1 6242 148 THE MATRICELLULAR PROTEIN SPARC DECREASES IN THE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. PURPOSE: SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE (SPARC) IS A MATRICELLULAR GLYCOPROTEIN ABUNDANTLY EXPRESSED IN BASEMENT MEMBRANES AND CAPSULES SURROUNDING A VARIETY OF ORGANS AND TISSUES. IT MEDIATES EXTRACELLULAR MATRIX ORGANIZATION AND HAS BEEN IMPLICATED IN CELL CONTRACTION. HERE, WE EVALUATED THE EXPRESSION OF SPARC IN THE MURINE LACRIMAL GLAND AT ADULTHOOD AND DURING INFLAMMATION. METHODS: LACRIMAL GLANDS OF YOUNG MICE (4-6 WEEKS OLD) AND ADULT MICE (32-40 WEEKS OLD) WERE USED FOR EXTRACTION OF DNA, RNA, AND PROTEIN. THE PRESENCE OF SPARC WAS ASSESSED BY QUANTITATIVE PCR, ELISA, AND IMMUNOFLUORESCENCE MICROSCOPY. 5-METHYLCYTOSINE AND DNA METHYLATION WERE EVALUATED USING ELISA AND BISULFITE GENOMIC SEQUENCING, RESPECTIVELY. THE EFFECTS OF CYTOKINES AND INFLAMMATION IN SPARC EXPRESSION WERE EVALUATED IN VITRO AND IN THE NON-OBESE DIABETIC (NOD) MOUSE MODEL OF SJOGREN'S SYNDROME. RESULTS: THE MRNA AND PROTEIN LEVELS OF SPARC WERE DOWNREGULATED IN LACRIMAL GLANDS OF MATURE ADULT MICE PRESENTING AGE-RELATED HISTOLOGICAL ALTERATIONS SUCH AS INCREASED DEPOSITION OF LIPOFUSCIN AND LIPIDS. EPIGENETIC ANALYSES INDICATED THAT GLANDS IN ADULT MICE CONTAIN HIGHER LEVELS OF GLOBAL DNA METHYLATION AND SHOW INCREASED HYPERMETHYLATION OF SPECIFIC CPG SITES WITHIN THE SPARC GENE PROMOTER. ANALYSIS OF SMOOTH MUSCLE ACTIN (SMA)-GREEN FLUORESCENT PROTEIN (GFP) TRANSGENIC MICE REVEALED THAT SPARC LOCALIZES PRIMARILY TO MYOEPITHELIAL CELLS WITHIN THE GLAND. TREATMENT OF MYOEPITHELIAL CELLS WITH IL-1BETA OR TNF-ALPHA AND THE DEVELOPMENT OF INFLAMMATION IN THE NOD MICE LED TO DECREASED TRANSCRIPTION OF SPARC. CONCLUSIONS: SPARC IS A NOVEL MATRICELLULAR GLYCOPROTEIN EXPRESSED BY MYOEPITHELIAL CELLS IN THE LACRIMAL GLAND. LOSS OF SPARC DURING ADULTHOOD AND CHRONIC INFLAMMATION MIGHT HAVE DETRIMENTAL CONSEQUENCES ON MYOEPITHELIAL CELL CONTRACTION AND THE SECRETION OF TEAR FLUID. 2022 2 1985 31 EPIGENETIC ALTERATIONS IN PRIMARY SJOGREN'S SYNDROME - AN OVERVIEW. PRIMARY SJOGREN'S SYNDROME (PSS) IS A CHRONIC AUTOIMMUNE RHEUMATIC DISEASE CHARACTERIZED BY INFLAMMATION OF EXOCRINE GLANDS, MAINLY SALIVARY AND LACRIMAL GLANDS. IN ADDITION, PSS MAY AFFECT MULTIPLE OTHER ORGANS RESULTING IN SYSTEMIC MANIFESTATIONS. ALTHOUGH THE PRECISE ETIOLOGY OF PSS REMAINS ELUSIVE, PSS IS CONSIDERED TO BE A MULTI-FACTORIAL DISEASE, WHERE UNDERLYING GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS CONTRIBUTE TO DISEASE DEVELOPMENT. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS, MAY CONSTITUTE A DYNAMIC LINK BETWEEN GENOME, ENVIRONMENT AND PHENOTYPIC MANIFESTATION BY THEIR MODULATING EFFECTS ON GENE EXPRESSION. A GROWING BODY OF STUDIES REPORTING ALTERED EPIGENETIC LANDSCAPES IN PSS SUGGESTS THAT EPIGENETIC MECHANISMS PLAY A ROLE IN THE PATHOGENESIS OF PSS, AND THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS SUGGESTS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC DYSREGULATION IN PSS. THIS ARTICLE REVIEWS OUR CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSS AND DISCUSSES IMPLICATIONS FOR NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES. 2018 3 823 37 CHARACTERIZATION OF COMPREHENSIVE DYNAMIC EPIGENETIC CHANGES DURING HUMAN PRIMARY SJOGREN'S SYNDROME PROGRESSION. BACKGROUND: PRIMARY SJOGREN'S SYNDROME (PSS) IS A SYSTEMIC AUTOIMMUNE DISEASE CHARACTERIZED BY REDUCED EXOCRINE GLAND (PRINCIPALLY THE SALIVARY AND LACRIMAL GLANDS) ACTIVITY CAUSED BY CHRONIC LYMPHOCYTIC INFILTRATION. ALTHOUGH PSS HAS BEEN CLOSELY ASSOCIATED WITH AN INCREASED RISK OF MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA, THE DYNAMIC EPIGENETIC CHANGES IN THE GLAND CELLS THAT ACCOMPANY THE PATHOGENESIS ARE NOT ENTIRELY UNDERSTOOD. METHODS: IN THIS