1 6194 121 THE IMPACT OF PROTEIN ACETYLATION/DEACETYLATION ON SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE IN WHICH THE BODY'S IMMUNE SYSTEM MISTAKENLY ATTACKS HEALTHY CELLS. ALTHOUGH THE EXACT CAUSE OF SLE HAS NOT BEEN IDENTIFIED, IT IS CLEAR THAT BOTH GENETICS AND ENVIRONMENTAL FACTORS TRIGGER THE DISEASE. IDENTICAL TWINS HAVE A 24% CHANCE OF GETTING LUPUS DISEASE IF THE OTHER ONE IS AFFECTED. INTERNAL FACTORS SUCH AS FEMALE GENDER AND SEX HORMONES, THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) LOCUS AND OTHER GENETIC POLYMORPHISMS HAVE BEEN SHOWN TO AFFECT SLE, AS WELL AS EXTERNAL, ENVIRONMENTAL INFLUENCES SUCH AS SUNLIGHT EXPOSURE, SMOKING, VITAMIN D DEFICIENCY, AND CERTAIN INFECTIONS. SEVERAL STUDIES HAVE REPORTED AND PROPOSED MULTIPLE ASSOCIATIONS BETWEEN THE ALTERATION OF THE EPIGENOME AND THE PATHOGENESIS OF AUTOIMMUNE DISEASE. EPIGENETIC FACTORS CONTRIBUTING TO SLE INCLUDE MICRORNAS, DNA METHYLATION STATUS, AND THE ACETYLATION/DEACETYLATION OF HISTONE PROTEINS. ADDITIONALLY, THE ACETYLATION OF NON-HISTONE PROTEINS CAN ALSO INFLUENCE CELLULAR FUNCTION. A BETTER UNDERSTANDING OF NON-GENOMIC FACTORS THAT REGULATE SLE WILL PROVIDE INSIGHT INTO THE MECHANISMS THAT INITIATE AND FACILITATE DISEASE AND ALSO CONTRIBUTE TO THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT CAN SPECIFICALLY TARGET PATHOGENIC MOLECULAR PATHWAYS. 2018 2 398 38 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 3 1463 48 DISSECTING COMPLEX EPIGENETIC ALTERATIONS IN HUMAN LUPUS. SYSTEMIC LUPUS ERYTHEMATOSUS IS A CHRONIC RELAPSING AUTOIMMUNE DISEASE THAT PRIMARILY AFFLICTS WOMEN, AND BOTH A GENETIC PREDISPOSITION AND APPROPRIATE ENVIRONMENTAL EXPOSURES ARE REQUIRED FOR LUPUS TO DEVELOP AND FLARE. THE GENETIC REQUIREMENT IS EVIDENCED BY AN INCREASED CONCORDANCE IN IDENTICAL TWINS AND BY THE VALIDATION OF AT LEAST 35 SINGLE-NUCLEOTIDE POLYMORPHISMS PREDISPOSING PATIENTS TO LUPUS. GENES ALONE, THOUGH, ARE NOT ENOUGH. THE CONCORDANCE OF LUPUS IN IDENTICAL TWINS IS OFTEN INCOMPLETE, AND WHEN CONCORDANT, THE AGE OF ONSET IS USUALLY DIFFERENT. LUPUS IS ALSO NOT PRESENT AT BIRTH, BUT ONCE THE DISEASE DEVELOPS, IT TYPICALLY FOLLOWS A CHRONIC RELAPSING COURSE. THUS, GENES ALONE ARE INSUFFICIENT TO CAUSE HUMAN LUPUS, AND ADDITIONAL FACTORS ENCOUNTERED IN THE ENVIRONMENT AND OVER TIME ARE REQUIRED TO INITIATE THE DISEASE AND SUBSEQUENT FLARES. THE NATURE OF THE ENVIRONMENTAL CONTRIBUTION, THOUGH, AND THE MECHANISMS BY WHICH ENVIRONMENTAL AGENTS MODIFY THE IMMUNE RESPONSE TO