1 3661 128 INDUCTION OF INNATE IMMUNE MEMORY BY ENGINEERED NANOPARTICLES IN MONOCYTES/MACROPHAGES: FROM HYPOTHESIS TO REALITY. THE CAPACITY OF ENGINEERED NANOPARTICLES TO ACTIVATE CELLS OF THE INNATE IMMUNE SYSTEM, IN PARTICULAR MONOCYTES AND MACROPHAGES, IS CONSIDERED AT THE BASIS OF THEIR TOXIC/INFLAMMATORY EFFECTS. IT IS, HOWEVER, EVIDENT THAT EVEN NANOPARTICLES THAT DO NOT DIRECTLY INDUCE INFLAMMATORY ACTIVATION, AND ARE THEREFORE CONSIDERED AS SAFE, CAN NEVERTHELESS INDUCE EPIGENETIC MODIFICATIONS AND AFFECT METABOLIC PATHWAYS IN MONOCYTES AND MACROPHAGES. SINCE EPIGENETIC AND METABOLIC CHANGES ARE THE MAIN MECHANISMS OF INNATE MEMORY, WE HAD PREVIOUSLY PROPOSED THAT NANOPARTICLES CAN INDUCE/MODULATE INNATE MEMORY, THAT IS, HAVE THE ABILITY OF SHAPING THE SECONDARY RESPONSE TO INFLAMMATORY CHALLENGES. IN LIGHT OF NEW DATA, IT IS NOW POSSIBLE TO SUPPORT THE ORIGINAL HYPOTHESIS AND SHOW THAT DIFFERENT TYPES OF NANOPARTICLES CAN BOTH DIRECTLY INDUCE INNATE MEMORY, PRIMING MACROPHAGES FOR A MORE POTENT RESPONSE TO SUBSEQUENT STIMULI, AND MODULATE BACTERIA-INDUCED MEMORY BY ATTENUATING THE PRIMING-INDUCED ENHANCEMENT. THIS EVIDENCE RAISES TWO IMPORTANT ISSUES. FIRST, IN ADDITION TO OVERT TOXIC/INFLAMMATORY EFFECTS, WE SHOULD CONSIDER EVALUATING THE CAPACITY TO INDUCE INNATE MEMORY AND THE RELATED EPIGENETIC AND METABOLIC CHANGES IN THE IMMUNOSAFETY ASSESSMENT OF NANOMATERIALS, SINCE MODULATION OF INNATE MEMORY MAY BE AT THE BASIS OF LONG-TERM UNWANTED IMMUNOLOGICAL EFFECTS. THE OTHER IMPORTANT CONSIDERATION IS THAT THIS CAPACITY OF NANOMATERIALS COULD OPEN A NEW AVENUE IN IMMUNOMODULATION AND THE POSSIBILITY OF USING ENGINEERED NANOMATERIALS FOR IMPROVING IMMUNE RESPONSES TO VACCINES AND RESISTANCE TO INFECTIONS, AND MODULATE ANOMALOUS IMMUNE/INFLAMMATORY REACTIONS IN CHRONIC INFLAMMATORY DISEASES, AUTOIMMUNITY, AND A RANGE OF OTHER IMMUNE-RELATED PATHOLOGIES. 2020 2 127 30 A TRANSCRIPTIONAL PERSPECTIVE ON HUMAN MACROPHAGE BIOLOGY. MACROPHAGES ARE A MAJOR CELL TYPE IN TISSUE HOMEOSTASIS AND CONTRIBUTE TO BOTH PATHOLOGY AND RESOLUTION IN ALL ACUTE AND CHRONIC INFLAMMATORY DISEASES RANGING FROM INFECTIONS, CANCER, OBESITY, ATHEROSCLEROSIS, AUTOIMMUNE DISORDERS TO NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S DISEASE. THE CELLULAR AND FUNCTIONAL DIVERSITY OF MACROPHAGES DEPENDS UPON TIGHTLY REGULATED TRANSCRIPTION. THE INNATE IMMUNE SYSTEM IS UNDER PROFOUND EVOLUTIONARY SELECTION. THERE IS INCREASING