1 1033 130 CITRULLINATION OF AUTOANTIGENS IMPLICATES NETOSIS IN THE INDUCTION OF AUTOIMMUNITY. TOLERANCE BLOCKS THE EXPRESSION OF AUTOANTIBODIES, WHEREAS AUTOIMMUNITY PROMOTES IT. HOW TOLERANCE BREAKS AND AUTOANTIBODY PRODUCTION BEGINS THUS ARE CRUCIAL QUESTIONS FOR UNDERSTANDING AND TREATMENT OF AUTOIMMUNE DISEASES. EVIDENCE IMPLICATES CELL DEATH AND AUTOANTIGEN MODIFICATIONS IN THE INITIATION OF AUTOIMMUNE REACTIONS. ONE FORM OF NEUTROPHIL CELL DEATH CALLED NETOSIS DESERVES ATTENTION BECAUSE IT REQUIRES THE POST-TRANSLATIONAL MODIFICATION OF HISTONES AND RESULTS IN THE EXTRACELLULAR RELEASE OF CHROMATIN. NETOSIS RECEIVED ITS NAME FROM NET, THE ACRONYM GIVEN TO NEUTROPHIL EXTRACELLULAR TRAP. THE EXTRACELLULAR CHROMATIN INCORPORATES HISTONES IN WHICH ARGININES HAVE BEEN CONVERTED TO CITRULLINES BY PEPTIDYLARGININE DEIMINASE IV (PAD4). THE DEIMINATED CHROMATIN MAY FUNCTION TO CAPTURE OR 'TRAP' BACTERIAL PATHOGENS, THUS GENERATING AN EXTRACELLULAR COMPLEX OF DEIMINATED HISTONES AND BACTERIAL CELL ADJUVANTS. THE COMPLEX OF BACTERIAL ANTIGENS AND DEIMINATED CHROMATIN MAY BE INTERNALISED BY HOST PHAGOCYTES DURING ACUTE INFLAMMATORY CONDITIONS, AS ARISE DURING BACTERIAL INFECTIONS OR CHRONIC AUTOINFLAMMATORY DISORDERS. THE UPTAKE AND PROCESSING OF DEIMINATED CHROMATIN TOGETHER WITH BACTERIAL ADJUVANTS BY PHAGOCYTES MAY INDUCE THE PRESENTATION OF MODIFIED HISTONE EPITOPES AND CO-STIMULATION, THUS YIELDING A POWERFUL STIMULUS TO BREAK TOLERANCE. AUTOANTIBODIES TO DEIMINATED HISTONES ARE PREVALENT IN FELTY'S SYNDROME PATIENTS AND ARE PRESENT IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND PATIENTS WITH RHEUMATOID ARTHRITIS (RA). THESE OBSERVATIONS CLEARLY IMPLICATE HISTONE DEIMINATION AS AN EPIGENETIC MARK THAT CAN ACT AS AN AUTOANTIBODY STIMULANT. 2014 2 3545 23 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 3 6178 31 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 4 1323 32 DENDRITIC CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS: FROM PATHOGENESIS TO THERAPEUTIC APPLICATIONS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A SEVERE CHRONIC SYSTEMIC AUTOIMMUNE DISEASE CAUSED BY COMPLICATED INTERACTIONS AMONG GENETIC, EPIGENETIC, AND IMMUNOLOGICAL FACTORS. DENDRITIC CELLS (DCS), AS THE MOST IMPORTANT ANTIGEN-PRESENTING CELLS, PLAY PIVOTAL ROLES IN BOTH TRIGGERING PATHOGENIC AUTOIMMUNE RESPONSES, AND ALSO MAINTAINING IMMUNE TOLERANCE. DISTINCT DC SUBSETS ARE ENDOWED WITH DIVERSIFIED PHENOTYPIC AND FUNCTIONAL CHARACTERISTICS, AND PLAY VARIABLE ROLES IN SHAPING IMMUNITY AND TOLERANCE DURING THE DEVELOPMENT OF SLE. ABNORMAL ACTIVATION OR DISABLED TOLERANCE OF DCS NOT ONLY