CAUSE LUPUS ONSET AND FLARES IN GENETICALLY PREDISPOSED PEOPLE HAVE BEEN CONTROVERSIAL. REPORTS THAT THE LUPUS-INDUCING DRUGS PROCAINAMIDE AND HYDRALAZINE ARE EPIGENETIC MODIFIERS, THAT EPIGENETICALLY MODIFIED T CELLS ARE SUFFICIENT TO CAUSE LUPUS-LIKE AUTOIMMUNITY IN ANIMAL MODELS, AND THAT PATIENTS WITH ACTIVE LUPUS HAVE EPIGENETIC CHANGES SIMILAR TO THOSE CAUSED BY PROCAINAMIDE AND HYDRALAZINE HAVE PROMPTED A GROWING INTEREST IN HOW EPIGENETIC ALTERATIONS CONTRIBUTE TO THIS DISEASE. UNDERSTANDING HOW EPIGENETIC MECHANISMS MODIFY T CELLS TO CONTRIBUTE TO LUPUS REQUIRES AN UNDERSTANDING OF HOW EPIGENETIC MECHANISMS REGULATE GENE EXPRESSION. THE ROLES OF DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS IN LUPUS PATHOGENESIS WILL BE REVIEWED HERE. 2013 4 6800 47 [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 5 4216 45 METHYL DONOR MICRONUTRIENTS: A POTENTIAL DIETARY EPIGENETIC TARGET IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY AN ABERRANT IMMUNE RESPONSE AND PERSISTENT INFLAMMATION. ITS PATHOGENESIS REMAINS UNKNOWN; HOWEVER, A COMPLEX INTERACTION BETWEEN ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN SUGGESTED TO CAUSE DISEASE ONSET. SEVERAL STUDIES HAVE DEMONSTRATED THAT EPIGENETIC ALTERATIONS, SUCH AS DNA HYPOMETHYLATION, MIRNA OVEREXPRESSION, AND ALTERED HISTONE ACETYLATION, MAY CONTRIBUTE TO SLE ONSET AND THE DISEASE'S CLINICAL MANIFESTATIONS. EPIGENETIC CHANGES, ESPECIALLY METHYLATION PATTERNS, ARE MODIFIABLE AND SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS DIET. IT IS WELL KNOWN THAT METHYL DONOR NUTRIENTS, SUCH AS FOLATE, METHIONINE, CHOLINE, AND SOME B VITAMINS, PLAY A RELEVANT ROLE IN DNA METHYLATION BY PARTICIPATING AS METHYL DONORS OR COENZYMES IN ONE-CARBON METABOLISM. BASED ON THIS KNOWLEDGE, THIS CRITICAL LITERATURE REVIEW AIMED TO INTEGRATE THE EVIDENCE IN ANIMAL MODELS AND HUMANS REGARDING THE ROLE OF NUTRIENTS IN EPIGENETIC HOMEOSTASIS AND THEIR IMPACT ON IMMUNE SYSTEM REGULATION TO SUGGEST A POTENTIAL EPIGENETIC DIET THAT COULD SERVE AS ADJUVANT THERAPY IN SLE. 2023 6 549 34 AUTOANTIGENS: NOVEL FORMS AND PRESENTATION TO THE IMMUNE SYSTEM. IT IS CLEAR THAT LUPUS AUTOIMMUNITY IS MARKED BY A VARIETY OF ABNORMALITIES, INCLUDING THOSE FOUND AT A MACROSCOPIC SCALE, CELLS AND TISSUES, AS WELL AS MORE MICROENVIRONMENTAL INFLUENCES, ORIGINATING AT THE INDIVIDUAL CELL SURFACE THROUGH TO THE NUCLEUS. THE CONVERGENCE OF GENETIC, EPIGENETIC, AND PERHAPS ENVIRONMENTAL INFLUENCES ALL LEAD TO THE OVERT CLINICAL EXPRESSION OF