1 1261 120 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 2 1985 38 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 6050 33 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 4 2515 39 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 5 4268 43 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 6 2591 43 EPIGENETICS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE, INVOLVING THE RAPID PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES AND ACTIVATION OF T CELLS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS A T CELL-DOMINANT IMMUNE DISORDER AFFECTED BY MULTIPLE FACTORS INCLUDING GENETIC SUSCEPTIBILITY, ENVIRONMENTAL FACTORS, INNATE AND ADAPTIVE IMMUNE RESPONSES, ETC. HOWEVER, THE EXACT ETIOLOGY IS LARGELY UNKNOWN. IN RECENT YEARS, EPIGENETIC INVOLVEMENTS, SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS, AND NONCODING RNA REGULATION ARE REPORTED TO BE CRITICAL FOR THE PATHOGENESIS OF PSORIASIS. HOWEVER, THE INTERPLAY BETWEEN THESE FACTORS HAS ONLY RECENTLY BEEN STARTED TO BE UNRAVELED. NOTABLY, INHIBITORS OF ENZYMES THAT WORK IN EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES, ARE BEGINNING TO APPEAR IN THE CLINICAL SETTING TO RESTORE NORMAL EPIGENETIC PATTERNS (GENERALI ET AL. IN J AUTOIMMUN 83:51-61, 2017), PROVIDING NOVEL THERAPEUTIC POTENTIAL AS NOVEL TREATMENT TARGETS FOR PSORIASIS. INDEED, MEDICATIONS PREVIOUSLY USED TO TREAT AUTOIMMUNE DISEASES HAVE LATER BEEN DISCOVERED TO EXERT THEIR ACTION VIA EPIGENETIC MECHANISMS. HEREIN, WE REVIEW THE FINDINGS ON EPIGENETICS ASSOCIATED WITH PSORIASIS, AND DISCUSS FUTURE PERSPECTIVES IN THIS FIELD. 2020 7 2553 33 EPIGENETICS IN PSORIASIS: PERSPECTIVE OF DNA METHYLATION. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EXCESSIVE PROLIFERATION OF KERATINOCYTES (KCS). ONSET OF PSORIASIS IS RELATED TO GENETIC, IMMUNE AND ENVIRONMENTAL FACTORS. THE ENVIRONMENT CAN INTERACT WITH THE GENOME THROUGH EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, AND THIS MODIFICATION IS INVOLVED IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION TO A SKIN DISEASE, PSORIASIS IS ALSO CONSIDERED A SYSTEMIC DISEASE. WE REVIEWED THE CURRENT LITERATURE OF PSORIATIC DNA METHYLATION FOR STUDIES FROM SEVERAL ASPECTS ON THE DNA METHYLATION DISTRIBUTION PATTERNS IN DIFFERENT TISSUES/CELLS, SINGLE-NUCLEOTIDE POLYMORPHISMS, AND CANDIDATE DISEASE GENES AND IDENTIFIED TARGET GENES REGULATED BY DNA METHYLATION THAT HAVE BEEN DIRECTLY/INDIRECTLY VALIDATED. THIS REVIEW CONTRIBUTES TO A COMPREHENSIVE UNDERSTANDING OF THE IMPORTANT A ROLE THAT DNA METHYLATION PLAYS IN PSORIASIS FROM A HOLISTIC PERSPECTIVE AND WILL PROMOTE THE IMPLEMENTATION OF DNA METHYLATION IN DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR PSORIATIC PATIENTS. 