STUDY, WE HARVESTED TISSUE SAMPLES FROM THE LABIAL GLAND WITH (LG_PSS) OR WITHOUT PSS (LG_NC) BEFORE MALT DEVELOPMENT, AS WELL AS THE PAROTID GLAND WITH TUMOR TISSUES (PG_MALT) AND PARACANCEROUS TISSUES (PG_NC) OF TWO PSS PATIENTS WITH MALT LYMPHOMA, AND CONDUCTED RNA-SEQ AND CHIP-SEQ FOR TRI-METHYLATED HISTONE 3 LYSINE 4, 9, 27, 36, AND 79 (H3K4/9/27/36/79ME3). RESULTS: TRANSCRIPTOME LANDSCAPES INDICATED TWO OUTCOMES OF PSS PROGRESSION WITH OR WITHOUT MALT LYMPHOMA REPRESENTED BY DISTINCT POPULATIONS OF DIFFERENTIALLY EXPRESSED GENES AND THEIR FUNCTIONS. FURTHERMORE, THE EPIGENETIC ATLAS OF GENOME-WIDE H3K4/9/27/36/79ME3 WAS IN DIFFERENT STAGES FOR VARIOUS SAMPLES, INDICATING THAT THE VARIANCE OF H3K4ME3 WAS THE EARLIEST EVENT, FOLLOWED BY SELECTIVE ALTERATIONS OF H3K9/27/36/79ME3. THESE FOUR EPIGENETIC MODIFICATIONS DETERMINE THE FINAL OUTCOME OF PSS PROGRESSION. CONCLUSIONS: OUR RESULTS NOT ONLY ADVANCE THE UNDERSTANDING OF THE DYNAMICS OF PSS PROGRESSION AND HIGHLIGHT THE IMPORTANCE OF EPIGENETIC ALTERATIONS IN REGULATING TRANSCRIPTION DURING THIS PATHOLOGICAL PROCESS, BUT ALSO IDENTIFY POTENTIAL THERAPEUTIC TARGETS FOR PSS TREATMENT AND LYMPHOMA INTERVENTION. 2021 4 1165 32 CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SJOGREN'S SYNDROME: A REVIEW. SJOGREN'S SYNDROME (SS) IS A CHRONIC SYSTEMIC DISEASE CHARACTERISED BY SALIVARY AND LACRIMAL GLAND DYSFUNCTION WITH SEVERE IMPLICATIONS FOR THE WELL-BEING OF BEARING INDIVIDUALS. ALTHOUGH ITS ORIGIN HAS NOT YET BEEN FULLY ELUCIDATED, IT IS KNOWN THAT GENETIC, ENVIRONMENTAL, AND EPIGENETIC FACTORS ARE IMPORTANT CONTRIBUTORS TO THE PATHOGENESIS OF THIS SYNDROME. DNA METHYLATION IS A RELEVANT, WIDELY STUDIED EPIGENETIC FACTOR THAT IS POSSIBLY RELATED TO THE ESTABLISHMENT OF SS. THE AIM OF THE PRESENT STUDY WAS TO PERFORM A SYSTEMATIC REVIEW OF THE LITERATURE TO COMPILE STUDIES ON THE CONTRIBUTION OF DNA METHYLATION TO THE PATHOGENESIS OF SS. A LITERATURE SEARCH WAS PERFORMED IN 4 DATABASES (PUBMED, WEB OF SCIENCE, LILACS, AND SCOPUS) USING PREVIOUSLY SELECTED MEDICAL SUBJECT HEADINGS (MESH) DESCRIPTORS, AND ARTICLE SELECTION CONSIDERED OBSERVATIONAL STUDIES ONLY. AFTER A FULL-TEXT READING OF THE SELECTED ARTICLES, 15 STUDIES WERE IN ACCORDANCE WITH THE ELIGIBILITY CRITERIA FOR DATA EXTRACTION. METHYLATION DETECTION APPROACHES INCLUDED GLOBAL METHYLATION, GENOME-WIDE ASSESSMENT OF DIFFERENTIALLY METHYLATED REGIONS, AND SITE-SPECIFIC METHYLATION. FOURTEEN ARTICLES REPORTED ASSOCIATIONS OF DNA METHYLATION PROFILES IN SS PATIENTS, BOTH GLOBALLY AND IN SEVERAL GENES IN SALIVARY GLANDS AND BLOOD CELLS. THUS, DNA METHYLATION MAY CONTRIBUTE TO THE PATHOGENESIS OF SS. THE FINDINGS REINFORCE THE IMPORTANCE OF EPIGENETIC MARKERS IN THE DYNAMICS OF SS AND MAY DIRECT EFFORTS TOWARD THE DEVELOPMENT OF NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES. 2022 5 6050 23 THE CONTRIBUTION OF EPIGENETICS IN SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS THAT COMBINES EXOCRINE GLAND DYSFUNCTIONS AND LYMPHOCYTIC INFILTRATIONS. WHILE THE PATHOGENESIS OF SS REMAINS UNCLEAR, ITS ETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC PREDISPOSITIONS, ENVIRONMENTAL FACTORS, AND EPIGENETIC FACTORS. RECENTLY, INTEREST HAS GROWN IN THE INVOLVEMENT OF EPIGENETICS IN AUTOIMMUNE DISEASES. EPIGENETICS IS DEFINED AS CHANGES IN GENE EXPRESSION, THAT ARE INHERITABLE AND THAT DO NOT ENTAIL CHANGES IN THE DNA SEQUENCE. IN SS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION THAT PREDOMINATES IN EPITHELIAL CELLS, AN ABNORMAL EXPRESSION OF MICRORNAS, AND ABNORMAL CHROMATIN POSITIONING-ASSOCIATED WITH AUTOANTIBODY PRODUCTION. LAST BUT NOT LEAST, EPIGENETIC MODIFICATIONS ARE REVERSIBLE AS OBSERVED IN MINOR SALIVARY GLANDS FROM SS PATIENTS AFTER B CELL DEPLETION USING RITUXIMAB. THUS EPIGENETIC FINDINGS IN SS OPEN NEW PERSPECTIVES FOR THERAPEUTIC APPROACHES AS WELL AS THE POSSIBLE IDENTIFICATION OF NEW BIOMARKERS. 