DISEASE, REFLECTED BY THE PRESENCES OF AUTOANTIBODIES AND TISSUE PATHOLOGY. THIS REVIEW WILL ADDRESS SEVERAL SPECIFIC AREAS THAT FALL AMONG THE NON-GENETIC FACTORS THAT CONTRIBUTE TO LUPUS AUTOIMMUNITY AND RELATED SYNDROMES. IN PARTICULAR, WE WILL DISCUSS THE IMPORTANCE OF UNDERSTANDING VARIOUS PROTEIN POST-TRANSLATIONAL MODIFICATIONS (PTMS), MECHANISMS THAT MEDIATE THE ABILITY OF "MODIFIED SELF" TO TRIGGER AUTOIMMUNITY, AND HOW THESE PTMS INFLUENCE LUPUS DIAGNOSIS. FINALLY, WE WILL DISCUSS ALTERED PATHWAYS OF AUTOANTIGEN PRESENTATION THAT MAY CONTRIBUTE TO THE PERPETUATION OF CHRONIC AUTOIMMUNE DISEASE. 2014 7 2529 29 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 8 6178 34 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 9 2516 38 EPIGENETICS AND SYSTEMIC LUPUS ERYTHEMATOSUS: UNMET NEEDS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC RELAPSING-REMITTING AUTOIMMUNE DISEASE AFFECTING SEVERAL ORGANS. ALTHOUGH THE MANAGEMENT OF LUPUS PATIENTS HAS IMPROVED IN THE LAST YEARS, SEVERAL ASPECTS STILL REMAIN CHALLENGING. MORE SENSITIVE AND SPECIFIC BIOMARKERS FOR AN EARLY DIAGNOSIS AS WELL AS FOR MONITORING DISEASE ACTIVITY AND TISSUE DAMAGE ARE NEEDED. GENOME-WIDE ASSOCIATION AND GENE MAPPING STUDIES HAVE SUPPORTED THE GENETIC BACKGROUND FOR SLE SUSCEPTIBILITY. HOWEVER, THE RELATIVELY MODEST RISK ASSOCIATION AND THE STUDIES IN TWINS HAVE SUGGESTED A ROLE FOR ENVIRONMENTAL AND EPIGENETIC FACTORS, AS WELL AS GENETIC-EPIGENETIC INTERACTION. ACCORDINGLY, THERE IS EVIDENCE THAT DIFFERENCES IN DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNA PROFILING CAN BE FOUND IN LUPUS PATIENTS VERSUS NORMAL SUBJECTS. MOREOVER, IMPAIRED DNA METHYLATION ON THE INACTIVE X-CHROMOSOME WAS SUGGESTED TO EXPLAIN, AT LEAST IN PART, THE FEMALE PREVALENCE OF THE DISEASE. EPIGENETIC MARKERS MAY BE HELP IN FULFILLING THE UNMET NEEDS FOR SLE BY OFFERING NEW DIAGNOSTIC TOOLS, NEW BIOMARKERS FOR MONITORING DISEASE ACTIVITY, OR TO BETTER CHARACTERIZE PATIENTS WITH A SILENT CLINICAL DISEASE BUT WITH AN ACTIVE SEROLOGY. ANTI-DNA, ANTI-PHOSPHOLIPID, AND ANTI-RO/SSA AUTOANTIBODIES ARE THOUGHT TO BE PATHOGENIC FOR GLOMERULONEPHRITIS, RECURRENT THROMBOSIS AND MISCARRIAGES, AND NEONATAL LUPUS, RESPECTIVELY. HOWEVER, TISSUE DAMAGE OCCURS OCCASIONALLY OR, IN SOME PATIENTS, ONLY IN SPITE OF THE PERSISTENT PRESENCE OF THE ANTIBODIES. PRELIMINARY STUDIES SUGGEST THAT EPIGENETIC MECHANISMS MAY EXPLAIN WHY THE DAMAGE TAKES PLACE IN SOME PATIENTS ONLY OR AT A GIVEN TIME. 2016 10 6262 46 