RECOGNITION THAT HUMAN MACROPHAGE BIOLOGY DIFFERS VERY SIGNIFICANTLY FROM THAT OF COMMONLY STUDIED ANIMAL MODELS, WHICH THEREFORE CAN HAVE A LIMITED PREDICTIVE VALUE. HERE WE REPORT ON THE NEWEST FINDINGS ON TRANSCRIPTIONAL CONTROL OF MACROPHAGE ACTIVATION, AND HOW WE ENVISION INTEGRATING STUDIES ON TRANSCRIPTIONAL AND EPIGENETIC REGULATION, AND MORE CLASSICAL APPROACHES IN MURINE MODELS. MOREOVER, WE PROVIDE NEW INSIGHTS INTO HOW WE CAN LEARN ABOUT TRANSCRIPTIONAL REGULATION IN THE HUMAN SYSTEM FROM LARGER EFFORTS SUCH AS THE FANTOM (FUNCTIONAL ANNOTATION OF THE MAMMALIAN GENOME) CONSORTIUM. 2015 3 1876 31 EMERGING ROLES FOR EPIGENETIC PROGRAMMING IN THE CONTROL OF INFLAMMATORY SIGNALING INTEGRATION IN HEATH AND DISEASE. MACROPHAGES AND DENDRITIC CELLS INITIATE THE INNATE IMMUNE RESPONSE TO INFECTION AND INJURY AND CONTRIBUTE TO INFLAMMATORY SIGNALING TO MAINTAIN THE HOMEOSTASIS OF VARIOUS TISSUES, WHICH INCLUDES RESIDENT MACROPHAGES FOR THE ELIMINATION OF INVADING MICROORGANISMS AND TISSUE DAMAGE. INAPPROPRIATE INFLAMMATORY SIGNALING CAN LEAD TO PERSISTENT INFLAMMATION AND FURTHER DEVELOP INTO AUTOIMMUNE AND INFLAMMATION-ASSOCIATED DISEASES. INFLAMMATORY SIGNALING PATHWAYS HAVE BEEN WELL CHARACTERIZED, BUT HOW THESE SIGNALING PATHWAYS ARE CONVERTED INTO SUSTAINED AND DIVERSE PATTERNS OF EXPRESSION OF CYTOKINES, CHEMOKINES, AND OTHER GENES IN RESPONSE TO ENVIRONMENTAL CHALLENGES IS UNCLEAR. EMERGING EVIDENCE SUGGESTS THE IMPORTANT ROLE OF EPIGENETIC MECHANISMS IN FINELY TUNING THE OUTCOME OF THE HOST INNATE IMMUNE RESPONSE. AN UNDERSTANDING OF EPIGENETIC REGULATION OF INNATE IMMUNE CELL IDENTITY AND FUNCTION WILL ENABLE THE IDENTIFICATION OF THE MECHANISM BETWEEN GENE-SPECIFIC HOST DEFENSES AND INFLAMMATORY DISEASE AND WILL ALSO ALLOW FOR EXPLORATION OF THE PROGRAM OF INNATE IMMUNE MEMORY IN HEALTH AND DISEASE. THIS INFORMATION COULD BE USED TO DEVELOP THERAPEUTIC AGENTS TO ENHANCE THE HOST RESPONSE, PREVENTING CHRONIC INFLAMMATION THROUGH PRESERVING TISSUES AND SIGNALING INTEGRITY. 2017 4 4200 39 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 5 2344 31 EPIGENETIC REGULATION OF MACROPHAGES: FROM HOMEOSTASIS MAINTENANCE TO HOST DEFENSE. MACROPHAGES ARE CRUCIAL MEMBERS OF THE INNATE IMMUNE RESPONSE AND IMPORTANT REGULATORS. THE DIFFERENTIATION AND ACTIVATION OF MACROPHAGES REQUIRE THE TIMELY REGULATION OF GENE EXPRESSION, WHICH DEPENDS ON THE INTERACTION OF A VARIETY OF FACTORS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC MODIFICATIONS. EPIGENETIC CHANGES ALSO GIVE MACROPHAGES THE ABILITY TO SWITCH RAPIDLY BETWEEN CELLULAR PROGRAMS, INDICATING THE ABILITY OF EPIGENETIC MECHANISMS TO AFFECT PHENOTYPE PLASTICITY. IN THIS REVIEW, WE FOCUS ON KEY EPIGENETIC EVENTS ASSOCIATED WITH MACROPHAGE FATE, HIGHLIGHTING EVENTS RELATED TO THE MAINTENANCE OF TISSUE HOMEOSTASIS, RESPONSES TO DIFFERENT STIMULI AND THE FORMATION OF INNATE IMMUNE MEMORY. FURTHER UNDERSTANDING OF THE EPIGENETIC REGULATION OF MACROPHAGES WILL BE HELPFUL FOR MAINTAINING TISSUE INTEGRITY, PREVENTING CHRONIC INFLAMMATORY DISEASES AND DEVELOPING THERAPIES TO ENHANCE HOST DEFENSE. 2020 6 4488 37 MONOCYTE AND HAEMATOPOIETIC PROGENITOR REPROGRAMMING AS COMMON MECHANISM UNDERLYING CHRONIC INFLAMMATORY AND CARDIOVASCULAR DISEASES. A LARGE NUMBER OF CARDIOVASCULAR EVENTS ARE NOT PREVENTED BY CURRENT THERAPEUTIC REGIMENS. IN SEARCH FOR ADDITIONAL, INNOVATIVE STRATEGIES, IMMUNE CELLS HAVE BEEN RECOGNIZED AS KEY PLAYERS CONTRIBUTING TO ATHEROSCLEROTIC PLAQUE PROGRESSION AND DESTABILIZATION. PARTICULARLY THE ROLE OF INNATE IMMUNE CELLS IS OF MAJOR INTEREST, FOLLOWING THE RECENT PARADIGM SHIFT THAT INNATE IMMUNITY, LONG CONSIDERED TO BE INCAPABLE OF LEARNING, DOES EXHIBIT IMMUNOLOGICAL MEMORY MEDIATED VIA EPIGENETIC REPROGRAMMING. COMPELLING EVIDENCE SHOWS THAT ATHEROSCLEROTIC RISK FACTORS PROMOTE IMMUNE CELL MIGRATION BY PRE-ACTIVATION OF CIRCULATING INNATE IMMUNE CELLS. INNATE IMMUNE CELL ACTIVATION VIA METABOLIC AND EPIGENETIC REPROGRAMMING PERPETUATES A SYSTEMIC LOW-GRADE INFLAMMATORY STATE IN CARDIOVASCULAR DISEASE (CVD) THAT IS ALSO COMMON IN OTHER CHRONIC INFLAMMATORY DISORDERS. THIS OPENS A NEW THERAPEUTIC AREA IN WHICH METABOLIC OR EPIGENETIC MODULATION OF INNATE IMMUNE CELLS MAY RESULT IN DECREASED SYSTEMIC CHRONIC INFLAMMATION, ALLEVIATING CVD, AND ITS CO-MORBIDITIES. 2018 7 3123 37 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 8 6496 57 TRAINED IMMUNITY CONTRIBUTION TO AUTOIMMUNE AND INFLAMMATORY DISORDERS. A DYSREGULATED IMMUNE RESPONSE TOWARD SELF-ANTIGENS CHARACTERIZES AUTOIMMUNE AND AUTOINFLAMMATORY (AIF) DISORDERS. AUTOANTIBODIES OR AUTOREACTIVE T CELLS CONTRIBUTE TO AUTOIMMUNE DISEASES, WHILE AUTOINFLAMMATION RESULTS FROM A HYPER-FUNCTIONAL INNATE IMMUNE SYSTEM. ASIDE FROM THEIR DIFFERENCES, MANY STUDIES SUGGEST THAT MONOCYTES AND MACROPHAGES (MO/MA) SIGNIFICANTLY CONTRIBUTE TO THE DEVELOPMENT OF BOTH TYPES OF DISEASE. MO/MA ARE