2014 6 1261 28 CURRENT VIEWS ON THE PATHOGENESIS OF SJOGREN'S SYNDROME. PURPOSE OF REVIEW: THE PURPOSE OF THIS REVIEW IS TO PROVIDE AN INSIGHT INTO THE PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE PATHOGENESIS OF PRIMARY SJOGREN'S SYNDROME (PSS), HIGHLIGHTING RECENT FINDINGS WITH POTENTIAL THERAPEUTIC REPERCUSSIONS. RECENT FINDINGS: IN THE LAST 2 YEARS, EPIGENETIC ANALYSES PROVIDED NEW INSIGHTS INTO PSS PATHOGENESIS. CHARACTERIZATION OF DNA METHYLATION PATTERNS, CHROMATIN STRUCTURES AND MICRORNA CONFIRMED THE IMPORTANCE OF ABERRANT INTERFERON AND B-CELL RESPONSES IN THE DEVELOPMENT OF THE DISEASE. THE FORMATION OF ECTOPIC B-CELL FOLLICLES WITH GERMINAL CENTERS IS NOW A WELL RECOGNIZED PATHOGENIC MECHANISM WITHIN SALIVARY GLANDS OF PSS. IN THE CONTEXT OF ECTOPIC GERMINAL CENTERS REACTION, T/B-CELL INTERACTIONS, THAT IS REGARDING T-HELPER 17 AND T-FOLLICULAR HELPER CELLS, AND THEIR RESPECTIVE COUNTERPARTS, T-REGULATORY AND T-FOLLICULAR REGULATORY CELLS, APPEAR PARTICULARLY RELEVANT IN PSS PATHOGENESIS AS THEIR IMBALANCE IS ASSOCIATED WITH A DYSREGULATION OF B-CELL DYNAMICS AND THE PRODUCTION OF AUTOANTIBODIES. SUMMARY: ADVANCES IN THE UNDERSTANDING OF PSS PATHOGENESIS HAVE PAVED THE WAY FOR CLINICAL TRIALS WITH NOVEL BIOLOGIC AGENTS TARGETING IMMUNE PATHWAYS REGULATING T/B-CELL INTERACTIONS AND DOWNSTREAM B-CELL ACTIVATION. REVERSE TRANSLATION FROM THESE STUDIES PROVIDES INVALUABLE NOVEL INFORMATION OF THE MECHANISMS SUSTAINING AUTOIMMUNITY AND CHRONIC INFLAMMATION IN PSS. 2018 7 1603 32 DNA METHYLATION STUDIES IN SALIVA OF PATIENTS WITH SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A RELATIVELY COMMON SYSTEMIC AUTOIMMUNE DISEASE OF UNKNOWN AETIOLOGY, ALTHOUGH GENETIC, HORMONAL, IMMUNOLOGIC, AND ENVIRONMENTAL FACTORS ARE THOUGHT TO BE INVOLVED IN DISEASE PATHOGENESIS. IT IS ALSO TERMED "AUTOIMMUNE EPITHELITIS", AND AFFLICTS MAINLY THE EPITHELIAL STRUCTURES OF SALIVARY AND LACHRYMAL GLANDS, THROUGH PERIEPITHELIAL LYMPHOCYTIC INFILTRATION RESPONSIBLE FOR THE OCCURRENCE OF DRYNESS SYMPTOMS. SJOGREN'S SYNDROME (SS) IS ALSO CHARACTERISED BY B CELL HYPERACTIVITY AS REFLECTED BY THE PRESENCE OF HYPERGAMMAGLOBULINEMIA AND THE PRODUCTION OF AUTOANTIBODIES, WHICH SEEMS TO BE ASSOCIATED WITH THE PRESENCE OF ECTOPIC GERMINAL CENTRES WITHIN THE INFLAMED MINOR SALIVARY GLANDS. CHRONIC ANTIGENIC STIMULATION MAY LEAD TO EXPANSION OF B CELL AUTOREACTIVE CLONES WITH RHEUMATOID FACTOR ACTIVITY, AND ADDITIONAL MOLECULAR EVENTS MEDIATE MALIGNANT TRANSFORMATION INTO NON-HODGKIN'S LYMPHOMAS OF B CELL ORIGIN. THEREFORE, THE INTERACTION BETWEEN THE IMMUNE CELLS OF THE INFLAMMATORY INFILTRATE AND THE SALIVARY EPITHELIUM SEEMS TO HAVE AN IMPORTANT CONTRIBUTION IN DISEASE PROCESS. RECENT HISTOPATHOLOGIC AND MOLECULAR STUDIES HAVE SHOWN THAT DNA METHYLATION LEVELS OF SS PATIENTS COMPARED TO HEALTHY INDIVIDUALS DIFFER IN EPITHELIAL CELLS OF SALIVARY GLANDS AND PERIPHERAL BLOOD MONONUCLEAR CELLS. IN THE PRESENT STUDY, WE INTEND TO ANALYSE THE EPIGENETIC MODIFICATIONS OF DNA IN THE SALIVA OF SS PATIENTS COMPARED TO HEALTHY CONTROLS. MORE SPECIFICALLY, SALIVARY DNA METHYLATION LEVELS OF SELECTED GENETIC LOCI PREVIOUSLY FOUND TO DIFFER IN OTHER TISSUES, WILL BE COMPARED BETWEEN SS PATIENTS AND HEALTHY CONTROLS. THE STUDY INCLUDES SALIVA COLLECTION FROM SS PATIENTS AND HEALTHY INDIVIDUALS, EXTRACTION OF GENOMIC DNA AND METHYLATION ASSESSMENT. THE EPIGENETIC PROFILE OF EACH GENETIC LOCUS WILL BE CORRELATED WITH SS PATIENTS' CLINICAL CHARACTERISTICS AND THE POSSIBILITY OF GENETIC LOCI WITH DIFFERENTIAL DIFFERENCES IN METHYLATION TO BE USED AS POTENTIAL DIAGNOSTIC BIOMARKERS WILL BE EXPLORED. THE CURRENT STUDY IS ANTICIPATED TO REVEAL POTENTIAL BIOMARKERS FOR DIAGNOSTIC AND THERAPEUTIC PURPOSES, OFFERING THE ADVANTAGE TO UTILISE THE EASILY COLLECTED AND HANDLED SALIVA AS THE MAIN BIOLOGIC MATERIAL. 