2021 8 209 37 ACTIVATION-INDUCED CYTIDINE DEAMINASE: IN SICKNESS AND IN HEALTH. ACTIVATION INDUCED CYTIDINE DEAMINASE (AID) IS AN ESSENTIAL ENZYME OF THE ADAPTIVE IMMUNE SYSTEM. ITS CANONICAL ACTIVITY IS RESTRICTED TO B LYMPHOCYTES, PLAYING AN ESSENTIAL ROLE IN THE DIVERSIFICATION OF ANTIBODIES BY ENHANCING SPECIFICITY AND CHANGING AFFINITY. THIS IS POSSIBLE THROUGH ITS DNA DEAMINASE FUNCTION, LEADING TO MUTATIONS IN DNA. IN THE LAST DECADE, AID HAS BEEN ASSIGNED AN ADDITIONAL FUNCTION: THAT OF A POWERFUL DNA DEMETHYLATOR. ADVERSE CELLULAR CONDITIONS SUCH AS CHRONIC INFLAMMATION CAN LEAD TO ITS DEREGULATION AND OVEREXPRESSION. IT IS AN IMPORTANT DRIVER OF B-CELL LYMPHOMA DUE TO ITS NATURAL ABILITY TO MODIFY DNA THROUGH DEAMINATION, LEADING TO MUTATIONS AND EPIGENETIC CHANGES. HOWEVER, THE DEREGULATION OF AID IS NOT RESTRICTED TO LYMPHOID CELLS. RECENT FINDINGS HAVE PROVIDED NEW INSIGHTS INTO THE ROLE THAT THIS PROTEIN PLAYS IN THE DEVELOPMENT OF NON-LYMPHOID CANCERS, WITH SOME RESEARCH SHEDDING LIGHT ON NOVEL AID-DRIVEN MECHANISMS OF CELLULAR TRANSFORMATION. IN THIS REVIEW, WE PROVIDE AN UPDATED NARRATIVE OF THE NORMAL PHYSIOLOGICAL FUNCTIONS OF AID. ADDITIONALLY, WE REVIEW AND DISCUSS THE RECENT RESEARCH STUDIES THAT HAVE IMPLICATED AID IN CARCINOGENESIS IN VARYING TISSUE TYPES INCLUDING LYMPHOID AND NON-LYMPHOID CANCERS. WE REVIEW THE MECHANISMS, WHEREBY AID PROMOTES CARCINOGENESIS AND HIGHLIGHT IMPORTANT AREAS OF FUTURE RESEARCH. 2020 9 1873 38 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 10 2294 40 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 11 4318 31 MICRORNAS IN ANKYLOSING SPONDYLITIS: FUNCTION, POTENTIAL AND CHALLENGES. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNA, ARE CONSIDERED THE ESSENTIAL CONNECTION BETWEEN A DISORDER'S ONSET AND THE ENVIRONMENT, ON A PERMISSIVE GENETIC BACKGROUND. AMONG AUTOIMMUNE AND INFLAMMATORY-MEDIATED DISORDERS, ANKYLOSING SPONDYLITIS (AS), A CHRONIC ARTHRITIS OF THE SPINE, IS A VERY GOOD EXAMPLE FOR THE WEIGHT OF EPIGENETICS' CONTRIBUTION. MICRORNAS (MIRNAS) ARE SINGLE-STRANDED NUCLEOTIDES WHICH REGULATE GENE EXPRESSION AND ARE INVOLVED IN PATHOLOGICAL AND PHYSIOLOGICAL PROCESSES. IN THIS MANUSCRIPT WE PROVIDE A CLARIFICATION ON THE ROLE OF MICRORNAS IN AS, WITH A FOCUS ON THE MECHANISMS OF PATHOGENESIS. IN SPECIFIC, WE HAVE EXAMINED THE CONTRIBUTION OF MIRNAS IN THE PROCESSES OF INFLAMMATION, NEW BONE FORMATION AND T-CELL FUNCTION, AND THE PATHWAYS (I.E. WNT, BMP, TGFBETA SIGNALLING ETC.) THEY REGULATE. THE UTILITY OF MIRNAS IN BETTER UNDERSTANDING AS PATHOGENESIS IS UNDISPUTED AND THEIR UTILITY AS THERAPEUTIC OPPORTUNITY IS STRONGLY INCREASING. 