMC9475031 DOI: 10.1038/s41598-022-19397-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/29/2022] [Indexed: 01/14/2023] Open
Abstract
Sjögren's syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren's syndrome were undertaken, including the quantitation of the frequency of selected cell-cell interactions in the disease milieu. Quantitative analyses of CD4+ T cell subsets and of CD8+ T cells in the labial salivary glands from untreated patients with primary Sjögren's syndrome revealed that activated CD8+ cytotoxic T cells (CD8+CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8+ T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren's syndrome is primarily driven by CD8+CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells.
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Tanaka T, Warner BM, Michael DG, Nakamura H, Odani T, Yin H, Atsumi T, Noguchi M, Chiorini JA. LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization. Autophagy 2022; 18:1629-1647. [PMID: 34802379 PMCID: PMC9298453 DOI: 10.1080/15548627.2021.1995150] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 10/06/2021] [Accepted: 10/14/2021] [Indexed: 01/18/2023] Open
Abstract
ABBREVIATIONS A253-control: A253 control for LAMP3 stable overexpression; A253- LAMP3: A253 LAPM3 stable overexpression; CASP1: caspase 1; CASP3: caspase 3; CHX: cycloheximide; CTSB: cathepsin B; CTSD: cathepsin D; CQ: chloroquine; DCs: dendritic cells; ER: endoplasmic reticulum; LGALS3: galectin 3; HCV: hepatitis C virus; HSG-control: HSG control for LAMP3 stable overexpression; HSG-LAMP3: HSG LAMP3 stable overexpression; HSP: heat shock protein; HTLV-1: human T-lymphocyte leukemia virus-1; IXA: ixazomib; LAMP: lysosomal associated membrane protein; MHC: major histocompatibility complex; mAb: monoclonal antibody; OE: overexpression; pepA: pepstatin A; pAb: polyclonal antibody; pSS: primary Sjögren syndrome; qRT-PCR: quantitative real- time reverse transcriptase polymerase chain reaction; SLE: systemic lupus erythematosus; SS: Sjögren syndrome; UPR: unfolded protein response; V-ATPase: vacuolar-type proton- translocating ATPase; Y-VAD: Ac-YVAD-cmk; Z-DEVD; Z-DEVD-fmk; Z-VAD: Z-VAD- fmk.
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Affiliation(s)
- Tsutomu Tanaka
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Blake M. Warner
- Salivary Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Drew G. Michael
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Hiroyuki Nakamura
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Toshio Odani
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Hongen Yin
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University, Sapporo, Japan
| | - Masayuki Noguchi
- Division of Cancer Biology, Institute for Genetic Medicine Hokkaido University, Sapporo, Japan
| | - John A. Chiorini
- Adeno-Associated Virus Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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Witas R, Rasmussen A, Scofield RH, Radfar L, Stone DU, Grundahl K, Lewis D, Sivils KL, Lessard CJ, Farris AD, Nguyen CQ. Defective Efferocytosis in a Murine Model of Sjögren's Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor. Int J Mol Sci 2021; 22:9711. [PMID: 34575873 PMCID: PMC8466327 DOI: 10.3390/ijms22189711] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 01/01/2023] Open
Abstract
Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjSS) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjSS mice, as evidenced by reduced Rac1 activation in SjSS mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjSS mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjSS mice.
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Affiliation(s)
- Richard Witas
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA;
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32608, USA
| | - Astrid Rasmussen
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (A.R.); (K.G.); (C.J.L.)
| | - Robert H. Scofield
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (R.H.S.); (K.L.S.); (A.D.F.)
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Lida Radfar
- Department of Oral Diagnosis and Radiology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Donald U. Stone
- Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Kiely Grundahl
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (A.R.); (K.G.); (C.J.L.)
| | - David Lewis
- Department of Oral Pathology, College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Kathy L. Sivils
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (R.H.S.); (K.L.S.); (A.D.F.)
| | - Christopher J. Lessard
- Genes and Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (A.R.); (K.G.); (C.J.L.)
| | - A. Darise Farris
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; (R.H.S.); (K.L.S.); (A.D.F.)
| | - Cuong Q. Nguyen
- Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA;
- Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL 32608, USA
- Center of Orphaned Autoimmune Diseases, University of Florida, Gainesville, FL 32611-0880, USA
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+3179G/A Insulin-Like Growth Factor-1 Receptor Polymorphism: A Novel Susceptibility Contributor in Anti-Ro/SSA Positive Patients with Sjögren's Syndrome: Potential Clinical and Pathogenetic Implications. J Clin Med 2021; 10:jcm10173960. [PMID: 34501407 PMCID: PMC8432056 DOI: 10.3390/jcm10173960] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Alterations of the insulin-like growth factor (IGF) pathway along with genetic variations of the IGF1 receptor (IGF1R) gene have been linked to the development of systemic autoimmunity, possibly through apoptosis induction. This study aims to investigate whether genetic variations of the IGF1R contribute to Sjögren’s syndrome (SS) pathogenesis and explores potential functional implications. Methods: DNA extracted from whole peripheral blood derived from 277 primary SS patients, complicated or not by lymphoma, and 337 Healthy controls (HC) was genotyped for the rs2229765 IGF1R polymorphism using the RFLP-PCR assay. Gene expression of IGF1R and IGF1 isoforms, caspases 1, 4, and 5, and inflammasome components NLRP3, ASC, IL1β, IL18, IL33, IGFBP3, and IGFBP6 were quantitated by RT-PCR in total RNA extracted from minor salivary gland biopsies (MSGs) of 50 SS patients and 13 sicca controls (SCs). In addition, IGF1R immunohistochemical (IHC) expression was assessed in formalin-fixed, paraffin-embedded MSG tissue sections derived from 10 SS patients and 5 SCs. Results: The prevalence of the A/A genotype of the rs2229765 IGF1R polymorphism was significantly higher in the anti-Ro/SSA positive SS population compared to healthy controls (24.8% vs. 10.7%, p = 0.001). Moreover, IGF1Rs at both mRNA and protein levels were reduced in SS-derived MSGs compared to SCs and were negatively associated with caspase 1 transcripts. The latter were positively correlated with NLRP3, ASC, and IL1β at the salivary gland tissue level. IGF1R expression in peripheral blood was negatively correlated with ESR and IgG serum levels and positively correlated with urine-specific gravity values. Conclusions: The rs2229765 IGF1R variant confers increased susceptibility for seropositive primary SS. Dampened IGF1R mRNA and protein expression in salivary gland tissues could be related to increased apoptosis and subsequently to the activation of inflammasome pathways.
