1 3699 82 INFLAMMATORY MEMORIES: IS EPIGENETICS THE MISSING LINK TO PERSISTENT STROMAL CELL ACTIVATION IN RHEUMATOID ARTHRITIS? RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE RECOGNIZED AS KEY CELLS IN THE PATHOGENESIS OF RA SINCE THEY ATTRACT AND ACTIVATE IMMUNE CELLS AND PRODUCE MATRIX DEGRADING ENZYMES. MOST NOTABLY SYNOVIAL FIBROBLASTS FROM PATIENTS WITH RA ARE STABLY ACTIVATED AND PRODUCE HIGH LEVELS OF DISEASE-PROMOTING MOLECULES WITHOUT FURTHER STIMULATION BY IMMUNE CELLS. ACCUMULATING DATA SUGGEST THAT EPIGENETIC CHANGES IN STROMAL CELL POPULATIONS MIGHT BE CRUCIALLY INVOLVED IN THE PATHOLOGY OF RA AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE CURRENT REVIEW, WE DISCUSS THE MECHANISMS BY WHICH EPIGENETIC CHANGES MIGHT CAUSE THE STABLE ACTIVATION OF SYNOVIAL FIBROBLASTS IN RA AND HOW CHANGES IN THE EPIGENOME MIGHT ALTER IMMUNE FUNCTION AND INFLAMMATORY RESPONSE AND THEREBY PROMOTE THE DEVELOPMENT OF CHRONIC DISEASES. 2011 2 783 33 CELL-SPECIFIC EPIGENETIC DRIVERS OF PATHOGENESIS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A COMPLEX, INFLAMMATORY AUTOIMMUNE DISEASE, WHICH IS CHARACTERIZED BY PAIN, SWELLING AND JOINT DAMAGE DRIVEN BY THE ALTERED BEHAVIOR OF A NUMBER OF DIFFERENT CELL TYPES SUCH AS SYNOVIAL FIBROBLASTS MACROPHAGES AND LYMPHOCYTES. THE MECHANISM UNDERLYING PATHOGENESIS IS UNCLEAR BUT INCREASING EVIDENCE POINTS TO ALTERED EPIGENETIC REGULATION WITHIN THESE CELL TYPES WHICH PROMOTES THE ACTIVATED DESTRUCTIVE BEHAVIOR THAT UNDERLIES DISEASE PATHOGENESIS. THIS REVIEW SUMMARIZES THE KEY EPIGENETIC MODIFICATIONS IN THE MOST IMPORTANT CELLS TYPES IN RHEUMATOID ARTHRITIS, WHICH ARE ASSOCIATED WITH DISEASE ACTIVITY. WE ALSO DISCUSS EMERGING AVENUES OF RESEARCH FOCUSING ON READERS OF EPIGENETIC MARKERS WHICH MAY SERVE TO BE POTENTIAL THERAPEUTIC TARGETS. 2021 3 2221 32 EPIGENETIC MODIFICATIONS IN RHEUMATOID ARTHRITIS, A REVIEW. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC JOINT INFLAMMATION AND PROGRESSIVE DESTRUCTION OF CARTILAGE AND BONE WHICH LEADS TO ULTIMATELY LOSS OF FUNCTION AND PAIN. ACTIVATED SYNOVIAL FIBROBLASTS ARE KEY EFFECTOR CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS. IN THE RECENT YEARS, EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND OTHER HISTONE MODIFICATIONS WERE IDENTIFIED THAT ARE ASSOCIATED WITH AN INTRINSIC ACTIVATION AND THE AGGRESSIVE PHENOTYPE OF THESE CELLS. SO FAR, NO THERAPIES TARGETING RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS EXIST. THIS REVIEW COMPRISES RECENT RESEARCH EFFORTS THAT PROPOSE EPIGENETIC MECHANISMS BEHIND THE ACTIVATION OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS AND OTHER CELL TYPES. 