1 6050 96 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 2 2515 43 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 3 4268 35 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 4 1603 42 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 5 2552 45 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 6 1873 33 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 7 2294 31 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 8 2529 40 EPIGENETICS CHANGES ASSOCIATED TO ENVIRONMENTAL TRIGGERS IN AUTOIMMUNITY. AUTOIMMUNE DISEASES (AIDS) ARE CHRONIC CONDITIONS INITIATED BY THE LOSS OF IMMUNOLOGICAL TOLERANCE TO SELF-ANTIGENS AND REPRESENT A HETEROGENEOUS GROUP OF DISORDERS THAT AFFECT SPECIFIC TARGET ORGANS OR MULTIPLE ORGANS IN DIFFERENT SYSTEMS. WHILE THE PATHOGENESIS OF AID REMAINS UNCLEAR, ITS AETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC, EPIGENETIC, IMMUNOLOGICAL AND ENVIRONMENTAL FACTORS. IN AIDS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION, ABNORMAL CHROMATIN POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION AND ABNORMALITIES IN THE EXPRESSION OF RNA INTERFERENCE (RNAI). IT IS KNOWN THAT ENVIRONMENTAL FACTORS MAY INTERFERE WITH DNA METHYLATION AND HISTONE MODIFICATIONS, HOWEVER, LITTLE IS KNOWN ABOUT EPIGENETIC CHANGES DERIVED OF REGULATION OF RNAI. AN APPROACH TO THE KNOWN ENVIRONMENTAL FACTORS AND THE MECHANISMS THAT ALTER THE EPIGENETIC REGULATION IN AIDS (WITH EMPHASIS IN SYSTEMIC LUPUS ERYTHEMATOSUS, THE PROTOTYPE OF SYSTEMIC AID) ARE SHOWED IN THIS REVIEW. 2016 9 6800 39 [EPIGENETIC DISTURBANCES IN SYSTEMIC LUPUS ERYTHEMATOSUS]. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT RESULTS IN UNCONTROLLED IMMUNE SYSTEM ACTIVATION AND OVERPRODUCTION OF AUTOANTIBODIES. THE PATHOGENESIS OF THE DISEASE IS COMPLEX AND NOT FULLY UNDERSTOOD, NEVERTHELESS, GENETIC AND ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE. SO FAR, ABOUT 30 GENES HAVE BEEN IDENTIFIED TO BE INVOLVED IN THE SLE PATHOMECHANISM. HOWEVER, NOT ALL GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP THE DISEASE. THIS PHENOMENON CAN BE ASSOCIATED WITH EPIGENETIC CHANGES THAT OCCUR UNDER THE INFLUENCE OF ENVIRONMENTAL FACTORS. THEY CAN AFFECT GENE EXPRESSION AND ARE POTENTIALLY HEREDITARY, BUT DO NOT LEAD TO CHANGES IN THE NUCLEOTIDE SEQUENCE. EPIGENETIC DYSFUNCTIONS, IDENTIFIED IN THE COURSE OF THE DISEASE, LEAD TO CHANGES IN THE EXPRESSION OF GENES THAT PLAY A KEY ROLE IN MAINTAINING THE BODY'S IMMUNE TOLERANCE. MAJOR MECHANISMS OF EPIGENETIC VARIABILITY ARE: DNA METHYLATION, HISTONE PROTEIN MODIFICATION, NON-CODING RNA EXPRESSION, AS WELL AS GENE IMPRINTING. THE MAJOR EPIGENETIC DYSFUNCTIONS AFFECTING THE PATHOGENESIS OF THE DISEASE ARE GLOBAL HYPOMETHYLATION ON CD4+ T CELLS RESULTING FROM ERK SIGNALING PATHWAY REGULATION, HISTONE HYPOACETYLATION, HISTONE H3 LYSINE METHYLATION, AND REACTIVATION OF INACTIVE CHROMOSOME X. IN LUPUS PATIENTS, VARIOUS EPIGENETIC MECHANISMS INTERACT WITH EACH OTHER, ENHANCING THE EXPRESSION OR SILENCING OF GENES RESPONSIBLE FOR THE PRODUCTION OF PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINES AND ACTIVATION OF AUTOREACTIVE B-LYMPHOCYTES. 