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 6345 45 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 12 6107 45 THE EMERGING ROLE OF NONCODING RNAS IN SYSTEMIC LUPUS ERYTHEMATOSUS: NEW INSIGHTS INTO THE MASTER REGULATORS OF DISEASE PATHOGENESIS. AUTO-IMMUNE DISEASES ARE A FORM OF CHRONIC DISORDERS IN WHICH THE IMMUNE SYSTEM DESTROYS THE BODY'S CELLS DUE TO A LOSS OF TOLERANCE TO SELF-ANTIGENS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), IDENTIFIED BY THE PRODUCTION OF AUTOANTIBODIES IN DIFFERENT BODY PARTS, IS ONE OF THE MOST WELL-KNOWN EXAMPLES OF THESE DISEASES. ALTHOUGH THE ETIOLOGY OF SLE IS UNCLEAR, THE DISEASE'S PROGRESSION MAY BE AFFECTED BY GENETIC AND ENVIRONMENTAL FACTORS. AS STUDIES IN TWINS PROVIDE ADEQUATE EVIDENCE FOR GENETIC INVOLVEMENT IN THE SLE, OTHER PHENOMENA SUCH AS METALLIZATION, HISTONE MODIFICATIONS, AND ALTERATIONS IN THE EXPRESSION OF NONCODING RNAS (NCRNAS) ALSO INDICATE THE INVOLVEMENT OF EPIGENETIC FACTORS IN THIS DISEASE. AMONG ALL THE EPIGENETIC ALTERATIONS, NCRNAS APPEAR TO HAVE THE MOST CRUCIAL CONTRIBUTION TO THE PATHOGENESIS OF SLE. THE NCRNAS' LENGTH AND SIZE ARE DIVIDED INTO THREE MAIN CLASSES: MICRO RNAS, LONG NONCODING RNAS (LNCRNA), AND CIRCULAR RNAS (CIRCRNAS). ACCUMULATING EVIDENCE SUGGESTS THAT DYSREGULATIONS IN THESE NCRNAS CONTRIBUTED TO THE PATHOGENESIS OF SLE. HENCE, CLARIFYING THE FUNCTION OF THESE GROUPS OF NCRNAS IN THE PATHOPHYSIOLOGY OF SLE PROVIDES A DEEPER UNDERSTANDING OF THE DISEASE. IT ALSO OPENS UP NEW OPPORTUNITIES TO DEVELOP TARGETED THERAPIES FOR THIS DISEASE. 2023 13 3545 31 IMMUNOMETABOLISM IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A TYPICAL AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND PATHOGENIC AUTO-ANTIBODIES. APART FROM B CELLS, DYSREGULATION OF OTHER IMMUNE CELLS ALSO PLAYS AN ESSENTIAL ROLE IN THE PATHOGENESIS AND DEVELOPMENT OF THE DISEASE INCLUDING CD4(+)T CELLS, DENDRITIC CELLS, MACROPHAGES AND NEUTROPHILS. SINCE METABOLIC PROGRAMS CONTROL IMMUNE CELL FATE AND FUNCTION, THEY ARE CRITICAL CHECKPOINTS IN AN EFFECTIVE IMMUNE RESPONSE AND ARE INVOLVED IN THE ETIOLOGY OF AUTOIMMUNE DISEASE. IN ADDITION, MITOCHONDRIA AND OXIDATIVE STRESS ARE BOTH INVOLVED IN CELLULAR METABOLISM AND IS ALSO ESSENTIAL IN IMMUNE RESPONSE. IN THIS REVIEW, APART FROM THE DISTURBED IMMUNE SYSTEM, WE WILL DISCUSS MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ABNORMAL METABOLISM (INCLUDING GLUCOSE, LIPID AND AMINO ACID METABOLISM) OF IMMUNE CELLS AS WELL AS EPIGENETIC CONTROL OF METABOLISM REPROGRAMMING TO ELUCIDATE THE UNDERLYING PATHOGENIC MECHANISMS OF SYSTEMIC LUPUS ERYTHEMATOSUS. 