2013 4 1608 32 DNA METHYLATION-GOVERNED GENE EXPRESSION IN AUTOIMMUNE ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE HALLMARKED BY PROGRESSIVE AND IRREVERSIBLE JOINT DESTRUCTION. RA PATHOGENESIS IS A T CELL-REGULATED AND B CELL-MEDIATED PROCESS IN WHICH ACTIVATED LYMPHOCYTE-PRODUCED CHEMOKINES AND CYTOKINES PROMOTE LEUKOCYTE INFILTRATION THAT ULTIMATELY LEADS TO DESTRUCTION OF THE JOINTS. THERE IS AN OBVIOUS NEED TO DISCOVER NEW DRUGS FOR RA TREATMENT THAT HAVE DIFFERENT BIOLOGICAL TARGETS OR MODES OF ACTION THAN THE CURRENTLY EMPLOYED THERAPEUTICS. ENVIRONMENTAL FACTORS SUCH AS CIGARETTE SMOKE, CERTAIN DIET COMPONENTS, AND ORAL PATHOGENS CAN SIGNIFICANTLY AFFECT GENE REGULATION VIA EPIGENETIC FACTORS. EPIGENETICS OPENED A NEW FIELD FOR PHARMACOLOGY, AND DNA METHYLATION AND HISTONE MODIFICATION-IMPLICATED FACTORS ARE FEASIBLE TARGETS FOR RA THERAPY. EXPLORING RA PATHOGENESIS INVOLVED EPIGENETIC FACTORS AND MECHANISMS IS CRUCIAL FOR DEVELOPING MORE EFFICIENT RA THERAPIES. HERE WE REVIEW EPIGENETIC ALTERATIONS ASSOCIATED WITH RA PATHOGENESIS INCLUDING DNA METHYLATION AND INTERACTING FACTORS. ADDITIONALLY, WE WILL SUMMARIZE THE LITERATURE REVEALING THE INVOLVED MOLECULAR STRUCTURES AND INTERACTIONS. FINALLY, POTENTIAL EPIGENETIC FACTOR-BASED THERAPIES WILL BE DISCUSSED THAT MAY HELP IN BETTER MANAGEMENT OF RA IN THE FUTURE. 2019 5 4842 33 ONE YEAR IN REVIEW 2017: PATHOGENESIS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. IT HAS BEEN POSTULATED THAT A HIGH-RISK GENETIC BACKGROUND, IN COMBINATION WITH EPIGENETIC MARKS AND ENVIRONMENTAL EXPOSURES, LEADS TO A CASCADE OF EVENTS INDUCING SYNOVITIS AND CONSEQUENT DESTRUCTIVE ARTHRITIS. THE CLINICAL PICTURE OF JOINT INVOLVEMENT IN RA IS THE RESULT OF CHRONIC INFLAMMATION OF THE SYNOVIUM, CHARACTERISED BY INTERACTIONS OF RESIDENT CELLS SUCH AS FIBROBLAST-LIKE SYNOVIOCYTES (FLS) WITH CELLS OF THE INNATE (E.G. MACROPHAGES, DENDRITIC CELLS, MAST CELLS AND NK CELLS, NEUTROPHILS) AND ADAPTIVE IMMUNE SYSTEM (E.G. B AND T LYMPHOCYTES). CURRENTLY, OUR UNDERSTANDING OF THE ROLE OF INNATE AND ADAPTIVE IMMUNITY IN THE PATHOGENESIS OF RA IS EXPANDING. THE CONCEPT OF HOW IMMUNE RESPONSES CONTRIBUTE TO THE DISEASE HAS DRAMATICALLY EVOLVED OVER THE LAST 50 YEARS. SHEDDING SOME LIGHT ON THE DIFFERENT ASPECTS OF RA PATHOGENESIS WILL HELP TO IDENTIFY NEW TARGETS FOR THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. THUS, IN THIS REVIEW WE REPORT NEW INSIGHTS IN RA PATHOGENESIS, RESULTING FROM A LITERATURE RESEARCH DATE PUBLISHED IN THE LAST YEAR. 2017 6 6245 34 THE MECHANISMS UNDERLYING CHRONIC INFLAMMATION IN RHEUMATOID ARTHRITIS FROM THE PERSPECTIVE OF THE EPIGENETIC LANDSCAPE. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT IS CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. THE ACTIVATION OF RA SYNOVIAL FIBROBLASTS (SFS), ALSO CALLED FIBROBLAST-LIKE SYNOVIOCYTES (FLS), CONTRIBUTES SIGNIFICANTLY TO PERPETUATION OF THE DISEASE. GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN REPORTED TO BE INVOLVED IN THE ETIOLOGY OF RA BUT ARE INSUFFICIENT TO EXPLAIN IT. IN RECENT YEARS, ACCUMULATING RESULTS HAVE SHOWN THE POTENTIAL ROLE OF EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, AND MICRORNAS, IN THE DEVELOPMENT OF RA. EPIGENETIC MECHANISMS REGULATE CHROMATIN STATE AND GENE TRANSCRIPTION WITHOUT ANY CHANGE IN DNA SEQUENCE, RESULTING IN THE ALTERATION OF PHENOTYPES IN SEVERAL CELL TYPES, ESPECIALLY RASFS. EPIGENETIC CHANGES POSSIBLY PROVIDE RASFS WITH AN ACTIVATED PHENOTYPE. IN THIS PAPER, WE REVIEW THE ROLES OF EPIGENETIC MECHANISMS RELEVANT FOR THE PROGRESSION OF RA. 2016 7 4412 31 MOLECULAR AND CELLULAR BASIS OF RHEUMATOID JOINT DESTRUCTION. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE ASSOCIATED WITH JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE KEY PLAYERS IN THIS PATHOLOGICAL PROCESS. THEY FAVORISE A PRO-INFLAMMATORY ENVIRONMENT IN THE SYNOVIAL TISSUE, INTERACT WITH THE IMMUNE SYSTEM AND REGULATE THE DIFFERENTIATION OF MONOCYTES INTO OSTEOCLASTS. SYNOVIAL HYPERPLASIA IS ANOTHER CHARACTERISTIC OF RA, REFLECTING NOT ONLY AN IMBALANCE BETWEEN PROLIFERATION AND APOPTOSIS, BUT ALSO THE MIGRATION OF CELLS INTO THE SYNOVIAL TISSUE. GENE TRANSFER EXPERIMENTS HAVE BEEN USED AS IMPORTANT TOOLS FOR THE UNDERSTANDING OF MOLECULAR AND CELLULAR CHANGES THAT CHARACTERIZE THE ACTIVATED RA SYNOVIAL FIBROBLASTS. ACTIVATED SYNOVIAL FIBROBLASTS CAN INVADE CARTILAGE AND BONE. SYNOVIAL ACTIVATION IS DRIVEN BY CYTOKINES, SUCH AS TNFALPHA AND IL-1, AS WELL AS IL-15, 16, 17, 18, 22, 23, BUT ALSO BY CYTOKINE-INDEPENDENT MECHANISMS THAT INVOLVE THE INNATE IMMUNE SYSTEM (I.E. TLRS), A UNIQUE COMMUNICATION NETWORK OF MICROPARTICLES AND EPIGENETIC CHANGES (E.G. L1 RETROELEMENTS). 2006 8 2054 38 EPIGENETIC CONTRIBUTIONS IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE DISEASE, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE JOINTS WITH SEVERE PAIN AND SWELLING, JOINT DAMAGE AND DISABILITY, WHICH LEADS TO JOINT DESTRUCTION AND LOSS OF FUNCTION. DESPITE EXTENSIVE RESEARCH EFFORTS, THE UNDERLYING CAUSE FOR RA IS STILL UNKNOWN AND CURRENT THERAPIES ARE MORE OR LESS EFFECTIVE IN CONTROLLING SYMPTOMS BUT STILL FAIL TO CURE THE DISEASE. IN RECENT YEARS, EPIGENETIC MODIFICATIONS WERE FOUND TO STRONGLY CONTRIBUTE TO THE DEVELOPMENT OF RA BY AFFECTING DIVERSE ASPECTS OF THE DISEASE AND MODIFYING GENE EXPRESSION LEVELS AND BEHAVIOR OF SEVERAL CELL TYPES, FIRST AND FOREMOST