2018 10 6262 37 THE MULTIFACETED FUNCTIONAL ROLE OF DNA METHYLATION IN IMMUNE-MEDIATED RHEUMATIC DISEASES. GENOMIC PREDISPOSITION CANNOT EXPLAIN THE ONSET OF COMPLEX DISEASES, AS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELLING AND NON-CODING RNA, ARE CONSIDERED TO BE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. THE PARADIGMATIC CASES OF RHEUMATOID ARTHRITIS (RA), SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), SYSTEMIC SCLEROSIS (SSC), SJOGREN'S SYNDROME (SJS) AND TYPE-1 DIABETES (T1D) SHARE THE LOSS OF IMMUNOLOGICAL TOLERANCE TO SELF-ANTIGEN INFLUENCED BY SEVERAL FACTORS, WITH A LARGELY INCOMPLETE ROLE OF INDIVIDUAL GENOMIC SUSCEPTIBILITY. THE MOST WIDELY INVESTIGATED EPIGENETIC MECHANISM IS DNA METHYLATION WHICH IS ASSOCIATED WITH GENE SILENCING AND IS DUE TO THE BINDING OF METHYL-CPG BINDING DOMAIN (MBD)-CONTAINING PROTEINS, SUCH AS MECP2, TO 5-METHYLCYTOSINE (5MC). INDEED, A CAUSAL RELATIONSHIP OCCURS BETWEEN DNA METHYLATION AND TRANSCRIPTION FACTORS OCCUPANCY AND RECRUITMENT AT SPECIFIC GENOMIC LOCUS. IN MOST CASES, THE RESULTS OBTAINED IN DIFFERENT STUDIES ARE CONTROVERSIAL IN TERMS OF DNA METHYLATION COMPARISON WHILE FASCINATING EVIDENCE COMES FROM THE COMPARISON OF THE EPIGENOME IN CLINICALLY DISCORDANT MONOZYGOTIC TWINS. IN THIS MANUSCRIPT, WE WILL REVIEW THE MECHANISMS OF EPIGENETICS AND DNA METHYLATION CHANGES IN SPECIFIC IMMUNE-MEDIATED RHEUMATIC DISEASES TO HIGHLIGHT REMAINING UNMET NEEDS AND TO IDENTIFY POSSIBLE SHARED MECHANISMS BEYOND DIFFERENT TISSUE INVOLVEMENTS WITH COMMON THERAPEUTIC OPPORTUNITIES. KEY POINTS * DNA METHYLATION HAS A CRUCIAL ROLE IN REGULATING AND TUNING THE IMMUNE SYSTEM. * EVIDENCES SUGGEST THAT DYSREGULATION OF DNA METHYLATION IS PIVOTAL IN THE CONTEXT OF IMMUNE-MEDIATED RHEUMATIC DISEASES. * DNA METHYLATION DYSREGULATION IN FOXP3 AND INTERFERONS-RELATED GENES IS SHARED WITHIN SEVERAL AUTOIMMUNE DISEASES. * DNA METHYLATION IS AN ATTRACTIVE MARKER FOR DIAGNOSIS AND THERAPY. 2021 11 207 37 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 12 1165 41 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 13 6178 32 THE HISTONE MODIFICATION CODE IN THE PATHOGENESIS OF AUTOIMMUNE DISEASES. AUTOIMMUNE DISEASES ARE CHRONIC INFLAMMATORY DISORDERS CAUSED BY A LOSS OF SELF-TOLERANCE, WHICH IS CHARACTERIZED BY THE APPEARANCE OF AUTOANTIBODIES AND/OR AUTOREACTIVE LYMPHOCYTES AND THE IMPAIRED SUPPRESSIVE FUNCTION OF REGULATORY T CELLS. THE PATHOGENESIS OF AUTOIMMUNE DISEASES IS EXTREMELY COMPLEX AND REMAINS LARGELY UNKNOWN. RECENT ADVANCES INDICATE THAT ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE DISEASES IN GENETICALLY PREDISPOSED INDIVIDUALS. IN ADDITION, ACCUMULATING RESULTS HAVE INDICATED A POTENTIAL ROLE OF EPIGENETIC MECHANISMS, SUCH AS HISTONE MODIFICATIONS, IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. HISTONE MODIFICATIONS REGULATE THE CHROMATIN STATES AND GENE TRANSCRIPTION WITHOUT ANY CHANGE IN THE DNA SEQUENCE, POSSIBLY RESULTING IN PHENOTYPE ALTERATION IN SEVERAL DIFFERENT CELL TYPES. IN THIS PAPER, WE DISCUSS THE SIGNIFICANT ROLES OF HISTONE MODIFICATIONS INVOLVED IN THE PATHOGENESIS OF AUTOIMMUNE DISEASES, INCLUDING RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, PRIMARY BILIARY CIRRHOSIS, AND TYPE 1 DIABETES. 