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Zhang J, Zhu L, Shi H, Zheng H. Protective effects of miR-155-5p silencing on IFN-γ-induced apoptosis and inflammation in salivary gland epithelial cells. Exp Ther Med 2021; 22:882. [PMID: 34194560 PMCID: PMC8237265 DOI: 10.3892/etm.2021.10314] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 01/08/2021] [Indexed: 12/28/2022] Open
Abstract
Previous studies have demonstrated that microRNAs (miRNAs/miRs) serve a vital role in the pathogenesis of Sjögren's syndrome (SS). The present study aimed to investigate the role of miR-155-5p in SS and determine its underlying molecular mechanism. An inflammatory lesion model was established by stimulating salivary gland epithelial cells (SGECs) with interferon-γ (IFN-γ). The apoptosis of SGECs was measured by using flow cytometry. Levels of proinflammatory factors were detected by reverse transcription-quantitative PCR and ELISA, respectively. Immunofluorescence was used for p65 staining. Dual-luciferase reporter assay was performed to verify the interaction between miR-155-5p and arrestin β2 (ARRB2). The protein levels in the NF-κB signaling pathway were assessed by western blotting. The results of the present study demonstrated that treatment with IFN-γ increased miR-155-5p expression, in addition to inducing apoptosis and inflammation in SGECs. Furthermore, overexpression of miR-155-5p promoted IFN-γ-induced apoptosis and inflammation in SGECs. Overexpression of miR-155-5p also increased Bax protein expression, enzyme activities of caspase 3 and caspase 9, release of inflammatory cytokines interleukin-6 and tumor necrosis factor-α, and decreased Bcl-2 protein expression in IFN-γ-treated SGECs. By contrast, all of the effects aforementioned were reversed following miR-155-5p knockdown. These results demonstrated that miR-155-5p activated the NF-κB signaling pathway, where treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate, reversed the effects of miR-155-5p overexpression on the inflammatory factors in IFN-γ-induced SGECs. miR-155-5p was demonstrated to target ARRB2 and negatively regulated its expression levels, such that overexpression of ARRB2 reversed the effects of miR-155-5p overexpression on the inflammatory response, apoptosis and the NF-κB signaling pathway in IFN-γ-treated SGECs. Collectively, results from the present study suggest that miR-155-5p may activate the NF-κB signaling pathway by negatively regulating ARRB2 to promote salivary gland damage during SS pathogenesis. This suggests that miR-155-5p may serve to be a potential target for the treatment of SS.
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Affiliation(s)
- Jingli Zhang
- Department of Rheumatology and Immunology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Lingling Zhu
- Department of Hematology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Hong Shi
- Department of Rheumatology and Immunology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
| | - Huizhe Zheng
- Department of Pathology, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China.,Key Laboratory of Tumor Prevention and Treatment of Heilongjiang Province, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang 157011, P.R. China
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De Benedittis G, Ciccacci C, Latini A, Novelli L, Novelli G, Borgiani P. Emerging Role of microRNAs and Long Non-Coding RNAs in Sjögren's Syndrome. Genes (Basel) 2021; 12:genes12060903. [PMID: 34208031 PMCID: PMC8230573 DOI: 10.3390/genes12060903] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/07/2021] [Accepted: 06/09/2021] [Indexed: 12/14/2022] Open
Abstract
Sjögren’s Syndrome (SS) is a chronic autoimmune inflammatory disease. It is considered a multifactorial pathology, in which underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to development. The epigenetic regulations represent a link between genetic predisposition and environmental factors. Recent studies suggested a regulatory role for non-coding RNAs in critical biological and disease processes. Among non-coding RNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play a critical role in the post-transcriptional mRNA expression, forming a complex network of gene expression regulation. This review aims to give an overview of the latest studies that have investigated the role of miRNAs and lncRNAs in the SS. We included papers that investigated the expression of non-coding RNAs on different tissues, in particular on peripheral blood mononuclear cells and salivary glands. However, regarding the involvement of non-coding RNAs genetic variability in SS susceptibility very few data are available. Further research could help to elucidate underlying pathogenic processes of SS and provide new opportunities for the development of targeted therapies.
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Affiliation(s)
- Giada De Benedittis
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy; (G.D.B.); (A.L.); (G.N.); (P.B.)
| | - Cinzia Ciccacci
- UniCamillus–Saint Camillus International University of Health Sciences, 00131 Rome, Italy;
- Correspondence: ; Tel.: +39-06-7259-6090
| | - Andrea Latini
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy; (G.D.B.); (A.L.); (G.N.); (P.B.)
| | - Lucia Novelli
- UniCamillus–Saint Camillus International University of Health Sciences, 00131 Rome, Italy;
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy; (G.D.B.); (A.L.); (G.N.); (P.B.)
- IRCCS Neuromed, 86077 Pozzilli, Italy
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy; (G.D.B.); (A.L.); (G.N.); (P.B.)
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CTRP3 promotes TNF-α-induced apoptosis and barrier dysfunction in salivary epithelial cells. Cell Signal 2021; 85:110042. [PMID: 33991612 DOI: 10.1016/j.cellsig.2021.110042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 04/17/2021] [Accepted: 05/11/2021] [Indexed: 11/20/2022]
Abstract
BACKGROUND C1q/tumour necrosis factor-related protein 3 (CTRP3) plays important roles in metabolism and inflammatory responses in various cells and tissues. However, the expression and function of CTRP3 in salivary glands have not been explored. METHODS The expression and distribution of CTRP3 were detected by western blot, polymerase chain reaction, immunohistochemical and immunofluorescence staining. The effects of CTRP3 on tumour necrosis factor (TNF)-α-induced apoptosis and barrier dysfunction were detected by flow cytometry, western blot, co-immunoprecipitation, and measurement of transepithelial resistance and paracellular tracer flux. RESULTS CTRP3 was distributed in both acinar and ductal cells of human submandibular gland (SMG) and was primarily located in the ducts of rat and mouse SMGs. TNF-α increased the apoptotic rate, elevated expression of cleaved caspase 3 and cytochrome C, and reduced B cell lymphoma-2 (Bcl-2) levels in cultured human SMG tissue and SMG-C6 cells, and CTRP3 further enhanced TNF-α-induced apoptosis response. Additionally, CTRP3 aggravated TNF-α-increased paracellular permeability. Mechanistically, CTRP3 promoted TNF-α-enhanced TNF type I receptor (TNFR1) expression, inhibited the expression of cellular Fas-associated death domain (FADD)-like interleukin-1β converting enzyme inhibitory protein (c-FLIP), and increased the recruitment of FADD with receptor-interacting protein kinase 1 and caspase 8. Moreover, CTRP3 was significantly increased in the labial gland of Sjögren's syndrome patients and in the serum and SMG of nonobese diabetic mice. CONCLUSIONS These findings suggest that the salivary glands are a novel source of CTRP3 synthesis and secretion. CTRP3 might promote TNF-α-induced cell apoptosis through the TNFR1-mediated complex II pathway.
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Loureiro-Amigo J, Palacio-García C, Martínez-Gallo M, Martínez-Valle F, Ramentol-Sintas M, Solans-Laqué R. Utility of lymphocyte phenotype profile to differentiate primary Sjögren syndrome from Sicca syndrome. Rheumatology (Oxford) 2021; 60:5647-5658. [PMID: 33620072 DOI: 10.1093/rheumatology/keab170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 02/07/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND blood B cell profile has been proposed to have diagnostic utility in primary Sjögren syndrome (pSS), but the potential utility of advanced lymphocyte profiling to differentiate between pSS and Sicca syndrome has not been fully investigated. METHODS distribution of peripheral lymphocyte subpopulations was analysed by flow cytometry in 68 patients with pSS, 26 patients with Sicca syndrome and 23 healthy controls. The ability to discriminate between pSS and Sicca syndrome was analysed using the area under the curve (AUC) of the receiver operating characteristic curve of the different lymphocyte subsets. RESULTS the ratio between naïve/memory B cell proportions showed an AUC of 0.742 to differentiate pSS and Sicca syndrome, with a sensitivity of 76.6% and a specificity of 72% for a cut-off value of 3.4. The ratio of non-switched memory B cells to activated CD4+ T cells percentage (BNSM/CD4ACT) presented the highest AUC (0.840) with a sensitivity of 83.3% and specificity of 81.7% for a cut-off value < 4.1. To differentiate seronegative pSS patients from Sicca patients the BNSM/CD4ACT ratio exhibited an AUC of 0.742 (sensitivity 75%, specificity 66.7%, cut-off value < 4.4), and the number of naïve CD4 T cells had an AUC of 0.821 (sensitivity 76.9%, specificity 88.9%, cut-off value < 312/mm3). CONCLUSION patients with pSS show a profound imbalance in the distribution of circulating T and B lymphocytes subsets. The ratio BNSM/CD4ACT is useful to discriminate between pSS and Sicca syndrome.