JOINT RESIDENT SYNOVIAL FIBROBLASTS (SF). RASF ARE THE MOST COMMON CELL TYPE AT THE SITE OF INVASION. OWING TO THEIR AGGRESSIVE, INTRINSICALLY ACTIVATED PHENOTYPE, RASF ARE ACTIVE CONTRIBUTORS IN JOINT DAMAGE. RASF ARE CHARACTERIZED BY THEIR ABILITY TO SECRETE CYTOKINES, CHEMOKINES AND JOINT-DAMAGING ENZYMES. FURTHERMORE, THESE CELLS ARE RESISTANT TO APOPTOSIS, LEADING TO HYPERPLASIA OF THE SYNOVIUM. IN ADDITION, RASF HAVE INVASIVE AND MIGRATORY PROPERTIES THAT COULD LEAD TO SPREADING OF THE DISEASE TO UNAFFECTED JOINTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE (DE)ACETYLATION, HISTONE METHYLATION AND HISTONE SUMOYLATION WERE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE CELL ACTIVATION IN VITRO AND IN DISEASE OUTCOME IN ANIMAL MODELS IN VIVO. IN THE LAST 5 YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. IN THIS REVIEW WE CONSIDER THE ROLE OF DIVERSE EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON EPIGENETIC MODIFICATIONS IN RASF. 2012 9 4684 28 NEW POTENTIAL THERAPEUTIC APPROACHES TARGETING SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS. SYNOVIAL CELLS PLAY A KEY ROLE IN JOINT DESTRUCTION DURING CHRONIC INFLAMMATION. IN PARTICULAR, ACTIVATED SYNOVIAL FIBROBLASTS (SFS) UNDERGO INTRINSIC ALTERATIONS LEADING TO AN AGGRESSIVE PHENOTYPE MEDIATING CARTILAGE DESTRUCTION AND BONE EROSION IN RHEUMATOID ARTHRITIS (RA). RECENT RESEARCH HAS REVEALED A NUMBER OF TARGETS TO CONTROL ARTHRITOGENIC CHANGES IN SFS. THEREFORE, IDENTIFICATION OF SF PHENOTYPES, CONTROL OF EPIGENETIC CHANGES, MODULATION OF CELLULAR FUNCTIONS, OR REGULATION OF THE ACTIVITY OF CATION CHANNELS AND DIFFERENT SIGNALING PATHWAYS HAS BEEN INVESTIGATED. ALTHOUGH MANY OF THESE APPROACHES HAVE SHOWN EFFICACY IN VITRO AND IN ANIMAL MODELS OF RA, FURTHER RESEARCH IS NEEDED TO SELECT THE MOST RELEVANT TARGETS FOR DRUG DEVELOPMENT. THIS REVIEW IS FOCUSED ON THE ROLE OF SFS AS A POTENTIAL STRATEGY TO DISCOVER NOVEL THERAPEUTIC TARGETS IN RA AIMED AT PRESERVING JOINT ARCHITECTURE AND FUNCTION. 2021 10 1565 30 DNA METHYLATION OF T LYMPHOCYTES AS A THERAPEUTIC TARGET: IMPLICATIONS FOR RHEUMATOID ARTHRITIS ETIOLOGY. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE DISEASE THAT CAN CAUSE JOINT DAMAGE AND DISABILITY. EPIGENETIC VARIATION, ESPECIALLY DNA METHYLATION, HAS BEEN SHOWN TO BE INVOLVED IN ALMOST ALL THE STAGES OF THE PATHOLOGY OF RA, FROM AUTOANTIBODY PRODUCTION TO VARIOUS SELF-EFFECTOR T CELLS AND THE DEFECTS OF PROTECTIVE T CELLS THAT CAN LEAD TO CHRONIC INFLAMMATION AND EROSION OF BONES AND JOINTS. GIVEN THE CRITICAL ROLE OF T CELLS IN THE PATHOLOGY OF RA, THE REGULATORY FUNCTIONS OF DNA METHYLATION IN T CELL BIOLOGY REMAIN UNCLEAR. IN THIS REVIEW, WE