Current Views on Pathophysiology and Potential Therapeutic Targets in Sjögren’s Syndrome: A Review from the Perspective of Viral Infections, Toll-like Receptors, and Long-Noncoding RNAs

Sjögren’s syndrome (SS) is a rheumatic disease characterized by sicca and extraglandular symptoms, such as interstitial lung disease and renal tubular acidosis. SS potentially affects the prognosis of patients, especially in cases of complicated extraglandular symptoms; however, only symptomatic therapies against xerophthalmia and xerostomia are currently included in the practice guidelines as recommended therapies for SS. Considering that SS is presumed to be a multifactorial entity caused by genetic and environmental factors, a multidisciplinary approach is necessary to clarify the whole picture of its pathogenesis and to develop disease-specific therapies for SS. This review discusses past achievements and future prospects for pursuing the pathophysiology and therapeutic targets for SS, especially from the perspectives of viral infections, toll-like receptors (TLRs), long-noncoding RNAs (lncRNAs), and related signals. Based on the emerging roles of viral infections, TLRs, long-noncoding RNAs and related signals, antiviral therapy, hydroxychloroquine, and vitamin D may lower the risk of or mitigate SS. Janus-kinase (JAK) inhibitors are also potential novel therapeutic options for several rheumatic diseases involving the JAK-signal transducer and activator of transcription pathways, which are yet to be ascertained in a randomized controlled study targeting SS.

[1]  K. Furukawa,et al.  The Toll-like Receptor 7-Mediated Ro52 Antigen-Presenting Pathway in the Salivary Gland Epithelial Cells of Sjögren’s Syndrome , 2023, Journal of clinical medicine.

[2]  De-juan Sun,et al.  Long non-coding RNAs as potential therapeutic targets in non-small cell lung cancer (Review) , 2023, International journal of molecular medicine.

[3]  Sayed-Hamidreza Mozhgani,et al.  Human T-cell lymphotropic virus type 1 (HTLV-1) proposed vaccines: a systematic review of preclinical and clinical studies , 2023, BMC Infectious Diseases.

[4]  Y. Shoenfeld,et al.  Vitamin D and Autoimmune Rheumatic Diseases , 2023, Biomolecules.

[5]  Huji Xu,et al.  A multi-center, open-label, randomized study to explore efficacy and safety of baricitinib in active primary Sjogren’s syndrome patients , 2023, Trials.

[6]  Kazuhisa Konishi,et al.  Severe COVID-19 as a Possible Mediator of Autoimmunity and Sjögren’s Syndrome , 2023, Cureus.

[7]  Lijun Wu,et al.  Hyperglobulinemia predicts increased risk of mortality in primary Sjögren's syndrome: based on a Chinese multicentre registry. , 2023, Modern rheumatology.

[8]  Ting Su,et al.  Ocular microvascular alteration in Sjögren’s syndrome treated with hydroxychloroquine: an OCTA clinical study , 2023, Therapeutic advances in chronic disease.

[9]  Yongqing Wang,et al.  The use of hydroxychloroquine in pregnancy and its effect on perinatal outcomes in a population with autoimmune abnormalities , 2022, Clinical Rheumatology.

[10]  Masaki Kusuda,et al.  Interferons and systemic lupus erythematosus: Pathogenesis, clinical features and treatments in interferon-driven disease. , 2022, Modern rheumatology.

[11]  A. Avan,et al.  Association between inflammatory factors, vitamin D, long non-coding RNAs, MALAT1 and Adiponectin antisense in individuals with metabolic syndrome. , 2022, Molecular Nutrition & Food Research.

[12]  P. Gaffney,et al.  Dysregulated long non-coding RNA in Sjögren’s disease impacts both interferon and adaptive immune responses , 2022, RMD Open.

[13]  Jinyu Wu,et al.  Microbiota dysbiosis in primary Sjögren's syndrome and the ameliorative effect of hydroxychloroquine. , 2022, Cell reports.

[14]  C. Tung,et al.  Association between Anti-Hepatitis C Viral Intervention Therapy and Risk of Sjögren’s Syndrome: A National Retrospective Analysis , 2022, Journal of Clinical Medicine.