2020 12 1172 31 CONTRIBUTION OF THE ENVIRONMENT, EPIGENETIC MECHANISMS AND NON-CODING RNAS IN PSORIASIS. DESPITE THE INCREASING RESEARCH AND CLINICAL INTEREST IN THE PREDISPOSITION OF PSORIASIS, A CHRONIC INFLAMMATORY SKIN DISEASE, THE MULTITUDE OF GENETIC AND ENVIRONMENTAL FACTORS INVOLVED IN ITS PATHOGENESIS REMAIN UNCLEAR. THIS COMPLEXITY IS FURTHER EXACERBATED BY THE SEVERAL CELL TYPES THAT ARE IMPLICATED IN PSORIASIS'S PROGRESSION, INCLUDING KERATINOCYTES, MELANOCYTES AND VARIOUS IMMUNE CELL TYPES. THE OBSERVED INTERACTIONS BETWEEN THE GENETIC SUBSTRATE AND THE ENVIRONMENT LEAD TO EPIGENETIC ALTERATIONS THAT DIRECTLY OR INDIRECTLY AFFECT GENE EXPRESSION. CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS THAT ALTER DNA-BINDING SITE ACCESSIBILITY, AS WELL AS NON-CODING RNAS IMPLICATED IN THE POST-TRANSCRIPTIONAL REGULATION, ARE MECHANISMS OF GENE TRANSCRIPTIONAL ACTIVITY MODIFICATION AND THEREFORE AFFECT THE PATHWAYS INVOLVED IN THE PATHOGENESIS OF PSORIASIS. IN THIS REVIEW, WE SUMMARIZE THE RESEARCH CONDUCTED ON THE ENVIRONMENTAL FACTORS CONTRIBUTING TO THE DISEASE ONSET, EPIGENETIC MODIFICATIONS AND NON-CODING RNAS EXHIBITING DEREGULATION IN PSORIASIS, AND WE FURTHER CATEGORIZE THEM BASED ON THE UNDER-STUDY CELL TYPES. WE ALSO ASSESS THE RECENT LITERATURE CONSIDERING THERAPEUTIC APPLICATIONS TARGETING MOLECULES THAT COMPROMISE THE EPIGENOME, AS A WAY TO SUPPRESS THE INFLAMMATORY CUTANEOUS CASCADE. 2022 13 5932 32 TARGETING EPIGENETIC REGULATORS FOR INFLAMMATION: MECHANISMS AND INTERVENTION THERAPY. EMERGING EVIDENCE INDICATES THAT RESOLUTION OF INFLAMMATION IS A CRITICAL AND DYNAMIC ENDOGENOUS PROCESS FOR HOST TISSUES DEFENDING AGAINST EXTERNAL INVASIVE PATHOGENS OR INTERNAL TISSUE INJURY. IT HAS LONG BEEN KNOWN THAT AUTOIMMUNE DISEASES AND CHRONIC INFLAMMATORY DISORDERS ARE CHARACTERIZED BY DYSREGULATED IMMUNE RESPONSES, LEADING TO EXCESSIVE AND UNCONTROL TISSUE INFLAMMATION. THE DYSREGULATION OF EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, POSTTRANSLATIONAL MODIFICATIONS TO HISTONE PROTEINS, AND NONCODING RNA EXPRESSION HAS BEEN IMPLICATED IN A HOST OF INFLAMMATORY DISORDERS AND THE IMMUNE SYSTEM. THE INFLAMMATORY RESPONSE IS CONSIDERED AS A CRITICAL TRIGGER OF EPIGENETIC ALTERATIONS THAT IN TURN INTERCEDE INFLAMMATORY ACTIONS. THUS, UNDERSTANDING THE MOLECULAR MECHANISM THAT DICTATES THE OUTCOME OF TARGETING EPIGENETIC REGULATORS FOR INFLAMMATORY DISEASE IS REQUIRED FOR INFLAMMATION RESOLUTION. IN THIS ARTICLE, WE ELUCIDATE THE CRITICAL ROLE OF THE NUCLEAR FACTOR-KAPPAB SIGNALING PATHWAY, JAK/STAT SIGNALING PATHWAY, AND THE NLRP3 INFLAMMASOME IN CHRONIC INFLAMMATORY DISEASES. AND WE FORMULATE THE RELATIONSHIP BETWEEN INFLAMMATION, CORONAVIRUS DISEASE 2019, AND HUMAN CANCERS. ADDITIONALLY, WE REVIEW THE MECHANISM OF EPIGENETIC MODIFICATIONS INVOLVED IN INFLAMMATION AND INNATE IMMUNE CELLS. ALL THAT MATTERS IS THAT WE PROPOSE AND DISCUSS THE REJUVENATION POTENTIAL OF INTERVENTIONS THAT TARGET EPIGENETIC REGULATORS AND REGULATORY MECHANISMS FOR CHRONIC INFLAMMATION-ASSOCIATED DISEASES TO IMPROVE THERAPEUTIC OUTCOMES. 