2021 8 2222 34 EPIGENETIC MODIFICATIONS IN SALIVARY GLANDS FROM PATIENTS WITH SJOGREN'S SYNDROME AFFECT CYTOKERATIN 19 EXPRESSION. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS, AND SEVERAL LINES OF EXPERIMENTS INDICATE THAT MULTIFACTORIAL FACTORS CONTRIBUTE TO SALIVARY GLAND EPITHELIAL CELLS (SGEC) DYSFUNCTIONS INCLUDING A COMBINATION OF ENVIRONMENTAL FACTORS, LYMPHOCYTIC INFILTRATIONS, GENETIC PREDISPOSITIONS AS WELL AS EPIGENETIC DEFECTS. SUCH STATEMENT IS REINFORCED BY THE OBSERVATION THAT GLOBAL DNA METHYLATION (5MECYT) IS ALTERED IN MINOR SALIVARY GLANDS FROM PSS PATIENTS AND THAT SUCH DEFECT IS ASSOCIATED CYTOKERATIN 19 (KRT19) OVEREXPRESSION. AN EPIGENETIC DEREGULATION OF THE KRT19 GENE WAS FURTHER TESTED BY TREATING THE HUMAN SALIVARY GLAND (HSG) CELL LINE WITH THE DNA DEMETHYLATING AGENT 5-AZACYTIDIN, AND WITH THE HISTONE ACETYLASE INHIBITOR TRICHOSTATIN A. BLOCKING DNA METHYLATION, BUT NOT HISTONE ACETYLATION, WITH 5-AZACYTIDIN WAS ASSOCIATED WITH KRT19 OVEREXPRESSION AT BOTH TRANSCRIPTIONAL AND PROTEIN LEVEL. NEXT, ANALYSIS OF THE CPG GENOME-WIDE METHYLOME ARRAY IN THE KTR19 LOCUS FROM LONG TERM CULTURED SGEC OBTAINED FROM 8 PSS PATIENTS REVEALED A MORE REDUCED DNA METHYLATION LEVEL IN THOSE PATIENTS WITH DEFECTIVE GLOBAL DNA METHYLATION. ALTOGETHER, OUR DATA, THEREFORE, SUGGEST THAT ALTERATION OF DNA METHYLATION IN SGEC MAY CONTRIBUTE TO PSS PATHOPHYSIOLOGY IN PART BY CONTROLLING THE EXPRESSION OF KRT19. 2016 9 5723 27 SJOGREN'S SYNDROME X-CHROMOSOME DOSE EFFECT: AN EPIGENETIC PERSPECTIVE. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING EXOCRINE GLANDS LEADING TO MOUTH AND EYES DRYNESS. THE EXTENT TO WHICH EPIGENETIC DNA METHYLATION CHANGES ARE RESPONSIBLE FOR AN X-CHROMOSOME DOSE EFFECT HAS YET TO BE DETERMINED. OUR OBJECTIVES WERE TO (I) DESCRIBE HOW EPIGENETIC DNA METHYLATION CHANGES COULD EXPLAIN AN X-CHROMOSOME DOSE EFFECT IN SS FOR WOMEN WITH NORMAL 46,XX GENOTYPE AND (II) DETERMINE THE RELEVANT RELATIONSHIPS TO THIS DOSE EFFECT, BETWEEN X-LINKED GENES, GENES CONTROLLING X-CHROMOSOME INACTIVATION (XCI) AND GENES ENCODING ASSOCIATED TRANSCRIPTION FACTORS, ALL OF WHICH ARE DIFFERENTIALLY EXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN THE SALIVARY GLANDS OF PATIENTS WITH SS. WE IDENTIFIED 58 UPREGULATED X-CHROMOSOME GENES, INCLUDING 22 GENES PREVIOUSLY SHOWN TO ESCAPE XCI, BASED ON THE ANALYSIS OF SS PATIENT SALIVARY GLAND GEO2R GENE EXPRESSION DATASETS. MOREOVER, WE FOUND XIST AND ITS CIS REGULATORS RLIM, FTX, AND CHIC1, AND POLYCOMB REPRESSOR GENES OF THE PRC1/2 COMPLEXES TO BE UPREGULATED. MANY OF THE X-CHROMOSOME GENES IMPLICATED IN SS PATHOGENESIS CAN BE REGULATED BY TRANSCRIPTION FACTORS WHICH WE FOUND TO BE OVEREXPRESSED AND/OR DIFFERENTIALLY METHYLATED IN PATIENTS WITH SS. DETERMINATION OF THE MECHANISMS UNDERLYING METHYLATION-DEPENDENT GENE EXPRESSION AND IMPAIRED XCI IS NEEDED TO FURTHER ELUCIDATE THE ETIOPATHOGENESIS OF SS. 2019 10 207 30 ACTIVATION OF THE TYPE I INTERFERON PATHWAY IN PRIMARY SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS), A CHRONIC AUTOIMMUNE SYSTEMIC DISEASE AFFECTING MIDDLE AGED WOMEN, IS CHARACTERIZED BY LYMPHOCYTIC INFILTRATION OF THE SALIVARY AND LACHRYMAL GLANDS RESULTING IN DRY EYES AND DRY MOUTH. RECENT ADVANCES HAVE REVEALED A MAJOR ROLE FOR ACTIVATION OF THE TYPE I INTERFERON (IFN) PATHWAY IN THE PATHOGENESIS OF THE SYNDROME, AS EVIDENCED BY THE INCREASED CIRCULATING TYPE I IFN ACTIVITY AND AN IFN "SIGNATURE" IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND MINOR SALIVARY GLAND (MSG) BIOPSIES FROM THESE PATIENTS. POLYMORPHISMS IN GENES INVOLVED IN THE IFNALPHA PATHWAY, SUCH AS IRF5 AND STAT4, HAVE BEEN FOUND TO BE ASSOCIATED WITH