INNATE IMMUNE CELLS THAT PROMOTE AN IMMUNE-MODULATORY, PRO-INFLAMMATORY, OR REPAIR RESPONSE DEPENDING ON THE MICROENVIRONMENT. HOWEVER, UNDERSTANDING THE CONTRIBUTION OF THESE CELLS TO DIFFERENT IMMUNE DISORDERS HAS BEEN DIFFICULT DUE TO THEIR HIGH FUNCTIONAL AND PHENOTYPIC PLASTICITY. SEVERAL FACTORS CAN INFLUENCE THE FUNCTION OF MO/MA UNDER THE LANDSCAPE OF AUTOIMMUNE/AUTOINFLAMMATORY DISEASES, SUCH AS GENETIC PREDISPOSITION, EPIGENETIC CHANGES, OR INFECTIONS. FOR INSTANCE, SOME VACCINES AND MICROORGANISMS CAN INDUCE EPIGENETIC CHANGES IN MO/MA, MODIFYING THEIR FUNCTIONAL RESPONSES. THIS PHENOMENON IS KNOWN AS TRAINED IMMUNITY. TRAINED IMMUNITY CAN BE MEDIATED BY MO/MA AND NK CELLS INDEPENDENTLY OF T AND B CELL FUNCTION. IT IS DEFINED AS THE ALTERED INNATE IMMUNE RESPONSE TO THE SAME OR DIFFERENT MICROORGANISMS DURING A SECOND ENCOUNTER. THE IMPROVEMENT IN CELL FUNCTION IS RELATED TO EPIGENETIC AND METABOLIC CHANGES THAT MODIFY GENE EXPRESSION. ALTHOUGH THE BENEFITS OF IMMUNE TRAINING HAVE BEEN HIGHLIGHTED IN A VACCINATION CONTEXT, THE EFFECTS OF THIS TYPE OF IMMUNE RESPONSE ON AUTOIMMUNITY AND CHRONIC INFLAMMATION STILL REMAIN CONTROVERSIAL. INDUCTION OF TRAINED IMMUNITY REPROGRAMS CELLULAR METABOLISM IN HEMATOPOIETIC STEM CELLS (HSCS), TRANSMITTING A MEMORY-LIKE PHENOTYPE TO THE CELLS. THUS, TRAINED MO/MA DERIVED FROM HSCS TYPICALLY PRESENT A METABOLIC SHIFT TOWARD GLYCOLYSIS, WHICH LEADS TO THE MODIFICATION OF THE CHROMATIN ARCHITECTURE. DURING TRAINED IMMUNITY, THE EPIGENETIC CHANGES FACILITATE THE SPECIFIC GENE EXPRESSION AFTER SECONDARY CHALLENGE WITH OTHER STIMULI. CONSEQUENTLY, THE ENHANCED PRO-INFLAMMATORY RESPONSE COULD CONTRIBUTE TO DEVELOPING OR MAINTAINING AUTOIMMUNE/AUTOINFLAMMATORY DISEASES. HOWEVER, THE PREDICTION OF THE OUTCOME IS NOT SIMPLE, AND OTHER STUDIES PROPOSE THAT TRAINED IMMUNITY CAN INDUCE A BENEFICIAL RESPONSE BOTH IN AIF AND AUTOIMMUNE CONDITIONS BY INDUCING ANTI-INFLAMMATORY RESPONSES. THIS ARTICLE DESCRIBES THE METABOLIC AND EPIGENETIC MECHANISMS INVOLVED IN TRAINED IMMUNITY THAT AFFECT MO/MA, CONTRAPOSING THE CONTROVERSIAL EVIDENCE ON HOW IT MAY IMPACT AUTOIMMUNE/AUTOINFLAMMATION CONDITIONS. 