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Affiliation(s)
- Jose Loureiro-Amigo
- Autoimmune Systemic Diseases Unit. Internal Medicine Department. Hospital Universitari Vall d'Hebron. Barcelona. Spain.,Department of Medicine, Faculty of Medicine. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Carlos Palacio-García
- Flow Cytometry Unit, Haematology Department. Hospital Universitari Vall d'Hebron. Barcelona. Spain
| | - Mónica Martínez-Gallo
- Immunology Department. Hospital Universitari Vall d'Hebron. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Fernando Martínez-Valle
- Autoimmune Systemic Diseases Unit. Internal Medicine Department. Hospital Universitari Vall d'Hebron. Barcelona. Spain.,Department of Medicine, Faculty of Medicine. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Marc Ramentol-Sintas
- Autoimmune Systemic Diseases Unit. Internal Medicine Department. Hospital Universitari Vall d'Hebron. Barcelona. Spain
| | - Roser Solans-Laqué
- Autoimmune Systemic Diseases Unit. Internal Medicine Department. Hospital Universitari Vall d'Hebron. Barcelona. Spain.,Department of Medicine, Faculty of Medicine. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
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Huijser E, Versnel MA. Making Sense of Intracellular Nucleic Acid Sensing in Type I Interferon Activation in Sjögren's Syndrome. J Clin Med 2021; 10:532. [PMID: 33540529 PMCID: PMC7867173 DOI: 10.3390/jcm10030532] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/26/2021] [Accepted: 01/29/2021] [Indexed: 12/13/2022] Open
Abstract
Primary Sjögren's syndrome (pSS) is a systemic autoimmune rheumatic disease characterized by dryness of the eyes and mucous membranes, which can be accompanied by various extraglandular autoimmune manifestations. The majority of patients exhibit persistent systemic activation of the type I interferon (IFN) system, a feature that is shared with other systemic autoimmune diseases. Type I IFNs are integral to anti-viral immunity and are produced in response to stimulation of pattern recognition receptors, among which nucleic acid (NA) receptors. Dysregulated detection of endogenous NAs has been widely implicated in the pathogenesis of systemic autoimmune diseases. Stimulation of endosomal Toll-like receptors by NA-containing immune complexes are considered to contribute to the systemic type I IFN activation. Accumulating evidence suggest additional roles for cytosolic NA-sensing pathways in the pathogenesis of systemic autoimmune rheumatic diseases. In this review, we will provide an overview of the functions and signaling of intracellular RNA- and DNA-sensing receptors and summarize the evidence for a potential role of these receptors in the pathogenesis of pSS and the sustained systemic type I IFN activation.
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Affiliation(s)
| | - Marjan A. Versnel
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands;
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31
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Lee J, Alam J, Choi E, Ko YK, Lee A, Choi Y. Association of a dysbiotic oral microbiota with the development of focal lymphocytic sialadenitis in IκB-ζ-deficient mice. NPJ Biofilms Microbiomes 2020; 6:49. [PMID: 33127905 PMCID: PMC7599236 DOI: 10.1038/s41522-020-00158-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/07/2020] [Indexed: 01/12/2023] Open
Abstract
Mice lacking IκB-ζ, a protein encoded by the Nfkbiz gene, spontaneously develop a Sjögren’s syndrome-like disease involving the lachrymal glands, but no salivary gland symptoms have been reported. We found that Nfkbiz−/− female mice presented a significantly reduced salivary flow rate, focal lymphocytic sialadenitis (FLS), and a dysbiotic oral microbiota at week 24. To dissect the contributions of genetic and environmental factors to the salivary gland phenotype, Nfkbiz+/+ and Nfkbiz−/− mice were cohoused after weaning and evaluated at week 20. Cohousing alleviated the salivary gland phenotype of Nfkbiz−/− mice but did not induce any disease phenotype in Nfkbiz+/+ mice. Additionally, the oral microbiota in the cohoused mice was synchronized toward that in Nfkbiz+/+ mice. In conclusion, IκB-ζ-deficient mice developed hyposalivation and FLS, in which a dysbiotic oral microbiota played an important role. This finding suggests that the dysbiotic oral microbiota could be a therapeutic target.
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Affiliation(s)
- Junho Lee
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea.,Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jehan Alam
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea.,Department of Ophthalmology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Eunji Choi
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Yeon Kyeong Ko
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Ahreum Lee
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Youngnim Choi
- Department of Immunology and Molecular Microbiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea.
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32
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Contributions of Major Cell Populations to Sjögren's Syndrome. J Clin Med 2020; 9:jcm9093057. [PMID: 32971904 PMCID: PMC7564211 DOI: 10.3390/jcm9093057] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Sjögren’s syndrome (SS) is a female dominated autoimmune disease characterized by lymphocytic infiltration into salivary and lacrimal glands and subsequent exocrine glandular dysfunction. SS also may exhibit a broad array of extraglandular manifestations including an elevated incidence of non-Hodgkin’s B cell lymphoma. The etiology of SS remains poorly understood, yet progress has been made in identifying progressive stages of disease using preclinical mouse models. The roles played by immune cell subtypes within these stages of disease are becoming increasingly well understood, though significant gaps in knowledge still remain. There is evidence for distinct involvement from both innate and adaptive immune cells, where cells of the innate immune system establish a proinflammatory environment characterized by a type I interferon (IFN) signature that facilitates propagation of the disease by further activating T and B cell subsets to generate autoantibodies and participate in glandular destruction. This review will discuss the evidence for participation in disease pathogenesis by various classes of immune cells and glandular epithelial cells based upon data from both preclinical mouse models and human patients. Further examination of the contributions of glandular and immune cell subtypes to SS will be necessary to identify additional therapeutic targets that may lead to better management of the disease.
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33
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Tanaka T, Warner BM, Odani T, Ji Y, Mo YQ, Nakamura H, Jang SI, Yin H, Michael DG, Hirata N, Suizu F, Ishigaki S, Oliveira FR, Motta ACF, Ribeiro-Silva A, Rocha EM, Atsumi T, Noguchi M, Chiorini JA. LAMP3 induces apoptosis and autoantigen release in Sjögren's syndrome patients. Sci Rep 2020; 10:15169. [PMID: 32939030 PMCID: PMC7494869 DOI: 10.1038/s41598-020-71669-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 08/10/2020] [Indexed: 12/16/2022] Open
Abstract
Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by dysfunction of secretory epithelia with only palliative therapy. Patients present with a constellation of symptoms, and the diversity of symptomatic presentation has made it difficult to understand the underlying disease mechanisms. In this study, aggregation of unbiased transcriptome profiling data sets of minor salivary gland biopsies from controls and Sjögren's syndrome patients identified increased expression of lysosome-associated membrane protein 3 (LAMP3/CD208/DC-LAMP) in a subset of Sjögren's syndrome cases. Stratification of patients based on their clinical characteristics suggested an association between increased LAMP3 expression and the presence of serum autoantibodies including anti-Ro/SSA, anti-La/SSB, anti-nuclear antibodies. In vitro studies demonstrated that LAMP3 expression induces epithelial cell dysfunction leading to apoptosis. Interestingly, LAMP3 expression resulted in the accumulation and release of intracellular TRIM21 (one component of SSA), La (SSB), and α-fodrin protein, common autoantigens in Sjögren's syndrome, via extracellular vesicles in an apoptosis-independent mechanism. This study defines a clear role for LAMP3 in the initiation of apoptosis and an independent pathway for the extracellular release of known autoantigens leading to the formation of autoantibodies associated with this disease.ClinicalTrials.gov Identifier: NCT00001196, NCT00001390, NCT02327884.