TRIGGERS ABERRANT PRODUCTION OF INFLAMMATORY MEDIATORS AND TYPE I INTERFERONS LEADING TO PATHOGENIC INNATE IMMUNITY AND AUTOINFLAMMATION, BUT ALSO CAUSES AN IMBALANCE OF EFFECTOR VERSUS REGULATORY T CELL RESPONSES AND SUSTAINED PRODUCTION OF AUTO-ANTIBODIES FROM B CELLS, LEADING TO CONTINUOUSLY AMPLIFIED AUTOIMMUNE PATHOGENESIS IN SLE. OVER THE PAST DECADE, SIGNIFICANT PROGRESS HAS BEEN MADE IN REVEALING THE CHANGES OF DC ACCUMULATION OR FUNCTION IN SLE, AND HOW THE FUNCTIONAL DYSREGULATIONS OF DCS CONTRIBUTE TO THE PATHOLOGICAL INFLAMMATION OF SLE, LEADING TO BREAKTHROUGHS IN DC-BASED THERAPEUTICS IN THE TREATMENT OF SLE. IN THIS REVIEW, WE REVIEW THE RECENT ADVANCES IN THE ACTIVATION AND FUNCTION OF THE MAJOR DC SUBSETS IN THE PATHOGENESIS OF SLE AS WELL AS THE THERAPEUTIC POTENTIAL OF TARGETING DC SUBSET OR STATUS AGAINST SLE. 2022 5 6800 37 [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 6 398 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 7 4030 23 LUPUS ERYTHEMATOSUS: A SHORT ACCOUNT. LUPUS ERYTHEMATOSUS IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISEASE WITH DIVERSE CLINICAL MANIFESTATIONS INCLUDING ARTHRITIS, SKIN DISORDERS AND KIDNEY DISEASE. PATHOLOGICALLY IT IS CHARACTERISED BY COMPLEX INTERACTIONS BETWEEN MULTIPLE GENETIC, EPIGENETIC AND EXTRANEOUS FACTORS; AND SEROLOGICALLY BY THE PRESENCE OF A VARIETY OF ANTIBODIES WHICH ARE REACTIVE TO INTRACELLULAR MOLECULAR CONSTITUENTS. IMPAIRED CLEARANCE OF APOPTOTIC CELLS AND OF IMMUNE COMPLEXES, LOSS OF IMMUNE TOLERANCE TO SELF-ANTIGENS AND DYSREGULATION OF THE CYTOKINE NETWORK ACT SYNERGISTICALLY WITH EXTRANEOUS FACTORS SUCH AS ULTRAVIOLET RADIATION, VIRUSES AND CERTAIN DRUGS TO INDUCE AND SUSTAIN LUPUS ERYTHEMATOSUS. 2011 8 549 26 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 9 2529 33 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 10 6597 30 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 11 6194 29 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 12 4958 26 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 13 1463 37 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 14 6345 37 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 15 4200 34 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 16 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 17 4411 32 MOLECULAR AND CELLULAR BASES OF IMMUNOSENESCENCE, INFLAMMATION, AND CARDIOVASCULAR COMPLICATIONS MIMICKING "INFLAMMAGING" IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN ARCHETYPE OF SYSTEMIC AUTOIMMUNE DISEASE, CHARACTERIZED BY THE PRESENCE OF DIVERSE AUTOANTIBODIES AND CHRONIC INFLAMMATION. THERE ARE MULTIPLE