DISEASE SUSCEPTIBILITY. WHILE THE INITIAL TRIGGERS OF THE INNATE IMMUNE RESPONSE IN SS REMAIN ELUSIVE, PRELIMINARY EVIDENCE SUPPORTS THE ROLE OF INAPPROPRIATELY EXPRESSED ENDOGENOUS LINE-1 (L1) RETROELEMENTS AS POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION IN SS, POSSIBLY THROUGH TOLL-LIKE RECEPTOR (TLR) DEPENDENT OR INDEPENDENT PATHWAYS. PROTEINS OF THE METHYLATION MACHINERY AND THE APOBEC FAMILY OF CYTIDINE DEAMINASES ARE COORDINATELY OVEREXPRESSED, SUGGESTING THAT THOSE PROTEINS MIGHT CONTRIBUTE TO REGULATION OF THE INAPPROPRIATELY EXPRESSED L1 ENDOGENOUS RETROELEMENTS IN SS. GIVEN THE APPARENT CENTRAL ROLE OF IFNALPHA IN THE PATHOGENESIS OF SS, BLOCKADE OF THIS CYTOKINE MAY BE A RATIONAL THERAPEUTIC APPROACH. IN THE CURRENT REVIEW WE SUMMARIZE THE CURRENT EVIDENCE REGARDING THE POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION AS WELL AS THE DATA SUPPORTING GENETIC AND EPIGENETIC REGULATION OF THE TYPE I IFN SYSTEM IN SS. 2010 11 2552 28 EPIGENETICS IN PRIMARY SJOGREN'S SYNDROME. PRIMARY SJOGREN'S SYNDROME (SJS) IS A CHRONIC AND SYSTEMIC AUTOIMMUNE EPITHELITIS WITH PREDOMINANT FEMALE INCIDENCE, WHICH IS CHARACTERIZED BY EXOCRINE GLAND DYSFUNCTION. INCOMPLETELY UNDERSTOOD, THE ETIOLOGY OF SJS IS MULTI-FACTORIAL AND EVIDENCE IS GROWING TO CONSIDER THAT EPIGENETIC FACTORS ARE PLAYING A CRUCIAL ROLE IN ITS DEVELOPMENT. INDEPENDENT FROM DNA SEQUENCE MUTATIONS, EPIGENETICS IS DESCRIBED AS INHERITABLE AND REVERSIBLE PROCESSES THAT MODIFY GENE EXPRESSION. EPIGENETIC MODIFICATIONS REPORTED IN MINOR SALIVARY GLAND AND LYMPHOCYTES FROM SJS PATIENTS ARE RELATED TO (I) AN ABNORMAL DNA METHYLATION PROCESS INDUCING IN TURN DEFECTIVE CONTROL OF NORMALLY REPRESSED GENES INVOLVING SUCH MATTERS AS AUTOANTIGENS, RETROTRANSPOSONS, AND THE X CHROMOSOME IN WOMEN; (II) ALTERED NUCLEOSOME POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION; AND (III) ALTERED CONTROL OF MICRORNA. RESULTS FROM EPIGENOME-WIDE ASSOCIATION STUDIES HAVE FURTHER REVEALED THE IMPORTANCE OF THE INTERFERON PATHWAY IN DISEASE PROGRESSION, THE CALCIUM SIGNALING PATHWAY FOR CONTROLLING FLUID SECRETIONS, AND A CELL-SPECIFIC CROSS TALK WITH RISK FACTORS ASSOCIATED WITH SJS. IMPORTANTLY, EPIGENETIC MODIFICATIONS ARE REVERSIBLE THUS OPENING OPPORTUNITIES FOR THERAPEUTIC PROCEDURES IN THIS CURRENTLY INCURABLE DISEASE. 2020 12 2515 28 EPIGENETICS AND SJOGREN'S SYNDROME. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE MUTATIONS IN THE DNA ITSELF, MAY PLAY AN ESSENTIAL ROLE IN AUTOIMMUNE DISEASES (AID). IN SJOGREN'S SYNDROME (SS), A CHRONIC AID CHARACTERIZED BY AN EPITHELIS OF THE EXOCRINE GLANDS, EPIGENETIC STUDIES HAVE FOCUSED ON THREE MECHANISMS: DNA METHYLATION AND ITS CONSEQUENCES INCLUDING HUMAN ENDOGENOUS RETROVIRUS (HERV) EXPRESSION; MICRORNA EXPRESSION; AND PROTEIN POST-TRANSLATIONAL MODIFICATIONS ASSOCIATED WITH AUTOANTIBODY PRODUCTION. ALTHOUGH IN ITS INFANCY, COMPREHENSION OF THE EPIGENETIC (DYS)REGULATION IN SS MAY HELP US TO UNDERSTAND: WHY SS AFFECTS PREDOMINANTLY MIDDLE-AGED WOMEN; WHY GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP SS BUT NOT OTHERS; WHY FLARE-UPS OCCUR; WHY TREATMENT RESPONSES DIFFER BETWEEN PATIENTS; AND WHY SOME PATIENTS DEVELOP LYMPHOMA. FROM THESE STUDIES WILL ARISE A BETTER COMPREHENSION OF THE PATHOPHYSIOLOGY OF SS AS WELL AS DEVELOPMENT OF NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS, AND NOVEL THERAPEUTICS FOR PREVENTION AND PERHAPS EARLY INTERVENTION. 