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Affiliation(s)
- Tsutomu Tanaka
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Blake M Warner
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Toshio Odani
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Youngmi Ji
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Ying-Qian Mo
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Hiroyuki Nakamura
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Shyh-Ing Jang
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Hongen Yin
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Drew G Michael
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA
| | - Noriyuki Hirata
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Futoshi Suizu
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Satoko Ishigaki
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - Fabiola Reis Oliveira
- Department of Clinical Medicine, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Ana Carolina F Motta
- Department of Stomatology, Public Health and Forensic Dentistry, School of Dentistry of Ribeirão Preto, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Alfredo Ribeiro-Silva
- Department of Pathology and Legal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Eduardo M Rocha
- Department of Ophthalmology, Otorhinolaryngology, Head and Neck Surgery, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Masayuki Noguchi
- Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
| | - John A Chiorini
- National Institute of Dental and Craniofacial Research, National Institutes of Health, NIH 10 Center Dr., Bethesda, MD, 20892, USA.
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34
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Yang Y, Hou Y, Li J, Zhang F, Du Q. Characterization of antiapoptotic microRNAs in primary Sjögren's syndrome. Cell Biochem Funct 2020; 38:1111-1118. [PMID: 32575162 DOI: 10.1002/cbf.3569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/23/2020] [Accepted: 05/25/2020] [Indexed: 02/02/2023]
Abstract
During the development of primary Sjögren's syndrome (pSS), aberrant expression of autoantigen is a hallmark event. To explore the regulation of autoantigen tripartite motif containing 21 (Ro/SSA, TRIM21), microRNA profiling was performed in our previous study. In which, two TRIM21-targeting microRNAs were identified, namely miR-1207-5p and miR-4695-3p. To further pursue their roles in the development of pSS, assays were performed with cultured human submandibular gland (HSG) cells, and salivary gland tissues. Results showed that transfection of miR-1207-5p or miR-4695-3p mimics down-regulated not only the expression of TRIM21, but also the levels of pro-apoptotic genes B cell lymphoma 2 associated X (BAX), Caspase 9 (CASP-9) and Caspase 8 (CASP-8). This finally led to antiapoptotic phenotypes in HSG cells. Consistent with the antiapoptotic activity, transfection of microRNA inhibitors up-regulated the expression of TRIM21 and led to a pro-apoptotic phenotype. These therefore propose miR-1207-5p and miR-4695-3p as two antiapoptotic microRNAs functioning through apoptosis pathway. Supporting this speculation, assays performed with salivary gland tissues revealed down-regulation of miR-1207-5p and miR-4695-3p, as well as up-regulation of TRIM21 and pro-apoptotic CASP-8 gene in pSS samples. SIGNIFICANCE OF THE STUDY: For pSS patients, apoptosis of acinar and ductal epithelial cells has been proposed to be a potential mechanism that impairs the secretion of salivary glands. In our study, two autoantigen-targeting microRNAs were characterized as antiapoptotic microRNAs functioning through apoptosis pathway, which may be potential targets for the treatment of pSS.
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Affiliation(s)
- Ying Yang
- Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yingzi Hou
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Jinghui Li
- Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Fangming Zhang
- Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Quan Du
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
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Shikayama T, Fujita-Yoshigaki J, Sago-Ito M, Nakamura-Kiyama M, Naniwa M, Hitomi S, Ujihara I, Kataoka S, Yada N, Ariyoshi W, Usui M, Nakashima K, Ono K. Hematogenous apoptotic mechanism in salivary glands in chronic periodontitis. Arch Oral Biol 2020; 117:104775. [PMID: 32512258 DOI: 10.1016/j.archoralbio.2020.104775] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 05/06/2020] [Accepted: 05/15/2020] [Indexed: 11/29/2022]
Abstract
OBJECTIVE The aim of the study is to investigate the apoptotic mechanism in salivary glands in the rat experimental periodontitis model. DESIGN A rat periodontitis model was prepared by using a ligature around the second upper molar. In the salivary (parotid and submandibular) glands and blood samples, putative apoptotic factors and pathway molecules were investigated in vivo and in vitro. RESULTS Four weeks of ligation (chronic periodontitis) demonstrated significant apoptotic atrophy of the salivary gland, but one week of ligation (initial periodontitis) did not. In the blood plasma, tumor necrosis factor-α (TNF-α) was increased in the periodontitis model, but interleukin-1β and -6 were not. TNF-α receptor type 1, which has an intracellular apoptotic pathway, was expressed in the salivary glands of rats. Western blot analysis of cultured rat primary salivary gland cells demonstrated that TNF-α induced cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3 in a dose-dependent manner, indicating apoptosis induction. Additionally, we found increment of circulating lymphocytes in the model. Expression of mRNA and immunoreactive cells for the B lymphocyte marker CD19 were increased in the salivary gland in the model. Western blotting showed that coculture with extracted B cells from the periodontitis model increased cleaved PARP in salivary gland cells. CONCLUSIONS Chronic periodontitis status leads to an increase in circulating TNF-α and B lymphocyte infiltration, resulting in apoptotic atrophy of the salivary gland as a periodontitis-induced systemic response.
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Affiliation(s)
- T Shikayama
- Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka, 803-8580, Japan; Division of Periodontology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - J Fujita-Yoshigaki
- Department of Physiology, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakaecho-nishi, Matsudo, Chiba 271-8587, Japan.
| | - M Sago-Ito
- Division of Orofacial Functions and Orthodontics, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - M Nakamura-Kiyama
- Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka, 803-8580, Japan; Division of Periodontology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - M Naniwa
- Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka, 803-8580, Japan; Division of Oral Health Sciences, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - S Hitomi
- Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka, 803-8580, Japan.
| | - I Ujihara
- Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka, 803-8580, Japan.
| | - S Kataoka
- Division of Anatomy, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - N Yada
- Division of Oral Pathology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - W Ariyoshi
- Division of Infections and Molecular Biology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - M Usui
- Division of Periodontology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - K Nakashima
- Division of Periodontology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka 803-8580, Japan.
| | - K Ono
- Division of Physiology, Kyushu Dental University, 2-6-1 Manazuru, Kokurakitaku, Kitakyushu, Fukuoka, 803-8580, Japan.