2022 14 2070 32 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 15 6213 37 THE INTESTINAL EPITHELIAL CELL CYCLE: UNCOVERING ITS 'CRYPTIC' NATURE. PURPOSE OF REVIEW: TO DISCUSS THE RECENT LANDMARK FINDINGS THAT HAVE INCREASED OUR UNDERSTANDING NOT ONLY OF THE ROLE OF THE EPITHELIAL CELL CYCLE IN THE HOMEOSTASIS OF THE SMALL INTESTINE, BUT ALSO ITS RELEVANCE TO INFLAMMATION AND CANCER. RECENT FINDINGS: RECENT DATA HAVE UNVEILED NOVEL INFORMATION ON PROTEIN INTERACTIONS DIRECTLY INVOLVED IN THE CELL CYCLE AS WELL AS IN THE PATHWAYS THAT TRANSDUCE EXTERNAL ENVIRONMENTAL SIGNALS TO THE CELL CYCLE. A GROWING BODY OF THE RECENT EVIDENCE CONFIRMS THE IMPORTANCE OF FOOD AS WELL AS HORMONAL REGULATION IN THE GUT ON CELL CYCLE. INFORMATION ON THE CONTRIBUTION OF THE EPITHELIAL MICROENVIRONMENT, INCLUDING THE MICROBIOTA, HAS GROWN SUBSTANTIALLY IN THE RECENT YEARS AS WELL AS ON THE GENE-ENVIRONMENT INTERACTIONS AND THE MULTIPLE EPIGENETIC MECHANISMS INVOLVED IN REGULATING CELL-CYCLE PROTEINS AND SIGNALLING. FINALLY, FURTHER STUDIES INVESTIGATING THE DYSREGULATION OF THE CELL CYCLE DURING INFLAMMATION AND PROLIFERATION HAVE INCREASED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCER. SUMMARY: THIS REVIEW HIGHLIGHTS SOME OF THE MOST RECENT ADVANCES THAT FURTHER EMPHASIZE THE IMPORTANCE OF THE CELL CYCLE IN THE SMALL INTESTINE DURING HOMEOSTASIS AS WELL AS IN INFLAMMATION AND CANCER. 2015 16 3703 26 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 17 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 18 6345 33 THE ROLE OF EPIGENETICS IN AUTOIMMUNE/INFLAMMATORY DISEASE. HISTORICALLY, SYSTEMIC SELF-INFLAMMATORY CONDITIONS WERE CLASSIFIED AS EITHER AUTOINFLAMMATORY AND CAUSED BY THE INNATE IMMUNE SYSTEM OR AUTOIMMUNE AND DRIVEN BY ADAPTIVE IMMUNE RESPONSES. HOWEVER, IT BECAME CLEAR THAT REALITY IS MUCH MORE COMPLEX AND THAT AUTOIMMUNE/INFLAMMATORY CONDITIONS RANGE ALONG AN "INFLAMMATORY SPECTRUM" WITH PRIMARILY AUTOINFLAMMATORY VS. AUTOIMMUNE CONDITIONS RESEMBLING EXTREMES AT EITHER END. EPIGENETIC MODIFICATIONS INFLUENCE GENE EXPRESSION AND ALTER CELLULAR FUNCTIONS WITHOUT MODIFYING THE GENOMIC SEQUENCE. METHYLATION OF CPG DNA DINUCLEOTIDES AND/OR THEIR HYDROXYMETHYLATION, POST-TRANSLATIONAL MODIFICATIONS TO AMINO TERMINI OF HISTONE PROTEINS, AND NON-CODING RNA EXPRESSION ARE MAIN EPIGENETIC EVENTS. THE PATHOPHYSIOLOGY OF AUTOIMMUNE/INFLAMMATORY DISEASES HAS BEEN CLOSELY