[15]  N. Ishimaru,et al.  Virus Infections Play Crucial Roles in the Pathogenesis of Sjögren’s Syndrome , 2022, Viruses.

[16]  L. Amezcua-Guerra,et al.  Interferon-alpha regulates expression of lncRNA MALAT1 and interferon-stimulated genes, as well as chemokine production, in primary Sjögren's syndrome. , 2022, Clinical and Experimental Rheumatology.

[17]  Y. Gong,et al.  Tacrolimus therapy in primary Sjögren's syndrome with refractory immune thrombocytopenia: a retrospective study. , 2022, Clinical and experimental rheumatology.

[18]  A. Kivitz,et al.  Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sjögren’s syndrome: a randomized, phase 2, double-blind, placebo-controlled study , 2022, Rheumatology.

[19]  Wen Zhang,et al.  Pilot study of baricitinib for active Sjogren’s syndrome , 2022, Annals of the Rheumatic Diseases.

[20]  T. Kuroki,et al.  Increased Expression of the lncRNA NRON Along With NFATc1/PIM-1 in Labial Salivary Glands of Sjögren’s Syndrome Patients , 2021, Applied immunohistochemistry & molecular morphology : AIMM.

[21]  Yang Li,et al.  Interferon alpha serum level association with low vitamin D levels in Chinese patients with primary Sjögren’s syndrome , 2021 .

[22]  Yan Du,et al.  Differential long non-coding RNA expression profile and function analysis in primary Sjogren’s syndrome , 2021, BMC Immunology.

[23]  C. Tung,et al.  Association between nucleos(t)ide analogue therapy for hepatitis B and Sjögren’s syndrome: 15‐year analysis of the national database of Taiwan , 2021, Journal of viral hepatitis.

[24]  R. Gerli,et al.  Comment on: Equal rights in autoimmunity: is Sjögren's syndrome ever 'secondary'? , 2020, Rheumatology.

[25]  Guoping Niu,et al.  Identification of Long Noncoding RNAs lnc-DC in Plasma as a New Biomarker for Primary Sjögren's Syndrome , 2020, Journal of immunology research.

[26]  Jiayao Fu,et al.  LncRNA Neat1 positively regulates MAPK signaling and is involved in the pathogenesis of Sjögren's syndrome. , 2020, International immunopharmacology.

[27]  Zhu-jun Shen,et al.  LncRNA and mRNA expression profiles and functional networks of hyposalivation of the submandibular gland in hypertension , 2020, Scientific Reports.

[28]  M. Azuma,et al.  Inhibition of JAK-STAT Signaling by Baricitinib Reduces Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal Cells , 2020, Inflammation.

[29]  A. Yoshimura,et al.  Identification of novel genes associated with dysregulation of B cells in patients with primary Sjögren’s syndrome , 2020, Arthritis Research & Therapy.

[30]  Q. Wang,et al.  JAK Inhibitors: Prospects in Connective Tissue Diseases , 2020, Clinical Reviews in Allergy & Immunology.

[31]  T. Dörner,et al.  Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology , 2020, Nature Reviews Rheumatology.

[32]  Wen Zhang,et al.  LncRNA and mRNA expression profile of peripheral blood mononuclear cells in primary Sjögren’s syndrome patients , 2019, Scientific Reports.

[33]  X. Mariette,et al.  EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies , 2019, Annals of the rheumatic diseases.

[34]  T. Takeuchi,et al.  Antigen-driven selection of antibodies against SSA, SSB and the centromere ‘complex’, including a novel antigen, MIS12 complex, in human salivary glands , 2019, Annals of the rheumatic diseases.

[35]  X. Mariette,et al.  Efficacy and safety of topical and systemic medications: a systematic literature review informing the EULAR recommendations for the management of Sjögren’s syndrome , 2019, RMD Open.

[36]  C. Vitali,et al.  Long Non-Coding RNAs Modulate Sjögren’s Syndrome Associated Gene Expression and Are Involved in the Pathogenesis of the Disease , 2019, Journal of clinical medicine.