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Serum 14-3-3η protein is associated with clinical and serologic features of Sjögren's syndrome in patients with systemic lupus erythematosus: a cross-sectional analysis. Clin Rheumatol 2020; 39:2603-2610. [PMID: 32206972 DOI: 10.1007/s10067-020-05033-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 12/30/2019] [Accepted: 03/05/2020] [Indexed: 10/24/2022]
Abstract
INTRODUCTION/OBJECTIVES Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) may coexist and carry a higher risk for future comorbidities. Although 14-3-3η protein is recently a known diagnostic marker in rheumatoid arthritis (RA), its role has not been investigated in SLE. The aim of this study was to compare serum 14-3-3η protein level in SLE and RA patients and to examine its association with clinical and laboratory features in SLE patients. METHODS Eighty-four SLE patients and 39 RA patients were included. Sociodemographic, SLE disease activity index (SLEDAI), and damage index were assessed for SLE patients. Data about secondary SS were collected. 14-3-3η was measured by ELISA; titres above 0.19 ng/ml were considered positive. RESULTS Serum 14-3-3η protein in SLE was significantly lower than in RA (0.37 ± 0.09 vs 1.5 ± 0.51; p < 0.001). 14-3-3η protein level was comparable between SLE patients with and without arthritis (0.29 ± 0.8 vs 0.15 ± 0.08 respectively; p = 0.20). Serum 14-3-3η protein level was higher in SLE with secondary SS features compared to those without (0.22 ± 0.10 IU/ml vs 0.11 ± 0.04 IU/ml; respectively, p < 0.001). There were no differences in 14-3-3η positivity for other lupus criteria or correlation of 14-3-3η titer with SLEDAI. 14-3-3η protein at 1.11 ng/mL yield a secondary SS diagnostic accuracy of 71%. CONCLUSIONS Serum 14-3-3η protein level is high in SLE-associated SS. The 14-3-3η protein level was able to distinguish patients with secondary SS among patients with SLE. Studying the role of 14-3-3η protein in Sjögren's syndrome would be considered in further larger scale studies to confirm the impact of any association. Key Points • Serum 14-3-3η protein level is significantly higher in systemic lupus patients with secondary Sjögren's syndrome (SS) in comparison to those without. • Serum 14-3-3η protein can be used as a useful marker to distinguish patients with secondary SS among patients with systemic lupus. • 14-3-3η protein level shows no difference between systemic lupus patients with and without arthritis.
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Fisher BA, Szanto A, Ng WF, Bombardieri M, Posch MG, Papas AS, Farag AM, Daikeler T, Bannert B, Kyburz D, Kivitz AJ, Carsons SE, Isenberg DA, Barone F, Bowman SJ, Espié P, Floch D, Dupuy C, Ren X, Faerber PM, Wright AM, Hockey HU, Rotte M, Milojevic J, Avrameas A, Valentin MA, Rush JS, Gergely P. Assessment of the anti-CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study. THE LANCET. RHEUMATOLOGY 2020; 2:e142-e152. [PMID: 38263652 DOI: 10.1016/s2665-9913(19)30135-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 11/25/2019] [Accepted: 11/26/2019] [Indexed: 11/20/2022]
Abstract
BACKGROUND Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40-CD154-mediated T cell-B cell interactions in primary Sjögren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjögren's syndrome. METHODS This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18-75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjögren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov, NCT02291029. FINDINGS Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96-9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo. INTERPRETATION To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjögren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40-CD154 interactions in primary Sjögren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further. FUNDING Novartis Pharma.
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Affiliation(s)
- Benjamin A Fisher
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Antonia Szanto
- Division of Clinical Immunology, Department of Internal Medicine, University of Debrecen, Debrecen, Hungary
| | - Wan-Fai Ng
- NIHR Newcastle Biomedical Research Centre and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Clinical Research Facility, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Michele Bombardieri
- William Harvey Research Institute, Queen Mary University of London, London, UK
| | | | - Athena S Papas
- Division of Oral Medicine, Tufts University School of Dental Medicine, Tufts University, Boston, USA
| | - Arwa M Farag
- Division of Oral Medicine, Tufts University School of Dental Medicine, Tufts University, Boston, USA; Department of Oral Diagnostic Science, Faculty of Dentistry, King AbdulAziz University, Jeddah, Saudi Arabia
| | - Thomas Daikeler
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland
| | - Bettina Bannert
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland
| | - Diego Kyburz
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland
| | - Alan J Kivitz
- Department of Rheumatology, Altoona Center for Clinical Research, Duncansville, PA, USA
| | - Steven E Carsons
- Division of Rheumatology, Allergy and Immunology NYU Winthrop Hospital, NYU Long Island School of Medicine, New York, NY, USA
| | - David A Isenberg
- Centre for Rheumatology, Department of Medicine, University College London Hospital, London, UK
| | - Francesca Barone
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon J Bowman
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre and Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Pascal Espié
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - David Floch
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Cyrielle Dupuy
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Xiaohui Ren
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Petra M Faerber
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | | | | - Michael Rotte
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Julie Milojevic
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | | | | - James S Rush
- Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Peter Gergely
- Novartis Institutes for Biomedical Research, Basel, Switzerland.
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Dolcino M, Tinazzi E, Vitali C, Del Papa N, Puccetti A, Lunardi C. Long Non-Coding RNAs Modulate Sjögren's Syndrome Associated Gene Expression and Are Involved in the Pathogenesis of the Disease. J Clin Med 2019; 8:jcm8091349. [PMID: 31480511 PMCID: PMC6780488 DOI: 10.3390/jcm8091349] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 08/22/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Primary Sjögren's syndrome (pSjS) is a chronic systemic autoimmune disorder, primarily affecting exocrine glands; its pathogenesis is still unclear. Long non-coding RNAs (lncRNAs) are thought to play a role in the pathogenesis of autoimmune diseases and a comprehensive analysis of lncRNAs expression in pSjS is still lacking. To this aim, the expression of more than 540,000 human transcripts, including those ascribed to more than 50,000 lncRNAs is profiled at the same time, in a cohort of 16 peripheral blood mononuclear cells PBMCs samples (eight pSjS and eight healthy subjects). A complex network analysis is carried out on the global set of molecular interactions among modulated genes and lncRNAs, leading to the identification of reliable lncRNA-miRNA-gene functional interactions. Taking this approach, a few lncRNAs are identified as targeting highly connected genes in the pSjS transcriptome, since they have a major impact on gene modulation in the disease. Such genes are involved in biological processes and molecular pathways crucial in the pathogenesis of pSjS, including immune response, B cell development and function, inflammation, apoptosis, type I and gamma interferon, epithelial cell adhesion and polarization. The identification of deregulated lncRNAs that modulate genes involved in the typical features of the disease provides insight in disease pathogenesis and opens avenues for the design of novel therapeutic strategies.
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Affiliation(s)
- Marzia Dolcino
- Department of Medicine, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy
| | - Elisa Tinazzi
- Department of Medicine, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy
| | - Claudio Vitali
- Sections of Rheumatology, Villa S. Giuseppe, Como and Casa di Cura di Lecco, 23900 Lecco, Italy
| | | | - Antonio Puccetti
- Department of Experimental Medicine, Section of Histology, University of Genova, Via G.B. Marsano 10, 16132 Genova, Italy
| | - Claudio Lunardi
- Department of Medicine, University of Verona, Piazzale L.A. Scuro 10, 37134 Verona, Italy.
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Du ZH, Ding C, Zhang Q, Zhang Y, Ge XY, Li SL, Yu GY. Stem cells from exfoliated deciduous teeth alleviate hyposalivation caused by Sjögren syndrome. Oral Dis 2019; 25:1530-1544. [PMID: 31046162 DOI: 10.1111/odi.13113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/08/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVES To evaluate the effect of stem cells from exfoliated deciduous teeth on the hyposalivation caused by Sjögren syndrome (SS) and investigate the mechanism. METHODS Stem cells were injected into the tail veins of non-obese diabetic mice, the animal model of SS. The saliva flow was measured after pilocarpine intraperitoneal injection. Apoptosis and autophagy were evaluated by TUNEL and Western blot. Lymphocyte proportions were detected by flow cytometer. RESULTS Fluid secretion was decreased in 21-week-old mice. Stem cell treatment increased fluid secretion, alleviated inflammation in the submandibular glands and reduced inflammatory cytokine levels in the serum, submandibular glands and saliva. Stem cells decreased the apoptotic cell number and the expressions of ATG5 and Beclin-1 in the submandibular glands. Stem cells have no effect on other organs. Furthermore, the infused stem cells migrated to the spleen and liver, not the submandibular gland. Stem cells directed T cells towards Treg cells and suppressed Th1 and Tfh cells in spleen lymphocytes. CONCLUSION Stem cells from exfoliated deciduous teeth alleviate the hyposalivation caused by SS via decreasing the inflammatory cytokines, regulating the inflammatory microenvironment and decreasing the apoptosis and autophagy. The stem cells regulated in T-cell differentiation are involved in the immunomodulatory effects.