2012 13 3021 28 GENETICS AND EPIGENETICS OF PRIMARY SJOGREN SYNDROME: IMPLICATIONS FOR FUTURE THERAPIES. IN PRIMARY SJOGREN SYNDROME (PSS), CHRONIC INFLAMMATION OF EXOCRINE GLANDS RESULTS IN TISSUE DESTRUCTION AND SICCA SYMPTOMS, PRIMARILY OF THE MOUTH AND EYES. FATIGUE, ARTHRALGIA AND MYALGIA ARE ALSO COMMON SYMPTOMS, WHEREAS EXTRAGLANDULAR MANIFESTATIONS THAT INVOLVE THE RESPIRATORY, NERVOUS AND VASCULAR SYSTEMS OCCUR IN A SUBSET OF PATIENTS. THE DISEASE PREDOMINANTLY AFFECTS WOMEN, WITH AN ESTIMATED FEMALE TO MALE RATIO OF 14 TO 1. THE AETIOLOGY OF PSS, HOWEVER, REMAINS INCOMPLETELY UNDERSTOOD, AND EFFECTIVE TREATMENT IS LACKING. LARGE-SCALE GENETIC AND EPIGENETIC INVESTIGATIONS HAVE REVEALED ASSOCIATIONS BETWEEN PSS AND GENES IN BOTH INNATE AND ADAPTIVE IMMUNE PATHWAYS. THE GENETIC VARIANTS MEDIATE CONTEXT-DEPENDENT EFFECTS, AND BOTH SEX AND ENVIRONMENTAL FACTORS CAN INFLUENCE THE OUTCOME. AS SUCH, GENETIC AND EPIGENETIC STUDIES CAN PROVIDE INSIGHT INTO THE DYSREGULATED MOLECULAR MECHANISMS, WHICH IN TURN MIGHT REVEAL NEW THERAPEUTIC POSSIBILITIES. THIS REVIEW DISCUSSES THE GENETIC AND EPIGENETIC FEATURES THAT HAVE BEEN ROBUSTLY CONNECTED WITH PSS, PUTTING THEM INTO THE CONTEXT OF CELLULAR FUNCTION, CARRIER SEX AND ENVIRONMENTAL CHALLENGES. IN ALL, THE OBSERVATIONS POINT TO SEVERAL NOVEL OPPORTUNITIES FOR EARLY DETECTION, TREATMENT DEVELOPMENT AND THE PATHWAY TOWARDS PERSONALIZED MEDICINE. 2023 14 1873 25 EMERGING ROLE OF MICRORNAS AND LONG NON-CODING RNAS IN SJOGREN'S SYNDROME. SJOGREN'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. 2021 15 4268 32 MICROBIAL AGENTS AS PUTATIVE INDUCERS OF B CELL LYMPHOMA IN SJOGREN'S SYNDROME THROUGH AN IMPAIRED EPIGENETIC CONTROL: THE STATE-OF-THE-ART. INTRODUCTION: UNDERSTANDING THE MECHANISMS UNDERLYING THE PATHOGENESIS OF SJOGREN'S SYNDROME (SS) IS CRUCIALLY IMPORTANT IN ORDER TO BE ABLE TO DISCRIMINATE THE STEPS THAT LEAD TO B CELL TRANSFORMATION AND PROMPTLY IDENTIFY THE PATIENTS AT RISK OF LYMPHOMAGENESIS. THE AIM OF THIS NARRATIVE REVIEW IS TO DESCRIBE THE EVIDENCE CONCERNING THE ROLE THAT INFECTIONS OR DYSBIOSIS PLAYS IN THE EPIGENETIC CONTROL OF GENE EXPRESSION IN SS PATIENTS AND THEIR POSSIBLE INVOLVEMENT IN B CELL LYMPHOMAGENESIS. MATERIALS AND METHODS: WE SEARCHED THE PUBMED AND GOOGLE SCHOLAR DATABASES AND SELECTED A TOTAL OF 92 ARTICLES PUBLISHED DURING THE LAST 25 YEARS THAT DESCRIBE EXPERIMENTAL AND CLINICAL STUDIES OF THE POTENTIAL ASSOCIATIONS OF MICROBIOTA AND EPIGENETIC ABERRATIONS WITH THE RISK OF B CELL LYMPHOMA IN SS PATIENTS. RESULTS AND DISCUSSION: THE GENETIC BACKGROUND OF SS PATIENTS IS CHARACTERIZED BY THE HYPEREXPRESSION OF GENES THAT ARE MAINLY INVOLVED IN REGULATING THE INNATE AND ADAPTIVE IMMUNE RESPONSES AND ONCOGENESIS. IN ADDITION, SALIVARY GLAND EPITHELIAL CELLS AND LYMPHOCYTES BOTH HAVE AN ALTERED EPIGENETIC BACKGROUND THAT ENHANCES THE ACTIVATION OF PROINFLAMMATORY AND SURVIVAL PATHWAYS. DYSBIOSIS OR CHRONIC LATENT INFECTIONS MAY TUNE THE IMMUNE RESPONSE AND MODIFY THE CELL EPIGENETIC MACHINERY IN SUCH A WAY AS TO GIVE B LYMPHOCYTES AN ACTIVATED OR TRANSFORMED PHENOTYPE. IT IS ALSO WORTH NOTING THAT TRANSPOSABLE INTEGRATED RETROELEMENTS MAY PARTICIPATE IN THE PATHOGENESIS OF SS AND B CELL LYMPHOMAGENESIS BY INDUCING DNA BREAKS, MODULATING CELL GENE EXPRESSION, OR GENERATING ABERRANT TRANSCRIPTS THAT CHRONICALLY STIMULATE THE IMMUNE SYSTEM. CONCLUSIONS: MICROORGANISMS MAY EPIGENETICALLY MODIFY TARGET CELLS AND INDUCE THEIR TRANSCRIPTOME TO GENERATE AN ACTIVATED OR TRANSFORMED PHENOTYPE. THE OCCURRENCE OF LYMPHOMA IN MORE THAN 15% OF SS PATIENTS MAY BE THE END RESULT OF A COMBINATION OF GENETICS, EPIGENETICS, AND DYSBIOSIS OR LATENT INFECTIONS. 