2022 9 6504 45 TRAINED INNATE IMMUNITY AND ITS IMPLICATIONS FOR MUCOSAL IMMUNITY AND INFLAMMATION. THE LONG-STANDING DOGMA THAT IMMUNOLOGICAL MEMORY IS THE EXCLUSIVE PREROGATIVE OF THE ADAPTIVE IMMUNE SYSTEM HAS BEEN CHALLENGED BY EMERGING EVIDENCE THAT INNATE IMMUNITY CAN ALSO MAINTAIN MEMORY OF PAST EVENTS. SUCH IMMUNOLOGICAL IMPRINTING TAKES TWO FORMS, TRAINED INNATE IMMUNITY AND TOLERANCE. TRAINED IMMUNITY INVOLVES METABOLIC AND EPIGENETIC ADAPTATIONS IN INNATE IMMUNE CELLS AND THEIR PROGENITORS IN THE BONE MARROW UPON EXPOSURE TO CERTAIN MICROBIAL AND/OR INFLAMMATORY STIMULI SO THAT THE "TRAINED" CELLS WOULD BE POISED TO RESPOND MUCH FASTER AND STRONGER TO A SUBSEQUENT CHALLENGE (E.G., A NEW INFECTION THAT IS NOT NECESSARILY THE SAME AS THE EARLIER ONE). CONVERSELY, TOLERANCE LEADS TO ATTENUATED IMMUNE RESPONSES TO SECONDARY STIMULI. THIS REVIEW FOCUSES ON TRAINED IMMUNITY AND DISCUSSES EVIDENCE FOR ITS EXISTENCE FROM LOWER ORGANISMS TO HUMANS, ITS MECHANISTIC UNDERPINNINGS, AND ITS TRANSLATIONAL RAMIFICATIONS. ALTHOUGH TRAINED IMMUNITY CAN BE CONSIDERED AS AN EVOLUTIONARILY CONSERVED BENEFICIAL RESPONSE AGAINST REINFECTIONS, IN THE SETTING OF MODERN SOCIETIES WITH HIGH PREVALENCE OF CHRONIC MUCOSAL AND SYSTEMIC INFLAMMATORY DISEASES, TRAINED IMMUNITY COULD ALSO PROMOTE MALADAPTIVE IMMUNE RESPONSES THAT AGGRAVATE PATHOLOGY. THUS, DEPENDING ON CONTEXT, INNATE IMMUNE MEMORY COULD BE THERAPEUTICALLY MANIPULATED USING DEFINED AGONISTS TO EITHER PROMOTE INNATE IMMUNE RESPONSES (PARTICULARLY USEFUL FOR THE TREATMENT OF INFECTIONS OR CHEMOTHERAPY-INDUCED MYELOSUPPRESSION) OR SUPPRESS EXCESSIVE INFLAMMATION IN INFLAMMATORY AND AUTOIMMUNE DISEASES. 2019 10 2070 24 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 11 806 29 CHALLENGES FOR MODELING AND INTERPRETING THE COMPLEX BIOLOGY OF SEVERE INJURY AND INFLAMMATION. HUMAN INJURY IS ASSOCIATED WITH INFLAMMATORY RESPONSES THAT ARE MODULATED BY THE ACUTE AND CHRONIC ACTIVITY OF ENDOGENOUS FACTORS AND EXOGENOUS INTERVENTIONS. A CHARACTERISTIC FEATURE OF CHRONIC, SEVERE INFLAMMATORY STATES IS THE DIMINISHED SIGNAL OUTPUT VARIABILITY OF MANY ORGAN SYSTEMS, INCLUDING INNATE IMMUNE RESPONSIVENESS AND ENDOGENOUS NEURAL AND ENDOCRINE-MEDIATED FUNCTIONS. THE ATTENUATION OF SIGNAL/RESPONSE VARIABILITY AND INTEGRATION OF FEEDBACK CAPACITY MAY CONTRIBUTE TO SYSTEMIC AND TISSUE-SPECIFIC DETERIORATION OF FUNCTION. SOME WELL-INTENTIONED THERAPIES DIRECTED TOWARD SUPPORT OF SYSTEMIC AND TISSUE FUNCTIONS MAY ACTUALLY PROMOTE THE LOSS OF SYSTEM(S) ADAPTABILITY AND CONTRIBUTE TO ADVERSE OUTCOMES IN SEVERELY STRESSED PATIENTS. IN VIVO AND IN SILICO MODELS OF STRESS, INJURY, AND INFECTION HAVE YET TO FULLY DEFINE THE INFLUENCES OF ONGOING STRESSFUL STIMULAE AS WELL AS