2017 14 398 27 AN UPDATE ON GENETIC SUSCEPTIBILITY IN LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY MULTIPLE SYSTEM INVOLVEMENT AND POSITIVE SERUM AUTOANTIBODIES. LUPUS NEPHRITIS (LN) IS THE MOST COMMON AND SERIOUS COMPLICATION OF SLE, AND IT IS THE MAIN CAUSE OF DEATH IN PATIENTS WITH SLE. ABNORMALITIES IN THE IMMUNE SYSTEM LEAD TO LN AND INVOLVE A VARIETY OF CELLS (T CELLS, B CELLS, MACROPHAGES, NK CELLS, ETC.), CYTOKINES (INTERLEUKIN, TUMOR NECROSIS FACTOR ALPHA, ETC.) AND THEIR RELATED PATHWAYS. PREVIOUS STUDIES HAVE SHOWN THAT THE INTERACTIONS OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS CONTRIBUTE TO THE PATHOGENESIS AND DEVELOPMENT OF LN. IN RECENT YEARS, ONE GENOME-WIDE ASSOCIATION STUDY (GWAS) AND A NUMBER OF GENE ASSOCIATION STUDIES HAVE EXPLORED THE SUSCEPTIBILITY GENES OF LN, INCLUDING IMMUNIZATION-, INFLAMMATION-, ADHESION- AND OTHER PATHWAY-RELATED GENES. THESE GENES PARTICIPATE IN OR SUGGEST THE PATHOGENESIS AND PROGRESSION OF LN. IN THIS REVIEW, WE SUMMARIZE THE GENETIC SUSCEPTIBILITY OF LN AND DISCUSS THE POSSIBLE MECHANISM UNDERLYING THE SUSCEPTIBILITY GENES OF LN. 2020 15 1985 34 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 16 4228 23 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020 17 2017 34 EPIGENETIC BIOMARKERS IN RHEUMATOLOGY - THE FUTURE? EPIGENETIC CHANGES ARE STABLE MODIFICATIONS OF DNA OR HISTONES THAT PROFOUNDLY ALTER GENE EXPRESSION. THEY CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES AND CAN THEN BE PASSED ON TO DAUGHTER CELLS OR VIA THE GERM LINE TO OFFSPRING. A VARIETY OF CHANGES IN EPIGENETIC MARKS AND IN THE EXPRESSION OF NONCODING RNA HAS BEEN FOUND IN CANCER AS WELL AS IN CHRONIC INFLAMMATORY DISEASES. INTERESTINGLY, IN BOTH DISEASES SIMILAR MECHANISMS AND PATHWAYS ARE AFFECTED ALBEIT OFTEN TO A DIFFERENT EXTENT. DNA METHYLATION IS OFTEN LOST IN REPETITIVE SEQUENCES, WHILE IN PROMOTER REGIONS HYPO- AS WELL AS HYPERMETHYLATION IS FOUND. CHANGES IN MICRORNA LEVELS TYPICALLY AFFECT MICRORNAS THAT ARE CHANGED BY AN INFLAMMATORY ENVIRONMENT, BUT DISEASE SPECIFIC CHANGES HAVE ALSO BEEN FOUND IN THE BLOOD AND VARIOUS CELL TYPES OF PATIENTS WITH RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER RHEUMATIC DISEASES. THEREFORE, CHANGES IN THE EXPRESSION OF MICRORNA IN PARTICULAR, BUT ALSO DEMETHYLATED GENE LOCI, HAVE BEEN PROPOSED AS POTENTIAL BIOMARKERS IN CHRONIC INFLAMMATORY DISEASES AND IN CANCER. POTENTIALLY, THESE CHANGES COULD BE USED FOR EARLY DIAGNOSIS AND ALSO TO PREDICT TREATMENT RESPONSE. UNFORTUNATELY MOST STUDIES IN RHEUMATOLOGY UP TO NOW WERE NOT DESIGNED TO VALIDATE THESE EPIGENETIC CHANGES AS BIOMARKERS. SINCE THE CANCER FIELD IS MUCH MORE ADVANCED IN THE USAGE OF BIOMARKERS FOR DISEASE SUBCLASSIFICATIONS AND SUBSEQUENT THERAPEUTIC DECISIONS, IT IS WORTHWHILE TO TAKE A CLOSER LOOK AT THE BIOMARKERS, METHODS AND PROCEDURES USED IN ONCOLOGY AND TO SEE WHICH OF THESE COULD ALSO BE APPLIED TO PREDICTING DISEASE SEVERITY AND THERAPEUTIC RESPONSE IN RHEUMATIC DISEASES. THIS ARTICLE WILL HIGHLIGHT COMMON EPIGENETIC PATHWAYS ACTIVATED IN CANCER AND VARIOUS RHEUMATIC DISEASES AND SUMMARISE EPIGENETIC CHANGES THAT HAVE THE POTENTIAL TO BECOME BIOMARKERS IN RHEUMATIC DISEASES. 