2019 16 1691 30 DUCTAL CELLS OF MINOR SALIVARY GLANDS IN SJOGREN'S SYNDROME EXPRESS LINE-1 ORF2P AND APOBEC3B. BACKGROUND: TYPE I INTERFERON ACTIVATION IS A HALLMARK EVENT IN SJOGREN'S SYNDROME. L1 RETROELEMENTS STIMULATE PLASMACYTOID DENDRITIC CELLS, ACTIVATING THE TYPE I INTERFERONS, AND ARE REGULATED BY VARIOUS MECHANISMS, INCLUDING THE APOBEC3 DEAMINASES. AS L1S ARE POTENTIAL TRIGGER FACTORS IN AUTOIMMUNITY, WE AIMED TO INVESTIGATE THE IMMUNOHISTOCHEMICAL LOCALIZATION OF L1 ORF2P AND ITS INHIBITOR APOBEC3B PROTEIN IN MINOR SALIVARY GLANDS OF SJOGREN'S SYNDROME PATIENTS. METHODS: TWENTY MINOR SALIVARY GLAND-TISSUE SAMPLES FROM 20 SJOGREN'S SYNDROME PATIENTS, CLASSIFIED ACCORDING TO TARPLEY'S HISTOLOGICAL CRITERIA, AND 10 CONTROLS WERE EVALUATED FOR L1 ORF2P AND APOBEC3B EXPRESSION VIA IMMUNOHISTOCHEMISTRY. RESULTS: L1 ORF2P WAS EXPRESSED IN 17/20 SS PATIENTS AND ALL CONTROLS. APOBEC3B EXPRESSION WAS OBSERVED IN 15/20 SJOGREN'S SYNDROME PATIENTS, 5/5 CHRONIC SIALADENITIS, AND 3/5 NORMAL MINOR SALIVARY GLANDS. BOTH ANTIBODIES STAINED THE CYTOPLASM OF THE DUCTAL EPITHELIAL CELLS. NEGATIVE STAINING WAS OBSERVED IN THE ACINAR CELLS. L1 ORF2P-POSITIVE IMMUNOSTAINING WAS SIGNIFICANTLY LOWER IN TARPLEY IV SJOGREN'S SYNDROME PATIENTS THAN CONTROLS (P = .039), AND APOBEC3B-POSITIVE STAINING WAS SIGNIFICANTLY LOWER IN TARPLEY I COMPARED TO TARPLEY II SJOGREN'S SYNDROME PATIENTS (P = .008) AND CONTROLS (P = .035). CONCLUSIONS: L1 ORF2P AND APOBEC3B ARE EXPRESSED IN THE DUCTAL EPITHELIAL CELLS OF MINOR SALIVARY GLANDS THAT ARE AMONG THE KEY TARGETS IN SJOGREN'S SYNDROME. L1 ORF2P EXPRESSION MAY PROMOTE THE L1 ABILITY TO ACT AS AN INTRINSIC ANTIGEN IN SJOGREN'S SYNDROME. THE POTENTIAL FUTURE USE OF L1 ORF2-REVERSE TRANSCRIPTASE INHIBITORS IN AUTOIMMUNITY SUPPORTS FURTHER INVESTIGATION OF L1 EPIGENETIC REGULATION BY APOBEC3 ENZYMES. 2018 17 2633 37 EPIGENOME-WIDE DNA METHYLATION PATTERNS ASSOCIATED WITH FATIGUE IN PRIMARY SJOGREN'S SYNDROME. OBJECTIVE: CHRONIC FATIGUE IS A COMMON, DISABLING AND POORLY UNDERSTOOD PHENOMENON. RECENT STUDIES INDICATE THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN THE EXPRESSION OF FATIGUE, A PROMINENT FEATURE OF PRIMARY SS (PSS). THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER DNA METHYLATION PROFILES OF WHOLE BLOOD ARE ASSOCIATED WITH FATIGUE IN PATIENTS WITH PSS. METHODS: FORTY-EIGHT PSS PATIENTS WITH HIGH (N = 24) OR LOW (N = 24) FATIGUE AS MEASURED BY A VISUAL ANALOGUE SCALE WERE INCLUDED. GENOME-WIDE DNA METHYLATION WAS INVESTIGATED USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY. AFTER QUALITY CONTROL, A TOTAL OF 383 358 CYTOSINE-PHOSPHATE-GUANINE (CPG) SITES REMAINED FOR FURTHER ANALYSIS. AGE, SEX AND DIFFERENTIAL CELL COUNT ESTIMATES WERE INCLUDED AS COVARIATES IN THE ASSOCIATION MODEL. A FALSE DISCOVERY RATE-CORRECTED P < 0.05 WAS CONSIDERED SIGNIFICANT, AND A CUT-OFF OF 3% AVERAGE DIFFERENCE IN METHYLATION LEVELS BETWEEN HIGH- AND LOW-FATIGUE PATIENTS WAS APPLIED. RESULTS: A TOTAL OF 251 DIFFERENTIALLY METHYLATED CPG SITES WERE ASSOCIATED WITH FATIGUE. THE CPG SITE WITH THE MOST PRONOUNCED HYPOMETHYLATION IN PSS HIGH FATIGUE ANNOTATED TO THE SBF2-ANTISENSE RNA1 GENE. THE MOST DISTINCT HYPERMETHYLATION WAS OBSERVED AT A CPG SITE ANNOTATED TO THE LYMPHOTOXIN ALPHA GENE. FUNCTIONAL PATHWAY ANALYSIS OF GENES WITH DIFFERENTLY METHYLATED CPG SITES IN SUBJECTS WITH HIGH VS LOW FATIGUE REVEALED ENRICHMENT IN SEVERAL PATHWAYS ASSOCIATED WITH INNATE AND ADAPTIVE IMMUNITY. CONCLUSION: SOME GENES INVOLVED IN REGULATION OF THE IMMUNE SYSTEM AND IN INFLAMMATION ARE DIFFERENTLY METHYLATED IN PSS PATIENTS WITH HIGH VS LOW FATIGUE. THESE FINDINGS POINT TO FUNCTIONAL NETWORKS THAT MAY UNDERLIE FATIGUE. EPIGENETIC CHANGES COULD CONSTITUTE A FATIGUE-REGULATING MECHANISM IN PSS. 2016 18 6576 23 TREATMENT OF PRIMARY SJOGREN SYNDROME. PRIMARY SJOGREN SYNDROME (PSS) IS A PROGRESSIVE AUTOIMMUNE DISEASE CHARACTERIZED BY SICCA AND SYSTEMIC MANIFESTATIONS. IN THIS REVIEW, WE SUMMARIZE THE AVAILABLE DATA ON TOPICAL AND SYSTEMIC MEDICATIONS, ACCORDING TO CLINICAL SIGNS AND DISEASE ACTIVITY, AND WE DESCRIBE THE ONGOING STUDIES USING BIOLOGIC DRUGS IN THE TREATMENT OF PSS. EXPANDING KNOWLEDGE ABOUT THE EPIDEMIOLOGY, CLASSIFICATION CRITERIA, SYSTEMIC ACTIVITY SCORING (ESSDAI) AND PATIENT-REPORTED OUTCOMES (ESSPRI) IS