FACTORS INVOLVED IN LUPUS PATHOGENESIS, INCLUDING GENETIC/EPIGENETIC PREDISPOSITION, SEXUAL HORMONE IMBALANCE, ENVIRONMENTAL STIMULANTS, MENTAL/PSYCHOLOGICAL STRESSES, AND UNDEFINED EVENTS. RECENTLY, MANY AUTHORS NOTED THAT "INFLAMMAGING", CONSISTING OF IMMUNOSENESCENCE AND INFLAMMATION, IS A COMMON FEATURE IN AGING PEOPLE AND PATIENTS WITH SLE. IT IS CONCEIVABLE THAT CHRONIC OXIDATIVE STRESSES ORIGINATING FROM MITOCHONDRIAL DYSFUNCTION, DEFECTIVE BIOENERGETICS, ABNORMAL IMMUNOMETABOLISM, AND PREMATURE TELOMERE EROSION MAY ACCELERATE IMMUNE CELL SENESCENCE IN PATIENTS WITH SLE. THE MITOCHONDRIAL DYSFUNCTIONS IN SLE HAVE BEEN EXTENSIVELY INVESTIGATED IN RECENT YEARS. THE MOLECULAR BASIS OF NORMOGLYCEMIC METABOLIC SYNDROME HAS BEEN FOUND TO BE RELEVANT TO THE PRODUCTION OF ADVANCED GLYCOSYLATED AND NITROSATIVE END PRODUCTS. BESIDES, IMMUNOSENESCENCE, AUTOIMMUNITY, ENDOTHELIAL CELL DAMAGE, AND DECREASED TISSUE REGENERATION COULD BE THE RESULTS OF PREMATURE TELOMERE EROSION IN PATIENTS WITH SLE. HEREIN, THE MOLECULAR AND CELLULAR BASES OF INFLAMMAGING AND CARDIOVASCULAR COMPLICATIONS IN SLE PATIENTS WILL BE EXTENSIVELY REVIEWED FROM THE ASPECTS OF MITOCHONDRIAL DYSFUNCTIONS, ABNORMAL BIOENERGETICS/IMMUNOMETABOLISM, AND TELOMERE/TELOMERASE DISEQUILIBRIUM. 2019 18 4842 28 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 19 5159 26 PRE-RHEUMATOID ARTHRITIS: PREDISPOSITION AND TRANSITION TO CLINICAL SYNOVITIS. MULTIPLE PROVEN AND POTENTIAL RISK FACTORS FOR THE DEVELOPMENT OF RHEUMATOID ARTHRITIS (RA) HAVE BEEN IDENTIFIED, AND REPRESENT INTERACTIONS BETWEEN GENES AND THE ENVIRONMENT. PROVEN RISK FACTORS INCLUDE GENETIC INFLUENCES ON THE FUNCTION OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS, SMOKING, ANTI-CITRULLINATED PROTEIN ANTIBODIES (ACPAS), AND RHEUMATOID FACTORS (RF). POTENTIAL RISK FACTORS INCLUDE EPIGENETIC CONTROL OF GENE EXPRESSION, THE MICROBIOME AND OTHER ENVIRONMENTAL FACTORS, TOLL-LIKE RECEPTORS, CYTOKINES, AND FC RECEPTORS. PRECLINICAL ABNORMALITIES SUCH AS CIRCULATING RF AND ACPAS MAY OCCUR MORE THAN 10 YEARS PRIOR TO THE ONSET OF CLINICAL DISEASE. HOWEVER, THE PRECISE MECHANISMS WHEREBY THESE RISK FACTORS LEAD TO CLINICAL DISEASE REMAIN UNCLEAR. IT IS POSSIBLE THAT, COMBINED WITH ACTIVATION OF THE INNATE IMMUNE SYSTEM, A SUBSET OF ACPAS INITIATES THE DISEASE IN THE CARTILAGE OR SYNOVIUM AFTER BINDING TO ENDOGENOUS CITRULLINATED PROTEINS. SUBSEQUENT ENGAGEMENT OF FC RECEPTORS AND COMPLEMENT ACTIVATION WOULD LEAD TO SECONDARY INFLAMMATION IN THE SYNOVIUM WITH INDUCTION OF A PERPETUATING CYCLE OF CHRONIC SYNOVITIS. 2012 20 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