[37]  Matthew A. Williams,et al.  Bystander T Cells: A Balancing Act of Friends and Foes. , 2018, Trends in immunology.

[38]  H. Nakamura,et al.  Activation of Toll‐like receptor 7 signaling in labial salivary glands of primary Sjögren's syndrome patients , 2018, Clinical and experimental immunology.

[39]  J. Sandling,et al.  Epigenetic alterations in primary Sjögren's syndrome - an overview. , 2018, Clinical immunology.

[40]  Jae-Woong Min,et al.  JAK‐1 Inhibition Suppresses Interferon‐Induced BAFF Production in Human Salivary Gland , 2018, Arthritis & rheumatology.

[41]  H. Gohlke,et al.  FK506 Resistance of Saccharomyces cerevisiae Pdr5 and Candida albicans Cdr1 Involves Mutations in the Transmembrane Domains and Extracellular Loops , 2018, Antimicrobial Agents and Chemotherapy.

[42]  M. Deng,et al.  Long non-coding RNA NRON is downregulated in HCC and suppresses tumour cell proliferation and metastasis. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[43]  Yoshiya Tanaka,et al.  Janus Kinase Inhibitor Baricitinib Modulates Human Innate and Adaptive Immune System , 2018, Front. Immunol..

[44]  Y. Obase,et al.  Lymphocytic focus score is positively related to airway and interstitial lung diseases in primary Sjögren's syndrome. , 2018, Respiratory medicine.

[45]  D. Sasaki,et al.  Detection of human T lymphotropic virus type-I bZIP factor and tax in the salivary glands of Sjögren's syndrome patients. , 2018, Clinical and experimental rheumatology.

[46]  K. Tsubota,et al.  Clinical practice guideline for Sjögren’s syndrome 2017 , 2018, Modern rheumatology.

[47]  P. Boor,et al.  JAK‐inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa , 2017, Translational research : the journal of laboratory and clinical medicine.

[48]  L. Criswell,et al.  2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome , 2016, Annals of the rheumatic diseases.

[49]  F. Sung,et al.  Association of Sjögrens Syndrome in Patients with Chronic Hepatitis Virus Infection: A Population-Based Analysis , 2016, PloS one.

[50]  R. H. Scofield,et al.  Autoantibodies in Sjögren's Syndrome. , 2016, Rheumatic diseases clinics of North America.

[51]  G. Illei,et al.  Targeting the Ca2 + Sensor STIM1 by Exosomal Transfer of Ebv-miR-BART13-3p is Associated with Sjögren's Syndrome , 2016, EBioMedicine.

[52]  Chuangqi Yu,et al.  Long non-coding RNA expression profile in minor salivary gland of primary Sjögren’s syndrome , 2016, Arthritis Research & Therapy.

[53]  Huaxi Xu,et al.  Upregulation of long noncoding RNA TMEVPG1 enhances T helper type 1 cell response in patients with Sjögren syndrome , 2016, Immunologic research.

[54]  B. Herrmann,et al.  Mechanisms of long noncoding RNA function in development and disease , 2016, Cellular and Molecular Life Sciences.

[55]  Hideki Nakamura,et al.  Analysis of the downstream mediators of toll-like receptor 3-induced apoptosis in labial salivary glands in patients with Sjögren's syndrome , 2016, Modern rheumatology.

[56]  D. Ye,et al.  Emerging role of long noncoding RNAs in autoimmune diseases. , 2015, Autoimmunity reviews.

[57]  B. Kostov,et al.  Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients , 2014, Annals of the rheumatic diseases.

[58]  P. Ravaud,et al.  Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial. , 2014, JAMA.

[59]  K. Tsubota,et al.  Primary and secondary surveys on epidemiology of Sjögren's syndrome in Japan , 2014, Modern rheumatology.

[60]  A. Mócsai,et al.  What is the future of targeted therapy in rheumatology: biologics or small molecules? , 2014, BMC Medicine.

[61]  J. Bijlsma,et al.  The prognostic value of routinely performed minor salivary gland assessments in primary Sjögren's syndrome , 2014, Annals of the rheumatic diseases.