2016 18 6340 30 THE ROLE OF EPIGENETIC FACTORS IN PSORIASIS. PSORIASIS IS A CHRONIC, SYSTEMIC, IMMUNE-MEDIATED DISEASE WITH AN INCIDENCE OF APPROXIMATELY 2%. THE PATHOGENESIS OF THE DISEASE IS COMPLEX AND NOT YET FULLY UNDERSTOOD. GENETIC FACTORS PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF THE DISEASE. IN PREDISPOSED INDIVIDUALS, MULTIPLE TRIGGER FACTORS MAY CONTRIBUTE TO DISEASE ONSET AND EXACERBATIONS OF SYMPTOMS. ENVIRONMENTAL FACTORS (STRESS, INFECTIONS, CERTAIN MEDICATIONS, NICOTINISM, ALCOHOL, OBESITY) PLAY A SIGNIFICANT ROLE IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION, EPIGENETIC MECHANISMS ARE CONSIDERED RESULT IN MODULATION OF INDIVIDUAL GENE EXPRESSION AND AN INCREASED LIKELIHOOD OF THE DISEASE. STUDIES HIGHLIGHT THE SIGNIFICANT ROLE OF EPIGENETIC FACTORS IN THE ETIOLOGY AND PATHOGENESIS OF PSORIASIS. EPIGENETIC MECHANISMS IN PSORIASIS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS. EPIGENETIC MECHANISMS INDUCE GENE EXPRESSION CHANGES UNDER THE INFLUENCE OF CHEMICAL MODIFICATIONS OF DNA AND HISTONES, WHICH ALTER CHROMATIN STRUCTURE AND ACTIVATE TRANSCRIPTION FACTORS OF SELECTED GENES, THUS LEADING TO TRANSLATION OF NEW MRNA WITHOUT AFFECTING THE DNA SEQUENCE. EPIGENETIC FACTORS CAN REGULATE GENE EXPRESSION AT THE TRANSCRIPTIONAL (VIA HISTONE MODIFICATION, DNA METHYLATION) AND POSTTRANSCRIPTIONAL LEVELS (VIA MICRORNAS AND LONG NON-CODING RNAS). THIS STUDY AIMS TO PRESENT AND DISCUSS THE DIFFERENT EPIGENETIC MECHANISMS IN PSORIASIS BASED ON A REVIEW OF THE AVAILABLE LITERATURE. 2021 19 1518 30 DNA METHYLATION AS AN EPIGENETIC MECHANISM IN THE DEVELOPMENT OF MULTIPLE SCLEROSIS. THE EPIGENETIC MECHANISMS OF GENE EXPRESSION REGULATION ARE A GROUP OF THE KEY CELLULAR AND MOLECULAR PATHWAYS THAT LEAD TO INHERITED ALTERATIONS IN GENES' ACTIVITY WITHOUT CHANGING THEIR CODING SEQUENCE. DNA METHYLATION AT THE C5 POSITION OF CYTOSINE IN CPG DINUCLEOTIDES IS AMONGST THE CENTRAL EPIGENETIC MECHANISMS. CURRENTLY, THE NUMBER OF STUDIES THAT ARE DEVOTED TO THE IDENTIFICATION OF METHYLATION PATTERNS SPECIFIC TO MULTIPLE SCLEROSIS (MS), A SEVERE CHRONIC AUTOIMMUNE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS ON A RAPID RISE. HOWEVER, THE ISSUE OF THE CONTRIBUTION OF DNA METHYLATION TO THE DEVELOPMENT OF THE DIFFERENT CLINICAL PHENOTYPES OF THIS HIGHLY HETEROGENEOUS DISEASE HAS ONLY BEGUN TO ATTRACT THE ATTENTION OF RESEARCHERS. THIS REVIEW SUMMARIZES THE DATA ON THE MOLECULAR MECHANISMS UNDERLYING DNA METHYLATION AND THE MS RISK FACTORS THAT CAN AFFECT THE DNA METHYLATION PROFILE AND, THEREBY, MODULATE THE EXPRESSION OF THE GENES INVOLVED IN THE DISEASE'S PATHOGENESIS. THE FOCUS OF OUR ATTENTION IS CENTERED ON THE ANALYSIS OF THE PUBLISHED DATA ON THE DIFFERENTIAL METHYLATION OF DNA FROM VARIOUS BIOLOGICAL SAMPLES OF MS PATIENTS OBTAINED USING BOTH THE CANDIDATE GENE APPROACH AND HIGH-THROUGHPUT METHODS. 2021 20 3703 24 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009