GENETIC VARIATION AND EPIGENETIC FACTORS IN THE CONTEXT OF AN EVOLVING INFLAMMATORY STATE. EXPERIMENTAL AND HUMAN MODELS INCORPORATING VARIABLE, ANTECEDENT STRESS(ES) AND ALTERED NEUROENDOCRINE RHYTHMS MIGHT APPROXIMATE THE ALTERED ADAPTABILITY IN IMMUNE AND ORGAN FUNCTION RESPONSES. SUCH MODELS MAY ALSO PROVIDE INSIGHTS INTO THE SALIENT MECHANISMS OF RISK AND OUTCOME MORE PRECISELY THAN DO THE CONSTRAINED STUDY CONDITIONS OF CURRENT ANIMAL OR HUMAN MODELS OF SYSTEMIC INFLAMMATION. 2008 12 5932 30 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 13 3703 25 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 14 6136 41 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 15 6101 25 THE EMERGING ROLE OF EPIGENETICS IN THE IMMUNE RESPONSE TO VACCINATION AND INFECTION: A SYSTEMATIC REVIEW. EXTENSIVE RESEARCH HAS HIGHLIGHTED THE ROLE OF INFECTION-INDUCED EPIGENETIC EVENTS IN THE DEVELOPMENT OF CANCER. MORE RECENTLY, ATTENTION HAS FOCUSED ON THE ABILITY OF NON-CARCINOGENIC INFECTIONS, AS WELL AS VACCINES, TO MODIFY THE HUMAN EPIGENOME AND MODULATE THE IMMUNE RESPONSE. THIS REVIEW EXPLORES THIS RAPIDLY EVOLVING AREA OF INVESTIGATION AND OUTLINES THE MANY AND VARIED WAYS IN WHICH VACCINATION AND NATURAL INFECTION CAN INFLUENCE THE HUMAN EPIGENOME FROM MODULATION OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE, TO BIOLOGICAL AGEING AND MODIFICATION OF DISEASE RISK. THE IMPLICATIONS OF THESE EPIGENETIC CHANGES ON IMMUNE REGULATION AND THEIR POTENTIAL APPLICATION TO THE DIAGNOSIS AND TREATMENT OF CHRONIC INFECTION AND VACCINE DEVELOPMENT ARE ALSO DISCUSSED. 2020 16 5410 30 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 17 4738 32 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 18 2525 41 EPIGENETICS AND TRAINED IMMUNITY. SIGNIFICANCE: A GROWING BODY OF CLINICAL AND EXPERIMENTAL EVIDENCE HAS CHALLENGED THE TRADITIONAL UNDERSTANDING THAT ONLY THE ADAPTIVE IMMUNE SYSTEM CAN MOUNT IMMUNOLOGICAL MEMORY. RECENT FINDINGS DESCRIBE THE ADAPTIVE CHARACTERISTICS OF THE INNATE IMMUNE SYSTEM, UNDERSCORED BY ITS ABILITY TO REMEMBER ANTECEDENT FOREIGN ENCOUNTERS AND RESPOND IN A NONSPECIFIC SENSITIZED MANNER TO REINFECTION. THIS HAS BEEN TERMED TRAINED INNATE IMMUNITY. ALTHOUGH BENEFICIAL IN THE CONTEXT OF RECURRENT INFECTIONS, THIS MIGHT ACTUALLY CONTRIBUTE TO CHRONIC IMMUNE-MEDIATED DISEASES, SUCH AS ATHEROSCLEROSIS. RECENT ADVANCES: IN LINE WITH ITS PROPOSED ROLE IN SUSTAINING CELLULAR MEMORIES, EPIGENETIC