ELABORATE ON THE RELATIONSHIP BETWEEN RA PATHOGENESIS AND DNA METHYLATION IN THE CONTEXT OF DIFFERENT T CELL POPULATIONS. WE SUMMARIZE THE RELEVANT METHYLATION EVENTS IN T CELL DEVELOPMENT, DIFFERENTIATION, AND T CELL-RELATED GENES IN DISEASE PREDICTION AND DRUG EFFICACY. UNDERSTANDING THE EPIGENETIC REGULATION OF T CELLS HAS THE POTENTIAL TO PROFOUNDLY TRANSLATE PRECLINICAL RESULTS INTO CLINICAL PRACTICE AND PROVIDE A FRAMEWORK FOR THE DEVELOPMENT OF NOVEL, INDIVIDUALIZED RA THERAPEUTICS. 2022 11 6597 28 TUNING MONOCYTES AND MACROPHAGES FOR PERSONALIZED THERAPY AND DIAGNOSTIC CHALLENGE IN RHEUMATOID ARTHRITIS. MONOCYTES/MACROPHAGES PLAY A CENTRAL ROLE IN CHRONIC INFLAMMATORY DISORDERS, INCLUDING RHEUMATOID ARTHRITIS (RA). ACTIVATION OF THESE CELLS RESULTS IN THE PRODUCTION OF VARIOUS MEDIATORS RESPONSIBLE FOR INFLAMMATION AND RA PATHOGENESIS. ON THE OTHER HAND, THE DEPLETION OF MACROPHAGES USING SPECIFIC ANTIBODIES OR CHEMICAL AGENTS CAN PREVENT THEIR SYNOVIAL TISSUE INFILTRATION AND SUBSEQUENTLY ATTENUATES INFLAMMATION. THEIR PLASTICITY IS A MAJOR FEATURE THAT HELPS THE SWITCH FROM A PRO-INFLAMMATORY PHENOTYPE (M1) TO AN ANTI-INFLAMMATORY STATE (M2). THEREFORE, UNDERSTANDING THE PRECISE STRATEGY TARGETING PRO-INFLAMMATORY MONOCYTES/MACROPHAGES SHOULD BE A POWERFUL WAY OF INHIBITING CHRONIC INFLAMMATION AND BONE EROSION. IN THIS REVIEW, WE DEMONSTRATE POTENTIAL CONSEQUENCES OF DIFFERENT EPIGENETIC REGULATIONS ON INFLAMMATORY CYTOKINES PRODUCTION BY MONOCYTES. IN ADDITION, WE PRESENT UNIQUE PROFILES OF MONOCYTES/MACROPHAGES CONTRIBUTING TO IDENTIFICATION OF NEW BIOMARKERS OF DISEASE ACTIVITY OR PREDICTING TREATMENT RESPONSE IN RA. WE ALSO OUTLINE NOVEL APPROACHES OF TUNING MONOCYTES/MACROPHAGES BY BIOLOGIC DRUGS, SMALL MOLECULES OR BY OTHER THERAPEUTIC MODALITIES TO REDUCE ARTHRITIS. FINALLY, THE IMPORTANCE OF CELLULAR HETEROGENEITY OF MONOCYTES/MACROPHAGES IS HIGHLIGHTED BY SINGLE-CELL TECHNOLOGIES, WHICH LEADS TO THE DESIGN OF CELL-SPECIFIC THERAPEUTIC PROTOCOLS FOR PERSONALIZED MEDICINE IN RA IN THE FUTURE. 2021 12 1136 31 COMPREHENSIVE OVERVIEW OF MICRORNA FUNCTION IN RHEUMATOID ARTHRITIS. MICRORNAS (MIRNAS), A CLASS OF ENDOGENOUS SINGLE-STRANDED SHORT NONCODING RNAS, HAVE EMERGED AS VITAL EPIGENETIC REGULATORS OF BOTH PATHOLOGICAL AND PHYSIOLOGICAL PROCESSES IN ANIMALS. THEY DIRECT FUNDAMENTAL CELLULAR PATHWAYS AND PROCESSES BY FINE-TUNING THE EXPRESSION OF MULTIPLE GENES AT THE POSTTRANSCRIPTIONAL LEVEL. GROWING EVIDENCE SUGGESTS THAT MIRNAS ARE IMPLICATED IN THE ONSET AND DEVELOPMENT OF RHEUMATOID ARTHRITIS (RA). RA IS A CHRONIC INFLAMMATORY DISEASE THAT MAINLY AFFECTS SYNOVIAL JOINTS. THIS COMMON AUTOIMMUNE DISORDER IS CHARACTERIZED BY A COMPLEX AND