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Affiliation(s)
- Zhi-Hao Du
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
| | - Chong Ding
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Qian Zhang
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yan Zhang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing, China
| | - Xi-Yuan Ge
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Sheng-Lin Li
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Guang-Yan Yu
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
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Toll-like receptor 9 signaling promotes autophagy and apoptosis via divergent functions of the p38/JNK pathway in human salivary gland cells. Exp Cell Res 2019; 375:51-59. [PMID: 30610847 DOI: 10.1016/j.yexcr.2018.12.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 12/24/2018] [Accepted: 12/31/2018] [Indexed: 12/25/2022]
Abstract
Abnormal signaling transduction in salivary gland cells is associated with the pathogenesis of Sjögren's syndrome (SS). Previously, we identified aberrant expression of toll-like receptor 9 (TLR9) in gland cells of SS patients and mouse models. In this study, we investigated the role of TLR9 and its downstream p38/mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling in mediating apoptosis and autophagy in human salivary gland (HSG) cells. We selected either CpG-Odn, a classical TLR9 activator, or lentivirus-packaged TLR9 full-length cDNA to activate TLR9 signaling transduction. Activation of TLR9 signaling induced phosphorylation of its downstream protein kinases, p38/MAPK and JNK, in a time-dependent manner, and decreased HSG cell viability. Western blotting of LC3B-II and p62 in both normal and autophagic flux-administered conditions revealed elevated autophagy upon TLR9 activation. Observing the cell cytoplasm through transmission electron microscopy and mRFP-GFP-LC3B-tagged fluorescence confirmed an increased number of autophagosomes and autolysosomes in TLR9-activated cells. Bax/Bcl-2 ratio calculations, caspase-3 activity assays and Hoechst nuclear staining were utilized to confirm the involvement of apoptosis in TLR9 signaling activation. Furthermore, we selected SB239063, a p38/MAPK signaling inhibitor, and SP600125, a JNK inhibitor, to identify the functions of p38/MAPK and JNK in TLR9-mediated signaling transduction. Multiple approaches, including Western blotting assays, fluorescence assessments and caspase-3 activity measurements, confirmed that inhibition of p38/MAPK signaling ameliorated both autophagy and apoptosis in TLR9-activated HSG cells, whereas inhibition of JNK signaling attenuated apoptosis but failed to modulate autophagy in the models mentioned above. Our results indicate a divergent function of p38/MAPK and JNK in TLR9-mediated autophagy and apoptosis in salivary gland cells.
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Pringle S, Wang X, Verstappen GMPJ, Terpstra JH, Zhang CK, He A, Patel V, Jones RE, Baird DM, Spijkervet FKL, Vissink A, Bootsma H, Coppes RP, Kroese FGM. Salivary Gland Stem Cells Age Prematurely in Primary Sjögren's Syndrome. Arthritis Rheumatol 2019; 71:133-142. [PMID: 29984480 PMCID: PMC6607019 DOI: 10.1002/art.40659] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 07/05/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE A 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. METHODS SGSCs 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. RESULTS SGSCs 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. CONCLUSION This 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.
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Affiliation(s)
- Sarah Pringle
- University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Xiaoyan Wang
- University of Groningen and University Medical Center, Groningen, The Netherlands
| | | | - Janneke H Terpstra
- University of Groningen and University Medical Center, Groningen, The Netherlands
| | | | - Aiqing He
- Bristol-Myers Squibb, Pennington, New Jersey
| | | | | | | | - Fred K L Spijkervet
- University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Arjan Vissink
- University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Hendrika Bootsma
- University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Robert P Coppes
- University of Groningen and University Medical Center, Groningen, The Netherlands
| | - Frans G M Kroese
- University of Groningen and University Medical Center, Groningen, The Netherlands
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Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren's Syndrome. Int J Mol Sci 2018; 19:ijms19082369. [PMID: 30103522 PMCID: PMC6121505 DOI: 10.3390/ijms19082369] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/08/2018] [Accepted: 08/10/2018] [Indexed: 12/11/2022] Open
Abstract
The pathogenesis of Sjögren’s syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients’ SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.
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Wu C, Yang P, Liu H, Xiao W, Zhao L. Increased frequency of CCR7 +CD4 + T cells from patients with primary Sjögren's syndrome: An indicator of disease activity rather than of damage severity. Cytokine 2018; 110:9-17. [PMID: 29684636 DOI: 10.1016/j.cyto.2018.04.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/26/2018] [Accepted: 04/13/2018] [Indexed: 12/11/2022]
Abstract
Expression of CCR7 on T cells has been reported to be associated with the lymphocytic migration and infiltration, which is recognized as a vital part of the pathogenesis of Primary Sjögren's syndrome (pSS). Here, we compared the expression of CCR7 on CD4+T cells between pSS patients and control groups, including healthy donors (HD) and patients with systemic lupus erythematosus (SLE) and examined correlations with disease activity and damage severity, which were evaluated by EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and Sjogren's Syndrome Disease Damage Index (SSDDI), respectively. Peripheral blood mononuclear Cells (PBMC) were obtained from patients and controls and expressions of CCR7 were evaluated by flow cytometry. CCR7 was selectively and frequently expressed on CD4+T cells, but less on CD8+ T cells of patients with pSS. In contrast, this phenomenon was neither seen in normal subjects nor in patients with SLE. The expression level of CCR7 in the peripheral blood CD4+ T cells is closely correlated with ESSDAI, but not SSDDI. Correspondently, the chemotactic index (CI) of CD4+T cells was higher than CD8+T cells in patients with pSS. Furthermore, the CI of CD4+T cells is also higher than that of other controls, which is correlated with ESSDAI. All the findings suggested that CCR7 might play an important role in the development of pSS by mediating the migration of CD4+cells. Thus, the expression of CCR7 in CD4+ T cells is probably a useful biomarker to evaluate and monitor disease activity. CCR7 can also potentially be a novel target for the therapy of pSS.
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Affiliation(s)
- Chunling Wu
- Department of Rhematology and Immunology, The First Hospital of China Medical University, 155 Nan Jing North Street, Shenyang 110001, China
| | - Pingting Yang
- Department of Rhematology and Immunology, The First Hospital of China Medical University, 155 Nan Jing North Street, Shenyang 110001, China
| | - Haina Liu
- Department of Rhematology and Immunology, The First Hospital of China Medical University, 155 Nan Jing North Street, Shenyang 110001, China
| | - Weiguo Xiao
- Department of Rhematology and Immunology, The First Hospital of China Medical University, 155 Nan Jing North Street, Shenyang 110001, China
| | - Lijuan Zhao
- Department of Rhematology and Immunology, The First Hospital of China Medical University, 155 Nan Jing North Street, Shenyang 110001, China.