2020 14 4958 36 PATHOGENESIS OF HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS: A CELLULAR PERSPECTIVE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING MULTIPLE ORGANS. A COMPLEX INTERACTION OF GENETICS, ENVIRONMENT, AND HORMONES LEADS TO IMMUNE DYSREGULATION AND BREAKDOWN OF TOLERANCE TO SELF-ANTIGENS, RESULTING IN AUTOANTIBODY PRODUCTION, INFLAMMATION, AND DESTRUCTION OF END-ORGANS. EMERGING EVIDENCE ON THE ROLE OF THESE FACTORS HAS INCREASED OUR KNOWLEDGE OF THIS COMPLEX DISEASE, GUIDING THERAPEUTIC STRATEGIES AND IDENTIFYING PUTATIVE BIOMARKERS. RECENT FINDINGS INCLUDE THE CHARACTERIZATION OF GENETIC/EPIGENETIC FACTORS LINKED TO SLE, AS WELL AS CELLULAR EFFECTORS. NOVEL OBSERVATIONS HAVE PROVIDED AN IMPROVED UNDERSTANDING OF THE CONTRIBUTION OF TISSUE-SPECIFIC FACTORS AND ASSOCIATED DAMAGE, T AND B LYMPHOCYTES, AS WELL AS INNATE IMMUNE CELL SUBSETS AND THEIR CORRESPONDING ABNORMALITIES. THE INTRICATE WEB OF INVOLVED FACTORS AND PATHWAYS DICTATES THE ADOPTION OF TAILORED THERAPEUTIC APPROACHES TO CONQUER THIS DISEASE. 2017 15 2027 37 EPIGENETIC CHANGES IN CHRONIC INFLAMMATORY DISEASES. THE NUMBER OF PEOPLE DIAGNOSED WITH CHRONIC INFLAMMATORY DISEASES HAS INCREASED NOTEWORTHY IN THE LAST 40 YEARS. SPONDYLOARTHRITIS (SPA), INFLAMMATORY BOWEL DISEASES (IBD), AND PSORIASIS ARE THE MOST FREQUENT CHRONIC INFLAMMATORY DISEASES, RESULTING FROM A COMBINATION OF GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL AND LONG NONCODING RNAS. THEY ARE INFLUENCED BY ENVIRONMENTAL EXPOSURE, LIFE-STYLE, AND AGING AND HAVE RECENTLY BEEN SHOWN TO BE ALTERED IN MANY COMPLEX DISEASES INCLUDING INFLAMMATORY DISEASES. WHILE EPIGENETIC MODIFICATIONS HAVE BEEN WELL CHARACTERIZED IN OTHER DISEASES SUCH AS CANCER AND AUTOIMMUNE DISEASES, KNOWLEDGE ON CHANGES IN INFLAMMATORY DISEASES IS LAGGING BEHIND WITH SOME DISEASE-SPECIFIC DIFFERENCES. WHILE THE DNA METHYLATION PROFILE OF DIFFERENT CELL TYPES IN PATIENTS WITH IBD HAS BEEN RELATIVELY WELL DESCRIBED, LESS IS KNOWN ON CHANGES IMPLICATED IN PSORIASIS, AND NO SYSTEMATIC GENOME-WIDE STUDIES HAVE SO FAR BEEN PERFORMED IN SPA. IN THIS CHAPTER, WE REVIEW IN DETAIL THE REPORTED CHANGES IN PATTERNS OF DNA METHYLATION AND POSTTRANSLATIONAL HISTONE MODIFICATIONS IN CHRONIC INFLAMMATORY DISEASES HIGHLIGHTING POTENTIAL CONNECTIONS BETWEEN DISEASE-ASSOCIATED PATHOPHYSIOLOGICAL CHANGES SUCH AS THE DYSBIOSIS OF THE MICROBIOME OR GENETIC VARIATIONS ASSOCIATED WITH DISEASE SUSCEPTIBILITY AND THE EPIGENOME. WE ALSO DISCUSS IMPORTANT PARAMETERS OF MEANINGFUL EPIGENETIC STUDIES SUCH AS THE USE OF WELL DEFINED, DISEASE-RELEVANT CELL POPULATIONS, AND ELUDE ON THE POTENTIAL FUTURE OF ENGINEERING OF THE EPIGENOME IN INFLAMMATORY DISEASES. 