DRIVING ACTIVE RESEARCH. TREATMENT DECISIONS ARE BASED ON THE EVALUATION OF SYMPTOMS AND EXTRAGLANDULAR MANIFESTATIONS. SYMPTOMATIC TREATMENT IS USUALLY APPROPRIATE, WHEREAS SYSTEMIC TREATMENT IS RESERVED FOR SYSTEMIC MANIFESTATIONS. SICCA IS MANAGED BY EDUCATION, ENVIRONMENT MODIFICATION, ELIMINATION OF CONTINGENT OFFENDING DRUGS, ARTIFICIAL TEARS, SECRETAGOGUES AND TREATMENTS FOR COMPLICATIONS. MILD SYSTEMIC SIGNS SUCH AS FATIGUE ARE TREATED BY EXERCISE. PAIN CAN REQUIRE SHORT-TERM MODERATE-DOSE GLUCOCORTICOID THERAPY AND, IN SOME CASES, DISEASE-MODIFYING DRUGS. SEVERE AND ACUTE SYSTEMIC MANIFESTATIONS INDICATE TREATMENT WITH GLUCOCORTICOIDS AND/OR IMMUNOSUPPRESSANT DRUGS. THE ROLE FOR BIOLOGIC AGENTS IS PROMISING, BUT NO DOUBLE-BLIND RANDOMIZED CONTROLLED TRIALS (RCTS) PROVING THE EFFICACY OF THESE DRUGS ARE AVAILABLE. TARGETS FOR NEW TREATMENTS DIRECTED AGAINST THE IMMUNOPATHOLOGICAL MECHANISMS OF PSS INCLUDE EPITHELIAL CELLS, T CELLS, B-CELL OVERACTIVITY, THE INTERFERON SIGNATURE, PROINFLAMMATORY CYTOKINES, ECTOPIC GERMINAL CENTRE FORMATION, CHEMOKINES INVOLVED IN LYMPHOID CELL HOMING, AND EPIGENETIC MODIFICATIONS. 2016 19 6373 16 THE ROLE OF MIRNAS AND EPIGENETIC MECHANISMS IN PRIMARY GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA. GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA IS A RARE LOW-GRADE B-CELL NON-HODGKIN LYMPHOMA ASSOCIATED WITH HELICOBACTER PYLORI INFECTION AND THE SUBSEQUENT CHRONIC INFLAMMATION. SIGNIFICANT PROGRESS IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE HAS ALREADY BEEN MADE. HOWEVER, THE EXACT MOLECULAR PATHWAYS OF LYMPHOMAGENESIS REMAIN UNCLEAR. FURTHERMORE, DIFFICULTIES REGARDING ACCURATE DIAGNOSIS OF GASTRIC MALT LYMPHOMA AND ITS DISCRIMINATION FROM GASTRITIS OR OTHER LYMPHOMA SUBTYPES ARISE. RECENT STUDIES EVALUATE THE ROLE OF MIRNAS AND EPIGENETIC ALTERATIONS ON MALT LYMPHOMA PATHOGENESIS AND PROGNOSIS. THIS REVIEW CRITICALLY SUMMARIZES THE MOST IMPORTANT DATA ON THE ROLE OF MIRNAS AND EPIGENETICS IN MALT LYMPHOMAS PATHOGENESIS, PROGNOSIS AND TREATMENT. 2016 20 2294 32 EPIGENETIC REGULATION IN THE PATHOGENESIS OF SJOGREN SYNDROME AND RHEUMATOID ARTHRITIS. AUTOIMMUNE RHEUMATIC DISEASES, SUCH AS SJOGREN SYNDROME (SS) AND RHEUMATOID ARTHRITIS (RA), ARE CHARACTERIZED BY CHRONIC INFLAMMATION AND AUTOIMMUNITY, WHICH CAUSE JOINT TISSUE DAMAGE AND DESTRUCTION BY TRIGGERING REDUCED MOBILITY AND DEBILITATION IN PATIENTS WITH THESE DISEASES. INITIATION AND MAINTENANCE OF CHRONIC INFLAMMATORY STAGES ACCOUNT FOR SEVERAL MECHANISMS THAT INVOLVE IMMUNE CELLS AS KEY PLAYERS AND THE INTERACTION OF THE IMMUNE CELLS WITH OTHER TISSUES. INDEED, THE OVERLAPPING OF CERTAIN CLINICAL AND SEROLOGIC MANIFESTATIONS BETWEEN SS AND RA MAY INDICATE THAT NUMEROUS IMMUNOLOGIC-RELATED MECHANISMS ARE INVOLVED IN THE PHYSIOPATHOLOGY OF BOTH THESE DISEASES. IT IS WIDELY ACCEPTED THAT EPIGENETIC PATHWAYS PLAY AN ESSENTIAL ROLE IN THE DEVELOPMENT AND FUNCTION OF THE IMMUNE SYSTEM. ALTHOUGH MANY PUBLISHED STUDIES HAVE ATTEMPTED TO ELUCIDATE THE RELATION BETWEEN EPIGENETIC MODIFICATIONS (E.G. DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS, MIRNAS) AND AUTOIMMUNE DISORDERS, THE CONTRIBUTION OF EPIGENETIC REGULATION TO THE PATHOGENESIS OF SS AND RA IS AT PRESENT POORLY UNDERSTOOD. THIS REVIEW ATTEMPTS TO SHED LIGHT FROM A CRITICAL POINT OF VIEW ON THE IDENTIFICATION OF THE MOST RELEVANT EPIGENETIC MECHANISMS RELATED TO RA AND SS BY EXPLAINING INTRICATE REGULATORY PROCESSES AND PHENOTYPIC FEATURES OF BOTH AUTOIMMUNE DISEASES. MOREOVER, WE POINT OUT SOME EPIGENETIC MARKERS WHICH CAN BE USED TO MONITOR THE INFLAMMATION STATUS AND THE DYSREGULATED IMMUNITY IN SS AND RA. FINALLY, WE DISCUSS THE INCONVENIENCE OF USING EPIGENETIC DATA OBTAINED FROM BULK IMMUNE CELL POPULATIONS INSTEAD SPECIFIC IMMUNE CELL SUBPOPULATIONS. 2019