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Unique glandular ex-vivo Th1 and Th17 receptor motifs in Sjögren's syndrome patients using single-cell analysis. Clin Immunol 2018; 192:58-67. [PMID: 29679709 DOI: 10.1016/j.clim.2018.04.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 03/28/2018] [Accepted: 04/17/2018] [Indexed: 02/06/2023]
Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disease in which the underlying cause has yet to be elucidated. The main objective of this study was to determine the T cell receptor (TCR) repertoires of individual infiltrating T helper (Th)-1 and 17 cells of pSS patients using single-cell analysis. Single-cell analysis of ex-vivo infiltrating T cells demonstrated that pSS patients had higher frequencies of activated Th17 cells. Single-cell TCR sequencing revealed that TCRβ variable (TRBV)3-1/joint (J)1-2 (CLFLSMSACVW) and TRBV20-1/J1-1 (SVGSTAIPP*T) were expressed by activated Th1 and Th17 cells in both cohorts. Uniquely, TCRα variable (TRAV)8-2/J5 (VVSDTVLETAGE) was expressed by Th1 cells present only in patients and complementarity-determining region (CDR)3α-specific motif (LSTD*E) present in both Th1/Th17 cells. The study demonstrates that both activated Th1 and Th17 cells of pSS patients showed restricted clonal diversities of which two CDR3 motifs were present in controls and patients, with another two motifs unique to pSS.
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Ainola M, Porola P, Takakubo Y, Przybyla B, Kouri VP, Tolvanen TA, Hänninen A, Nordström DC. Activation of plasmacytoid dendritic cells by apoptotic particles - mechanism for the loss of immunological tolerance in Sjögren's syndrome. Clin Exp Immunol 2017; 191:301-310. [PMID: 29105068 DOI: 10.1111/cei.13077] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2017] [Indexed: 01/03/2023] Open
Abstract
Sjögren's syndrome (SS) is a common autoimmune disease targeting salivary and lacrimal glands. It is strongly female-dominant, characterized by low oestrogen levels combined with a local intracrine dihydrotestosterone defect. We hypothesized that these hormonal deficits lead to increased apoptosis of the epithelial cells and plasmacytoid dendritic cell (pDC)-mediated proinflammatory host responses. Expression of Toll-like receptors (TLRs)-7 and -9 and cytokine profiles was studied in pDCs treated with apoptotic particles collected in consecutive centrifugation steps of media from apoptotic cells. Expression and localization of SS autoantigens in these particles was also analysed. Furthermore, the effects of sex steroids were studied in pDCs cultured with several concentrations of dihydrotestosterone and 17-β-oestradiol, and in saliva of patient treated with dehydroepiandrosterone. Apoptosis of the epithelial cells led to cleavage and translocation of SS-autoantigens, α-fodrin and SS-A, into apoptotic particles. The apoptosis-induced apoptotic particles also contained another SS-autoantigen, hy1-RNA. These particles were internalized by pDCs in a size-dependent manner and affected TLR-7 and -9 expression and the production of proinflammatory cytokines. The analysed androgens protected cells from apoptosis, influenced redistribution of autoantigens and diminished the apoptotic particle-stimulated increase of the TLRs in pDCs. Our findings suggest that the formation of apoptotic particles may play a role in loss of immune tolerance, manifested by production of autoantibodies and the onset of autoinflammation in SS.
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Affiliation(s)
- M Ainola
- Department of Medicine, Clinicum, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
| | - P Porola
- Department of Medicine, Clinicum, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
| | - Y Takakubo
- Department of Orthopaedic Surgery, Yamagata University, Yamagata, Japan
| | - B Przybyla
- Hematology and Cancer Center, Helsinki University Central Hospital, Helsinki, Finland
| | - V P Kouri
- Department of Medicine, Clinicum, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland
| | - T A Tolvanen
- Department of Pathology, University of Helsinki, Helsinki, Finland
| | - A Hänninen
- Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
| | - D C Nordström
- Department of Internal Medicine and Rehabilitation, Helsinki University Central Hospital, and University of Helsinki, Helsinki, Finland
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Kang Y, Sun Y, Zhang Y, Wang Z. Cytochrome c is important in apoptosis of labial glands in primary Sjogren's syndrome. Mol Med Rep 2017; 17:1993-1997. [PMID: 29257225 DOI: 10.3892/mmr.2017.8083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 11/03/2017] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the expression and effect of cytochrome c (Cytc) in patients with primary Sjogren's syndrome (pSS). In total, 35 newly diagnosed pSS patients and 35 healthy subjects were enrolled in the present study. The mRNA expression levels of Cytc were detected using reverse transcription‑polymerase chain reaction and RT‑quantitative PCR. The expression of the Cytc protein in labial salivary glands was detected by immunohistochemistry and was associated with the integral optical density (IOD) of clinical and laboratory variables. In addition, the content of Cytc in the cytoplasm and mitochondria were examined. The mRNA and protein expression levels of Cytc, and the content of Cytc in the cytoplasm of the pSS patients was increased significantly compared with the healthy controls (P<0.05). The content of Cytc in the mitochondria was significantly decreased compared with the healthy controls (P<0.05). The IOD of Cytc protein levels was positively correlated with immunoglobin G (r=0.8142, P<0.05) and erythrocyte sedimentation rate (r=0.7512, P<0.05). Cytc was upregulated in the pSS patients, indicating the potential role of Cytc in the pathogenesis and development of pSS. Further studies may facilitate the development of targeting this molecular pathway for the treatment of pSS.
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Affiliation(s)
- Yuanyuan Kang
- Department of Emergency and Oral Medicine, The School of Stomatology, China Medical University and Liaoning Institute of Dental Research and Liaoning Province Key Laboratory of Oral Diseases and Liaoning Province Translational Medicine Research Center of Oral Diseases, Shenyang, Liaoning 110002, P.R. China
| | - Yan Sun
- Department of Emergency and Oral Medicine, The School of Stomatology, China Medical University and Liaoning Institute of Dental Research and Liaoning Province Key Laboratory of Oral Diseases and Liaoning Province Translational Medicine Research Center of Oral Diseases, Shenyang, Liaoning 110002, P.R. China
| | - Ying Zhang
- Department of Emergency and Oral Medicine, The School of Stomatology, China Medical University and Liaoning Institute of Dental Research and Liaoning Province Key Laboratory of Oral Diseases and Liaoning Province Translational Medicine Research Center of Oral Diseases, Shenyang, Liaoning 110002, P.R. China
| | - Zhe Wang
- Department of Pathology, The Second Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110004, P.R. China
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Wanchoo A, Voigt A, Sukumaran S, Stewart CM, Bhattacharya I, Nguyen CQ. Single-cell analysis reveals sexually dimorphic repertoires of Interferon-γ and IL-17A producing T cells in salivary glands of Sjögren's syndrome mice. Sci Rep 2017; 7:12512. [PMID: 28970488 PMCID: PMC5624952 DOI: 10.1038/s41598-017-12627-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 09/13/2017] [Indexed: 12/23/2022] Open
Abstract
The development of Sjögren's syndrome (SjS) is a dynamic and temporal process with a female predilection. Following the initial influx of immune cells, T cell clusters develop, accelerating the pathology in the salivary glands. Proinflammatory cytokines, IFN-γ and IL-17A, produced by T cells contribute synergistically to the disease. In this study, we examined the sexual dimorphism in cellular infiltrates of the salivary glands by using functional single-cell microengraving analysis. Using high-throughput sequencing, we investigated the clonal diversity of the T cell receptors (TCRs) of infiltrating IFN-γ and IL-17A-producing T cells in male and female SjS-susceptible (SjSs) C57BL/6.NOD-Aec1Aec2 mice. There were elevated frequencies of IFN-γ and IL-17A-producing effector T cell populations in female SjSS mice compared to male SjSS mice. MEME analysis shows high frequency and unique, sexually dimorphic motifs in the TCR hypervariable regions in the SjSS mice. Male mice selected for TRAV8/TRAJ52 (CATDLNTGANTGKLTFG) TCR genes in Th1 cells and TRBV16/(TRBD1/2)TRBJ1-7 (CGGKRRLESIFR) in Th1 and Th17 cells. Female SjSS mice selected for TRAV8/TRAJ52 (CATDLNTGANTGKLTFG), TRAV13D-2/TRAJ23 (CVYLEHHFE), and TRBV23/(TRBD2)TRBJ2-2 (CRKLHSCATCALNFL) in Th1 cells. These findings suggest that there is an elevated prevalence of pathogenic effector T cells in the glands with a sexually dimorphic selection bias of TCR repertoires.