2017 16 6275 41 THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS: HARNESSING BIG DATA TO UNDERSTAND THE MOLECULAR BASIS OF LUPUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, SYSTEMIC AUTOIMMUNE DISEASE THAT CAUSES DAMAGE TO MULTIPLE ORGAN SYSTEMS. DESPITE DECADES OF RESEARCH AND AVAILABLE MURINE MODELS THAT CAPTURE SOME ASPECTS OF THE HUMAN DISEASE, NEW TREATMENTS FOR SLE LAG BEHIND OTHER AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS AND CROHN'S DISEASE. BIG DATA GENOMIC ASSAYS HAVE TRANSFORMED OUR UNDERSTANDING OF SLE BY PROVIDING IMPORTANT INSIGHTS INTO THE MOLECULAR HETEROGENEITY OF THIS MULTIGENIC DISEASE. GENE WIDE ASSOCIATION STUDIES HAVE DEMONSTRATED MORE THAN 100 RISK LOCI, SUPPORTING A MODEL OF MULTIPLE GENETIC HITS INCREASING SLE RISK IN A NON-LINEAR FASHION, AND PROVIDING EVIDENCE OF ANCESTRAL DIVERSITY IN SUSCEPTIBILITY LOCI. EPIGENETIC STUDIES TO DETERMINE THE ROLE OF METHYLATION, ACETYLATION AND NON-CODING RNAS HAVE PROVIDED NEW UNDERSTANDING OF THE MODULATION OF GENE EXPRESSION IN SLE PATIENTS AND IDENTIFIED NEW DRUG TARGETS AND BIOMARKERS FOR SLE. GENE EXPRESSION PROFILING HAS LED TO A GREATER UNDERSTANDING OF THE ROLE OF MYELOID CELLS IN THE PATHOGENESIS OF SLE, CONFIRMED ROLES FOR T AND B CELLS IN SLE, PROMOTED CLINICAL TRIALS BASED ON THE PROMINENT INTERFERON SIGNATURE FOUND IN SLE PATIENTS, AND IDENTIFIED CANDIDATE BIOMARKERS AND CELLULAR SIGNATURES TO FURTHER DRUG DEVELOPMENT AND DRUG REPURPOSING. GENE EXPRESSION STUDIES ARE ADVANCING OUR UNDERSTANDING OF THE UNDERLYING MOLECULAR HETEROGENEITY IN SLE AND PROVIDING HOPE THAT PATIENT STRATIFICATION WILL EXPEDITE NEW THERAPIES BASED ON PERSONAL MOLECULAR SIGNATURES. ALTHOUGH BIG DATA ANALYSES PRESENT UNIQUE INTERPRETATION CHALLENGES, BOTH COMPUTATIONALLY AND BIOLOGICALLY, ADVANCES IN MACHINE LEARNING APPLICATIONS MAY FACILITATE THE ABILITY TO PREDICT CHANGES IN SLE DISEASE ACTIVITY AND OPTIMIZE THERAPEUTIC STRATEGIES. 