MULTIFACETED PATHOGENESIS, AND ITS MORBIDITY, DISABILITY AND MORTALITY RATES REMAIN CONSISTENTLY HIGH. MORE IN-DEPTH INSIGHTS INTO THE UNDERLYING MECHANISMS OF RA ARE REQUIRED TO ADDRESS UNMET CLINICAL NEEDS AND OPTIMIZE TREATMENT. HEREIN, WE COMPREHENSIVELY REVIEW THE DEREGULATED MIRNAS AND IMPAIRED CELLULAR FUNCTIONS IN RA TO SHED LIGHT ON SEVERAL ASPECTS OF RA PATHOGENESIS, WITH A FOCUS ON EXCESSIVE INFLAMMATION, SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DAMAGE. THIS REVIEW ALSO PROVIDES PROMISING TARGETS FOR INNOVATIVE THERAPIES OF RA. IN ADDITION, WE DISCUSS THE REGULATORY ROLES AND CLINICAL POTENTIAL OF EXTRACELLULAR MIRNAS IN RA, HIGHLIGHTING THEIR PROSPECTIVE APPLICATIONS AS DIAGNOSTIC AND PREDICTIVE BIOMARKERS. 2023 13 4657 31 NEW ADVANCES OF DNA METHYLATION AND HISTONE MODIFICATIONS IN RHEUMATOID ARTHRITIS, WITH SPECIAL EMPHASIS ON MECP2. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA IN MANY HUMAN DISEASES, ESPECIALLY IN AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS (RA). RA IS AN AUTOIMMUNE DISEASE WITH UNCLEAR ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND JOINT DESTRUCTION AND FIBROBLAST-LIKE SYNOVIOCYTES (FLS) DISPLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF RA. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RA IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF EPIGENETIC MODIFICATION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE METHYLATION AND HISTONE (DE)ACETYLATION ARE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE FLS ACTIVATION IN PATIENTS AND ANIMAL MODELS. IN THE LAST 3YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. METHYL-CPG-BINDING PROTEIN 2 (MECP2) IS FIRST IDENTIFIED AS A TRANSCRIPTIONAL REPRESSOR THAT INHIBITS GENE EXPRESSION THROUGH THE INTERPRETATION OF TWO EPIGENETIC MARKERS, DNA METHYLATION AND HISTONE MODIFICATION. THE COOPERATIVE ACTION AMONG MECP2, DNA METHYLATION AND HISTONE MODIFICATIONS INDICATES THAT MECP2 SHOULD PARTICIPATE IN THE PATHOGENESIS OF RA THROUGH SILENCE OF CERTAIN GENE TRANSCRIPTION. IN THIS REVIEW, WE CONSIDER THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON INCREASED MECP2 EXPRESSION IN RA ANIMAL MODELS. 2013 14 1726 33 DYSREGULATION OF LNCRNAS IN RHEUMATOID ARTHRITIS: BIOMARKERS, PATHOGENESIS AND POTENTIAL THERAPEUTIC TARGETS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE OF UNKNOWN ETIOLOGY, MAINLY MANIFESTED BY PERSISTENT ABNORMAL PROLIFERATION OF FIBROBLAST-LIKE SYNOVIOCYTES (FLSS), INFLAMMATION, SYNOVIAL HYPERPLASIA AND CARTILAGE EROSION, ACCOMPANIED BY JOINT SWELLING AND JOINT DESTRUCTION. ABNORMAL EXPRESSION OR FUNCTION OF LONG NONCODING RNAS (LNCRNAS) ARE CLOSELY RELATED TO HUMAN DISEASES, INCLUDING