LINKED WITH DISEASE CAUSING GENE MUTATIONS (RARE) OR A COMBINATION OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS ARISING FROM EXPOSURE TO THE ENVIRONMENT (MORE COMMON). OVER RECENT YEARS, PROGRESS HAS BEEN MADE IN UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN SYSTEMIC INFLAMMATION AND THE CONTRIBUTION OF INNATE AND ADAPTIVE IMMUNE RESPONSES. EPIGENETIC EVENTS HAVE BEEN IDENTIFIED AS (I) CENTRAL PATHOPHYSIOLOGICAL FACTORS IN ADDITION TO GENETIC DISEASE PREDISPOSITION AND (II) AS CO-FACTORS DETERMINING CLINICAL PICTURES AND OUTCOMES IN INDIVIDUALS WITH MONOGENIC DISEASE. THUS, A COMPLETE UNDERSTANDING OF EPIGENETIC CONTRIBUTORS TO AUTOIMMUNE/INFLAMMATORY DISEASE WILL RESULT IN APPROACHES TO PREDICT INDIVIDUAL DISEASE OUTCOMES AND THE INTRODUCTION OF EFFECTIVE, TARGET-DIRECTED, AND TOLERABLE THERAPIES. HERE, WE SUMMARIZE RECENT FINDINGS THAT SIGNIFY THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN AUTOIMMUNE/INFLAMMATORY DISORDERS ALONG THE INFLAMMATORY SPECTRUM CHOOSING THREE EXAMPLES: THE AUTOINFLAMMATORY BONE CONDITION CHRONIC NONBACTERIAL OSTEOMYELITIS (CNO), THE "MIXED PATTERN" DISORDER PSORIASIS, AND THE AUTOIMMUNE DISEASE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). 2019 19 1258 36 CURRENT UNDERSTANDING OF OSTEOARTHRITIS PATHOGENESIS AND RELEVANT NEW APPROACHES. OSTEOARTHRITIS (OA) IS THE MOST COMMON DEGENERATIVE JOINT DISEASE THAT CAUSES PAINFUL SWELLING AND PERMANENT DAMAGE TO THE JOINTS IN THE BODY. THE MOLECULAR MECHANISMS OF OA ARE CURRENTLY UNKNOWN. OA IS A HETEROGENEOUS DISEASE THAT AFFECTS THE ENTIRE JOINT, AND MULTIPLE TISSUES ARE ALTERED DURING OA DEVELOPMENT. TO BETTER UNDERSTAND THE PATHOLOGICAL MECHANISMS OF OA, NEW APPROACHES, METHODS, AND TECHNIQUES NEED TO BE USED TO UNDERSTAND OA PATHOGENESIS. IN THIS REVIEW, WE FIRST FOCUS ON THE EPIGENETIC REGULATION OF OA, WITH A PARTICULAR FOCUS ON DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA REGULATION, FOLLOWED BY A SUMMARY OF SEVERAL KEY MEDIATORS IN OA-ASSOCIATED PAIN. WE THEN INTRODUCE SEVERAL INNOVATIVE TECHNIQUES THAT HAVE BEEN AND WILL CONTINUE TO BE USED IN THE FIELDS OF OA AND OA-ASSOCIATED PAIN, SUCH AS CRISPR, SCRNA SEQUENCING, AND LINEAGE TRACING. NEXT, WE DISCUSS THE TIMELY UPDATES CONCERNING CELL DEATH REGULATION IN OA PATHOLOGY, INCLUDING PYROPTOSIS, FERROPTOSIS, AND AUTOPHAGY, AS WELL AS THEIR INDIVIDUAL ROLES IN OA AND POTENTIAL MOLECULAR TARGETS IN TREATING OA. FINALLY, OUR REVIEW HIGHLIGHTS NEW DIRECTIONS ON THE ROLE OF THE SYNOVIAL LYMPHATIC SYSTEM IN OA. AN IMPROVED UNDERSTANDING OF OA PATHOGENESIS WILL AID IN THE DEVELOPMENT OF MORE SPECIFIC AND EFFECTIVE THERAPEUTIC INTERVENTIONS FOR OA. 2022 20 2533 38 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014