[62]  A. Fatica,et al.  Long non-coding RNAs: new players in cell differentiation and development , 2013, Nature Reviews Genetics.

[63]  P. Angus,et al.  Cyclosporine and tacrolimus have inhibitory effects on toll‐like receptor signaling after liver transplantation , 2013, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[64]  Yoshiya Tanaka,et al.  The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells , 2013, Annals of the rheumatic diseases.

[65]  Denise P Barlow,et al.  Gene regulation by the act of long non-coding RNA transcription , 2013, BMC Biology.

[66]  S. Yamasaki,et al.  TLR3-mediated apoptosis and activation of phosphorylated Akt in the salivary gland epithelial cells of primary Sjögren’s syndrome patients , 2013, Rheumatology International.

[67]  Mathew W. Wright,et al.  Naming 'junk': Human non-protein coding RNA (ncRNA) gene nomenclature , 2011, Human Genomics.

[68]  A. Bowie,et al.  Recent insights into the role of Toll‐like receptors in viral infection , 2010, Clinical and experimental immunology.

[69]  Chi Yang,et al.  Expression of Toll-like receptors 7, 8, and 9 in primary Sjögren's syndrome. , 2010, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[70]  G. Baron,et al.  EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome , 2009, Annals of the rheumatic diseases.

[71]  M. Cutolo.  Vitamin D and autoimmune rheumatic diseases. , 2008, Rheumatology.

[72]  H. Drexhage,et al.  Systemic increase in type I interferon activity in Sjögren's syndrome: A putative role for plasmacytoid dendritic cells , 2008, European journal of immunology.

[73]  X. Mariette,et al.  Viruses induce high expression of BAFF by salivary gland epithelial cells through TLR‐ and type‐I IFN‐dependent and ‐independent pathways , 2008, European journal of immunology.

[74]  K. Eguchi,et al.  EGF activates PI3K-Akt and NF-κB via distinct pathways in salivary epithelial cells in Sjögren’s syndrome , 2007, Rheumatology International.

[75]  K. Eguchi,et al.  Toll-like receptor in salivary glands from patients with Sjögren's syndrome: functional analysis by human salivary gland cell line. , 2007, The Journal of rheumatology.

[76]  S. Batalov,et al.  A Strategy for Probing the Function of Noncoding RNAs Finds a Repressor of NFAT , 2005, Science.

[77]  I. Jonassen,et al.  Gene expression profiling of minor salivary glands clearly distinguishes primary Sjögren's syndrome patients from healthy control subjects. , 2005, Arthritis and rheumatism.

[78]  A. Hüttenhofer,et al.  Non-coding RNAs: hope or hype? , 2005, Trends in genetics : TIG.

[79]  M. Peterson,et al.  Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. , 2005, Arthritis and rheumatism.

[80]  R. Jonsson,et al.  Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group , 2002, Annals of the rheumatic diseases.

[81]  S. Eddy,et al.  A computational screen for methylation guide snoRNAs in yeast. , 1999, Science.

[82]  S. Nagataki,et al.  High prevalence of Sjögren’s syndrome in patients with HTLV-I associated myelopathy , 1997, Annals of the rheumatic diseases.

[83]  S. Nagataki,et al.  Prevalence of serum and salivary antibodies to HTLV-1 in Sjögren's syndrome , 1994, The Lancet.

[84]  K. Eguchi,et al.  Primary Sjögren's syndrome with antibodies to HTLV-I: clinical and laboratory features. , 1992, Annals of the rheumatic diseases.

[85]  J. Greenspan,et al.  The histopathology of Sjögren's syndrome in labial salivary gland biopsies. , 1974, Oral surgery, oral medicine, and oral pathology.

[86]  Liu Yang,et al.  Genome-wide analysis of long noncoding RNA profile in human gastric epithelial cell response to Helicobacter pylori. , 2015, Japanese journal of infectious diseases.

[87]  S. Akira,et al.  TLR signaling. , 2006, Current topics in microbiology and immunology.

[88]  Wayne A. Decatur,et al.  Genome-wide searching for pseudouridylation guide snoRNAs: analysis of the Saccharomyces cerevisiae genome. , 2004, Nucleic acids research.