CANCERS, MENTAL DISEASES, AUTOIMMUNE DISEASES AND OTHERS. THE ABNORMAL SEQUENCE AND SPATIAL STRUCTURE OF LNCRNAS, THE DISORDER EXPRESSION AND THE ABNORMAL INTERACTION WITH THE BINDING PROTEIN WILL LEAD TO THE CHANGE OF GENE EXPRESSION IN THE WAY OF EPIGENETIC MODIFICATION. INCREASING EVIDENCE DEMONSTRATED THAT LNCRNAS WERE INVOLVED IN THE ACTIVATION OF FLSS, WHICH PLAYED A KEY ROLE IN THE PATHOGENESIS OF RA. IN THIS REVIEW, THE RESEARCH PROGRESS OF LNCRNAS IN THE PATHOGENESIS OF RA WAS SYSTEMATICALLY SUMMARIZED, INCLUDING THE ROLE OF LNCRNAS IN THE DIAGNOSIS OF RA, THE REGULATORY MECHANISM OF LNCRNAS IN THE PATHOGENESIS OF RA, AND THE INTERVENTION ROLE OF LNCRNAS IN THE TREATMENT OF RA. FURTHERMORE, THE ACTIVATED SIGNAL PATHWAYS, THE ROLE OF DNA METHYLATION AND OTHER MECHANISM HAVE ALSO BEEN OVERVIEW IN THIS REVIEW. 2021 15 4380 32 MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN RHEUMATOID ARTHRITIS. CONTROL OF EXCESSIVE MITOCHONDRIAL OXIDATIVE STRESS COULD PROVIDE NEW TARGETS FOR BOTH PREVENTIVE AND THERAPEUTIC INTERVENTIONS IN THE TREATMENT OF CHRONIC INFLAMMATION OR ANY PATHOLOGY THAT DEVELOPS UNDER AN INFLAMMATORY SCENARIO, SUCH AS RHEUMATOID ARTHRITIS (RA). INCREASING EVIDENCE HAS DEMONSTRATED THE ROLE OF MITOCHONDRIAL ALTERATIONS IN AUTOIMMUNE DISEASES MAINLY DUE TO THE INTERPLAY BETWEEN METABOLISM AND INNATE IMMUNITY, BUT ALSO IN THE MODULATION OF INFLAMMATORY RESPONSE OF RESIDENT CELLS, SUCH AS SYNOVIOCYTES. THUS, MITOCHONDRIAL DYSFUNCTION DERIVED FROM SEVERAL DANGER SIGNALS COULD ACTIVATE TRICARBOXYLIC ACID (TCA) DISRUPTION, THEREBY FAVORING A VICIOUS CYCLE OF OXIDATIVE/MITOCHONDRIAL STRESS. MITOCHONDRIAL DYSFUNCTION CAN ACT THROUGH MODULATING INNATE IMMUNITY VIA REDOX-SENSITIVE INFLAMMATORY PATHWAYS OR DIRECT ACTIVATION OF THE INFLAMMASOME. BESIDES, MITOCHONDRIA ALSO HAVE A CENTRAL ROLE IN REGULATING CELL DEATH, WHICH IS DEEPLY ALTERED IN RA. ADDITIONALLY, MULTIPLE EVIDENCE SUGGESTS THAT PATHOLOGICAL PROCESSES IN RA CAN BE SHAPED BY EPIGENETIC MECHANISMS AND THAT IN TURN, MITOCHONDRIA ARE INVOLVED IN EPIGENETIC REGULATION. FINALLY, WE WILL DISCUSS ABOUT THE INVOLVEMENT OF SOME DIETARY COMPONENTS IN THE ONSET AND PROGRESSION OF RA. 2022 16 2556 22 EPIGENETICS IN RHEUMATOID ARTHRITIS. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA. IN MANY HUMAN DISEASES, ESPECIALLY IN CANCERS, BUT ALSO IN AUTOIMMUNE DISEASES, EPIGENETIC ABERRATIONS HAVE BEEN FOUND. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND DESTRUCTION OF SYNOVIAL JOINTS. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RHEUMATOID ARTHRITIS IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF GENETIC PREDISPOSITION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL INFLUENCES. TO GAIN A BETTER UNDERSTANDING OF THIS DISEASE, RESEARCHERS HAVE BECOME INTERESTED IN STUDYING EPIGENETIC CHANGES IN RHEUMATOID ARTHRITIS. HERE, WE WANT TO REVIEW THE CURRENT KNOWLEDGE ON EPIGENETICS IN RHEUMATOID ARTHRITIS. 2010 17 2294 42 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 18 6328 24 THE ROLE OF CELL ORGANELLES IN RHEUMATOID ARTHRITIS WITH FOCUS ON EXOSOMES. AUTO-IMMUNE DISEASES INVOLVED AT LEAST 25% OF THE POPULATION IN WEALTHY COUNTRIES. SEVERAL FACTORS INCLUDING GENETIC, EPIGENETIC, AND ENVIRONMENTAL ELEMENTS ARE IMPLICATED IN DEVELOPMENT OF RHEUMATOID ARTHRITIS AS AN AUTOIMMUNE DISEASE. AUTOANTIBODIES CAUSE SYNOVIAL INFLAMMATION AND ARTHRITIS, IF LEFT UNTREATED OR BEING UNDER CONTINUAL EXTERNAL STIMULATION, COULD RESULT IN CHRONIC INFLAMMATION, JOINT INJURY, AND DISABILITY. T- AND B-CELLS, SIGNALING MOLECULES, PROINFLAMMATORY MEDIATORS, AND SYNOVIUM-SPECIFIC TARGETS ARE AMONG THE NEW THERAPEUTIC TARGETS. EXOSOMES COULD BE EMPLOYED AS THERAPEUTIC VECTORS IN THE TREATMENT OF AUTOIMMUNE DISEASES. HEREIN, THE ROLE OF CELL ORGANELLE PARTICULARLY EXOSOMES IN RHEUMATOID ARTHRITIS HAD DISCUSSED AND SOME THERAPEUTIC APPLICATIONS OF EXOSOME HIGHLIGHTED. 2021 19 3789 37 INTERLEUKIN 17 CONTRIBUTES TO THE CHRONICITY OF INFLAMMATORY DISEASES SUCH AS RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION AND BONE RESORPTION. THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 17 (IL-17), PRIMARILY PRODUCED BY TH17 CELLS, HAS BEEN SHOWN TO BE INVOLVED IN ALL STAGES OF THE DISEASE AND TO BE AN IMPORTANT CONTRIBUTOR OF RA CHRONICITY. THREE MAJOR PROCESSES DRIVE THE IL-17-MEDIATED CHRONICITY. SEVERAL EPIGENETIC EVENTS, ENHANCED IN RA PATIENTS, LEAD TO THE INCREASED PRODUCTION OF IL-17 BY TH17 CELLS. IL-17 THEN INDUCES THE PRODUCTION OF SEVERAL INFLAMMATORY MEDIATORS IN THE DISEASED SYNOVIUM, WHICH ARE FURTHER SYNERGISTICALLY ENHANCED VIA COMBINATIONS OF IL-17 WITH OTHER CYTOKINES. IL-17 ALSO PROMOTES THE SURVIVAL OF BOTH THE SYNOVIOCYTES AND INFLAMMATORY CELLS AND PROMOTES THE MATURATION OF THESE IMMUNE CELLS. THIS LEADS TO AN INCREASED NUMBER OF SYNOVIOCYTES AND INFLAMMATORY CELLS IN THE SYNOVIAL FLUID AND IN THE SYNOVIUM LEADING TO THE HYPERPLASIA AND EXACERBATED INFLAMMATION OBSERVED IN JOINTS OF RA PATIENTS. FURTHERMORE, THESE IL-17-DRIVEN EVENTS INITIATE SEVERAL FEEDBACK-LOOP MECHANISMS LEADING TO INCREASED EXPANSION OF TH17 CELLS AND THEREBY INCREASED PRODUCTION OF IL-17. IN THIS REVIEW, WE AIM TO DEPICT A COMPLETE PICTURE OF THE IL-17-DRIVEN VICIOUS CIRCLE LEADING TO RA CHRONICITY AND TO PINPOINT THE KEY ASPECTS THAT REQUIRE FURTHER EXPLORATION. 2014 20 6178 28 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