2020 17 1719 33 DYSREGULATED MICRORNAS IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS: A COMPREHENSIVE REVIEW. SYSTEMIC LUPUS ERYTHEMATOSUS IS A CHRONIC AUTOIMMUNE DISEASE OF WHICH CLINICAL PRESENTATION IS VASTLY HETEROGENEOUS, RANGING FROM MILD SKIN RASHES TO SEVERE RENAL DISEASES. TREATMENT GOAL OF THIS ILLNESS IS TO MINIMIZE DISEASE ACTIVITY AND PREVENT FURTHER ORGAN DAMAGE. IN RECENT YEARS, MUCH RESEARCH HAS BEEN DONE ON THE EPIGENETIC ASPECTS OF SLE PATHOGENESIS, FOR AMONG THE VARIOUS FACTORS KNOWN TO CONTRIBUTE TO THE PATHOGENIC PROCESS, EPIGENETIC FACTORS, ESPECIALLY MICRORNAS, BEAR THE MOST THERAPEUTIC POTENTIAL THAT CAN BE ALTERED UNLIKE CONGENITAL GENETIC FACTORS. THIS ARTICLE REVIEWS AND UPDATES WHAT HAS BEEN DISCOVERED SO FAR ABOUT THE PATHOGENESIS OF LUPUS, WHILE FOCUSING ON THE DYSREGULATION OF MICRORNAS IN LUPUS PATIENTS IN COMPARISON TO HEALTHY CONTROLS ALONG WITH THE POTENTIALLY PATHOGENIC ROLES OF THE MICRORNAS COMMONLY REPORTED TO BE EITHER UPREGULATED OR DOWNREGULATED. FURTHERMORE, THIS REVIEW INCLUDES MICRORNAS OF WHICH RESULTS ARE CONTROVERSIAL, SUGGESTING POSSIBLE EXPLANATIONS FOR SUCH DISCREPANCIES AND DIRECTIONS FOR FUTURE RESEARCH. MOREOVER, WE AIMED TO EMPHASIZE THE POINT THAT HAD BEEN OVERLOOKED SO FAR IN STUDIES REGARDING MICRORNA EXPRESSION LEVELS; THAT IS, WHICH SPECIMEN WAS USED TO ASSESS THE DYSREGULATION OF MICRORNAS. TO OUR SURPRISE, A VAST NUMBER OF STUDIES HAVE NOT CONSIDERED THIS FACTOR AND HAVE ANALYZED THE POTENTIAL ROLE OF MICRORNAS IN GENERAL. DESPITE EXTENSIVE INVESTIGATIONS DONE ON MICRORNA LEVELS, THEIR SIGNIFICANCE AND POTENTIAL ROLE REMAIN A MYSTERY, WHICH CALLS FOR FURTHER STUDIES ON THIS PARTICULAR SUBJECT IN REGARD OF WHICH SPECIMEN IS USED FOR ASSESSMENT. 2023 18 6288 45 THE POTENTIAL ROLE OF EPIGENETIC MODIFICATIONS ON DIFFERENT FACETS IN THE PERIODONTAL PATHOGENESIS. PERIODONTITIS IS A CHRONIC INFLAMMATORY DISEASE THAT AFFECTS THE SUPPORTING STRUCTURES OF TEETH. IN THE LITERATURE, THE ASSOCIATION BETWEEN THE PATHOGENICITY OF BACTERIA AND ENVIRONMENTAL FACTORS IN THIS REGARD HAVE BEEN EXTENSIVELY EXAMINED. IN THE PRESENT STUDY, WE WILL SHED LIGHT ON THE POTENTIAL ROLE THAT EPIGENETIC CHANGE CAN PLAY ON DIFFERENT FACETS OF ITS PROCESS, MORE PARTICULARLY THE MODIFICATIONS CONCERNING THE GENES INVOLVED IN INFLAMMATION, DEFENSE, AND IMMUNE SYSTEMS. SINCE THE 1960S, THE ROLE OF GENETIC VARIANTS IN THE ONSET AND SEVERITY OF PERIODONTAL DISEASE HAS BEEN WIDELY DEMONSTRATED. THESE MAKE SOME PEOPLE MORE SUSCEPTIBLE TO DEVELOPING IT THAN OTHERS. IT HAS BEEN DOCUMENTED THAT THE WIDE VARIATION IN ITS FREQUENCY FOR VARIOUS RACIAL AND ETHNIC POPULATIONS IS DUE PRIMARILY TO THE COMPLEX INTERPLAY AMONG GENETIC FACTORS WITH THOSE AFFECTING THE ENVIRONMENT AND THE DEMOGRAPHY. IN MOLECULAR BIOLOGY, EPIGENETIC