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Affiliation(s)
- Arun Wanchoo
- Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville Florida, USA
| | - Alexandria Voigt
- Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville Florida, USA
| | - Sukesh Sukumaran
- Rheumatology Section, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock Arkansas, USA
| | - Carol M Stewart
- Department of Oral and Maxillofacial Diagnostic Sciences, Gainesville Florida, USA
- Center of Orphaned Autoimmune Diseases, University of Florida, Gainesville Florida, USA
| | - Indraneel Bhattacharya
- Department of Oral and Maxillofacial Diagnostic Sciences, Gainesville Florida, USA
- Center of Orphaned Autoimmune Diseases, University of Florida, Gainesville Florida, USA
| | - Cuong Q Nguyen
- Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville Florida, USA.
- Department of Oral Biology, Gainesville Florida, USA.
- Center of Orphaned Autoimmune Diseases, University of Florida, Gainesville Florida, USA.
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48
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The inflammatory role of phagocyte apoptotic pathways in rheumatic diseases. Nat Rev Rheumatol 2017; 12:543-58. [PMID: 27549026 DOI: 10.1038/nrrheum.2016.132] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Rheumatoid arthritis affects nearly 1% of the world's population and is a debilitating autoimmune condition that can result in joint destruction. During the past decade, inflammatory functions have been described for signalling molecules classically involved in apoptotic and non-apoptotic death pathways, including, but not limited to, Toll-like receptor signalling, inflammasome activation, cytokine production, macrophage polarization and antigen citrullination. In light of these remarkable advances in the understanding of inflammatory mechanisms of the death machinery, this Review provides a snapshot of the available evidence implicating death pathways, especially within the phagocyte populations of the innate immune system, in the perpetuation of rheumatoid arthritis and other rheumatic diseases. Elevated levels of signalling mediators of both extrinsic and intrinsic apoptosis, as well as the autophagy, are observed in the joints of patients with rheumatoid arthritis. Furthermore, risk polymorphisms are present in signalling molecules of the extrinsic apoptotic and autophagy death pathways. Although research into the mechanisms underlying these pathways has made considerable progress, this Review highlights areas where further investigation is particularly needed. This exploration is critical, as new discoveries in this field could lead to the development of novel therapies for rheumatoid arthritis and other rheumatic diseases.
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Abstract
Apoptosis is an important component of normal tissue physiology, and the prompt removal of apoptotic cells is equally essential to avoid the undesirable consequences of their accumulation and disintegration. Professional phagocytes are highly specialized for engulfing apoptotic cells. The recent ability to track cells that have undergone apoptosis in situ has revealed a division of labor among the tissue resident phagocytes that sample them. Macrophages are uniquely programmed to process internalized apoptotic cell-derived fatty acids, cholesterol and nucleotides, as a reflection of their dominant role in clearing the bulk of apoptotic cells. Dendritic cells carry apoptotic cells to lymph nodes where they signal the emergence and expansion of highly suppressive regulatory CD4 T cells. A broad suppression of inflammation is executed through distinct phagocyte-specific mechanisms. A clever induction of negative regulatory nodes is notable in dendritic cells serving to simultaneously shut down multiple pathways of inflammation. Several of the genes and pathways modulated in phagocytes in response to apoptotic cells have been linked to chronic inflammatory and autoimmune diseases such as atherosclerosis, inflammatory bowel disease and systemic lupus erythematosus. Our collective understanding of old and new phagocyte functions after apoptotic cell phagocytosis demonstrates the enormity of ways to mediate immune suppression and enforce tissue homeostasis.
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Affiliation(s)
- J Magarian Blander
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
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50
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Brito-Zerón P, Baldini C, Bootsma H, Bowman SJ, Jonsson R, Mariette X, Sivils K, Theander E, Tzioufas A, Ramos-Casals M. Sjögren syndrome. Nat Rev Dis Primers 2016; 2:16047. [PMID: 27383445 DOI: 10.1038/nrdp.2016.47] [Citation(s) in RCA: 519] [Impact Index Per Article: 57.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Sjögren syndrome (SjS) is a systemic autoimmune disease that primarily affects the exocrine glands (mainly the salivary and lacrimal glands) and results in the severe dryness of mucosal surfaces, principally in the mouth and eyes. This disease predominantly affects middle-aged women, but can also be observed in children, men and the elderly. The clinical presentation of SjS is heterogeneous and can vary from sicca symptoms to systemic disease (characterized by peri-epithelial lymphocytic infiltration of the affected tissue or the deposition of the immune complex) and lymphoma. The mechanism underlying the development of SjS is the destruction of the epithelium of the exocrine glands, as a consequence of abnormal B cell and T cell responses to the autoantigens Ro/SSA and La/SSB, among others. Diagnostic criteria for SjS include the detection of autoantibodies in patient serum and histological analysis of biopsied salivary gland tissue. Therapeutic approaches for SjS include both topical and systemic treatments to manage the sicca and systemic symptoms of disease. SjS is a serious disease with excess mortality, mainly related to the systemic involvement of disease and the development of lymphomas in some patients. Knowledge of SjS has progressed substantially, but this disease is still characterized by sicca symptoms, the systemic involvement of disease, lymphocytic infiltration to exocrine glands, the presence of anti-Ro/SSA and anti-La/SSB autoantibodies and the increased risk of lymphoma in patients with SjS.
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Affiliation(s)
- Pilar Brito-Zerón
- Autoimmune Diseases Unit, Department of Medicine, Hospital CIMA-Sanitas, Barcelona, Spain.,Sjögren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep Font, IDIBAPS-CELLEX, Barcelona, Spain.,Department of Autoimmune Diseases, ICMiD, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, Spain
| | | | - Hendrika Bootsma
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Simon J Bowman
- Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Roland Jonsson
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Rheumatology, Haukeland University Hospital, Bergen, Norway
| | - Xavier Mariette
- Université Paris Sud, INSERM, Paris, France.,Center for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, Paris, France
| | - Kathy Sivils
- Oklahoma Sjögren's syndrome Center of Research Translation, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Elke Theander
- Department of Rheumatology, Malmö University Hospital, Lund University, Lund, Sweden
| | - Athanasios Tzioufas
- Department of Pathophysiology, School of Medicine, National University of Athens, Athens, Greece
| | - Manuel Ramos-Casals
- Sjögren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep Font, IDIBAPS-CELLEX, Barcelona, Spain.,Department of Autoimmune Diseases, ICMiD, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, Spain.,Department of Medicine, University of Barcelona, Barcelona, Spain
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