REPROGRAMMING HAS EMERGED AS A CRITICAL DETERMINANT OF TRAINED IMMUNITY. RECENT TECHNOLOGICAL AND COMPUTATIONAL ADVANCES THAT IMPROVE UNBIASED ACQUISITION OF EPIGENOMIC PROFILES HAVE SIGNIFICANTLY ENHANCED OUR APPRECIATION FOR THE COMPLEXITIES OF CHROMATIN ARCHITECTURE IN THE CONTEXTS OF DIVERSE IMMUNOLOGICAL CHALLENGES. CRITICAL ISSUES: KEY TO RESOLVING THE DISTINCT CHROMATIN SIGNATURES OF INNATE IMMUNE MEMORY IS A COMPREHENSIVE UNDERSTANDING OF THE PRECISE PHYSIOLOGICAL TARGETS OF REGULATORY PROTEINS THAT RECOGNIZE, DEPOSIT, AND REMOVE CHEMICAL MODIFICATIONS FROM CHROMATIN AS WELL AS OTHER GENE-REGULATING FACTORS. DRAWING FROM A RAPIDLY EXPANDING COMPENDIUM OF EXPERIMENTAL AND CLINICAL STUDIES, THIS REVIEW DETAILS A CURRENT PERSPECTIVE OF THE EPIGENETIC PATHWAYS THAT SUPPORT THE ADAPTED PHENOTYPES OF MONOCYTES AND MACROPHAGES. FUTURE DIRECTIONS: WE EXPLORE FUTURE STRATEGIES THAT ARE AIMED AT EXPLOITING THE MECHANISM OF TRAINED IMMUNITY TO IMPROVE THE PREVENTION AND TREATMENT OF INFECTIONS AND IMMUNE-MEDIATED CHRONIC DISORDERS. 2018 19 6135 32 THE EPIGENETICS OF INFLAMMAGING: THE CONTRIBUTION OF AGE-RELATED HETEROCHROMATIN LOSS AND LOCUS-SPECIFIC REMODELLING AND THE MODULATION BY ENVIRONMENTAL STIMULI. A GROWING AMOUNT OF EVIDENCES INDICATES THAT INFLAMMAGING - THE CHRONIC, LOW GRADE INFLAMMATION STATE CHARACTERISTIC OF THE ELDERLY - IS THE RESULT OF GENETIC AS WELL AS ENVIRONMENTAL OR STOCHASTIC FACTORS. SOME OF THESE, SUCH AS THE ACCUMULATION OF SENESCENT CELLS THAT ARE PERSISTENT DURING AGING OR ACCOMPANY ITS PROGRESSION, SEEM TO BE SUFFICIENT TO INITIATE THE AGING PROCESS AND TO FUEL IT. OTHERS, LIKE EXPOSURE TO ENVIRONMENTAL COMPOUNDS OR INFECTIONS, ARE TEMPORARY AND RESOLVE WITHIN A (RELATIVELY) SHORT TIME. IN BOTH CASES, HOWEVER, A CELLULAR MEMORY OF THE EVENT CAN BE ESTABLISHED BY MEANS OF EPIGENETIC MODULATION OF THE GENOME. IN THIS REVIEW WE WILL SPECIFICALLY DISCUSS THE RELATIONSHIP BETWEEN EPIGENETICS AND INFLAMMAGING. IN PARTICULAR, WE WILL SHOW HOW AGE-ASSOCIATED EPIGENETIC MODIFICATIONS CONCERNED WITH HETEROCHROMATIN LOSS AND GENE-SPECIFIC REMODELLING, CAN PROMOTE INFLAMMAGING. FURTHERMORE, WE WILL RECALL HOW THE EXPOSURE TO SPECIFIC NUTRITIONAL, ENVIRONMENTAL AND MICROBIAL STIMULI CAN AFFECT THE RATE OF INFLAMMAGING THROUGH EPIGENETIC MECHANISMS, TOUCHING ALSO ON THE RECENT INSIGHT GIVEN BY THE CONCEPT OF TRAINED IMMUNITY. 2018 20 6344 28 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