MODIFICATIONS ARE DEFINED AS ANY CHANGE IN THE PROMOTER FOR THE CPG ISLANDS, IN THE STRUCTURE OF THE HISTONE PROTEIN, AS WELL AS POST-TRANSLATIONAL REGULATION BY MICRORNAS (MIRNAS), BEING KNOWN TO CONTRIBUTE TO THE ALTERATION IN GENE EXPRESSION FOR COMPLEX MULTIFACTORIAL DISEASES SUCH AS PERIODONTITIS. THE KEY ROLE OF EPIGENETIC MODIFICATION IS TO UNDERSTAND THE MECHANISM INVOLVED IN THE GENE-ENVIRONMENT INTERACTION, AND THE DEVELOPMENT OF PERIODONTITIS IS NOW THE SUBJECT OF MORE AND MORE STUDIES THAT ATTEMPT TO IDENTIFY WHICH FACTORS ARE STIMULATING IT, BUT ALSO AFFECT THE REDUCED RESPONSE TO THERAPY. 2023 19 6344 25 THE ROLE OF EPIGENETICS IN AGING AND AUTOIMMUNITY. THE DECLINE IN IMMUNOCOMPETENCE WITH AGE IS ACCOMPANIED BY THE INCREASE IN THE INCIDENCE OF AUTOIMMUNE DISEASES. AGING OF THE IMMUNE SYSTEM, OR IMMUNOSENESCENCE, IS CHARACTERIZED BY A DECLINE OF BOTH T AND B CELL FUNCTION, AND PARADOXICALLY THE PRESENCE OF LOW-GRADE CHRONIC INFLAMMATION. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF INHERITED CHANGES IN GENE EXPRESSION THAT ARE NOT ENCODED BY THE DNA SEQUENCE ITSELF, CHANGES WITH AGING. INTERESTINGLY, EMERGING EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETICS IN HUMAN PATHOLOGIES, INCLUDING INFLAMMATORY AND NEOPLASTIC DISORDERS. HERE, WE WILL REVIEW THE POTENTIAL MECHANISMS THAT CONTRIBUTE TO THE INCREASE IN AUTOIMMUNE RESPONSES IN AGING. IN PARTICULAR, WE WILL DISCUSS HOW EPIGENETIC ALTERATIONS, ESPECIALLY DNA METHYLATION AND HISTONE ACETYLATION, ARE ACCUMULATED DURING AGING AND HOW THESE EVENTS CONTRIBUTE TO AUTOIMMUNITY RISK. 2010 20 2945 29 GENETIC AND EPIGENETIC BASIS OF PSORIASIS PATHOGENESIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WHOSE PREVALENCE VARIES AMONG DIFFERENT POPULATIONS WORLDWIDE. IT IS A COMPLEX MULTI-FACTORIAL DISEASE AND THE EXACT ETIOLOGY IS LARGELY UNKNOWN. FAMILY BASED STUDIES HAVE INDICATED A GENETIC PREDISPOSITION; HOWEVER THEY CANNOT FULLY EXPLAIN THE DISEASE PATHOGENESIS. IN ADDITION TO GENETIC SUSCEPTIBILITY, ENVIRONMENTAL AS WELL AS GENDER AND AGE RELATED FACTORS WERE ALSO BEEN FOUND TO BE ASSOCIATED. RECENTLY, IMBALANCES IN EPIGENETIC NETWORKS ARE INDICATED TO BE CAUSATIVE ELEMENTS IN PSORIASIS. THE PRESENT KNOWLEDGE OF EPIGENETIC INVOLVEMENT, MAINLY THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND MIRNA DEREGULATION IS SURVEYED HERE. AN INTEGRATED APPROACH CONSIDERING GENETIC AND EPIGENETIC ANOMALIES IN THE LIGHT OF IMMUNOLOGICAL NETWORK MAY EXPLORE THE PATHOGENESIS OF PSORIASIS. 2015