1 1309 172 DEFINING AND TARGETING PATTERNS OF T CELL DYSFUNCTION IN INBORN ERRORS OF IMMUNITY. INBORN ERRORS OF IMMUNITY (IEIS) ARE A GROUP OF MORE THAN 450 MONOGENIC DISORDERS THAT IMPAIR IMMUNE DEVELOPMENT AND FUNCTION. A SUBSET OF IEIS BLEND INCREASED SUSCEPTIBILITY TO INFECTION, AUTOIMMUNITY, AND MALIGNANCY AND ARE KNOWN COLLECTIVELY AS PRIMARY IMMUNE REGULATORY DISORDERS (PIRDS). WHILE MANY ASPECTS OF IMMUNE FUNCTION ARE ALTERED IN PIRDS, ONE KEY IMPACT IS ON T-CELL FUNCTION. BY THEIR NATURE, PIRDS PROVIDE UNIQUE INSIGHTS INTO HUMAN T-CELL SIGNALING; ALTERATIONS IN INDIVIDUAL SIGNALING MOLECULES TUNE DOWNSTREAM SIGNALING PATHWAYS AND EFFECTOR FUNCTION. QUANTIFYING T-CELL DYSFUNCTION IN PIRDS AND THE UNDERLYING CAUSATIVE MECHANISMS IS CRITICAL TO IDENTIFYING EXISTING THERAPIES AND POTENTIAL NOVEL THERAPEUTIC TARGETS TO TREAT OUR RARE PATIENTS AND GAIN DEEPER INSIGHT INTO THE BASIC MECHANISMS OF T-CELL FUNCTION. THOUGH THERE ARE MANY TYPES OF T-CELL DYSFUNCTION, HERE WE WILL FOCUS ON T-CELL EXHAUSTION, A KEY PATHOPHYSIOLOGICAL STATE. EXHAUSTION HAS BEEN DESCRIBED IN BOTH HUMAN AND MOUSE MODELS OF DISEASE, WHERE THE CHRONIC PRESENCE OF ANTIGEN AND INFLAMMATION (E.G., CHRONIC INFECTION OR MALIGNANCY) INDUCES A STATE OF ALTERED IMMUNE PROFILE, TRANSCRIPTIONAL AND EPIGENETIC STATES, AS WELL AS IMPAIRED T-CELL FUNCTION. SINCE A SUBSET OF PIRDS AMPLIFY T-CELL RECEPTOR (TCR) SIGNALING AND/OR INFLAMMATORY CYTOKINE SIGNALING CASCADES, IT IS POSSIBLE THAT THEY COULD INDUCE T-CELL EXHAUSTION BY GENETICALLY MIMICKING CHRONIC INFECTION. HERE, WE REVIEW THE FUNDAMENTALS OF T-CELL EXHAUSTION AND ITS POSSIBLE ROLE IN IEIS IN WHICH GENETIC MUTATIONS MIMIC PROLONGED OR AMPLIFIED T-CELL RECEPTOR AND/OR CYTOKINE SIGNALING. GIVEN THE POTENTIAL INSIGHT FROM THE MANY FORMS OF PIRDS IN UNDERSTANDING T-CELL FUNCTION AND THE CHALLENGES IN OBTAINING PRIMARY CELLS FROM THESE RARE DISORDERS, WE ALSO DISCUSS ADVANCES IN CRISPR-CAS9 GENOME-EDITING TECHNOLOGIES AND POTENTIAL APPLICATIONS TO EDIT HEALTHY DONOR T CELLS THAT COULD FACILITATE FURTHER STUDY OF MECHANISMS OF IMMUNE DYSFUNCTIONS IN PIRDS. EDITING T CELLS TO MATCH PIRD PATIENT GENETIC VARIANTS WILL ALLOW INVESTIGATIONS INTO THE MECHANISMS UNDERPINNING STATES OF DYSREGULATED T-CELL FUNCTION, INCLUDING T-CELL EXHAUSTION. 2022 2 2446 26 EPIGENETIC STRATEGIES SYNERGIZE WITH PD-L1/PD-1 TARGETED CANCER IMMUNOTHERAPIES TO ENHANCE ANTITUMOR RESPONSES. IMMUNOTHERAPY STRATEGIES TARGETING THE PROGRAMMED CELL DEATH LIGAND 1 (PD-L1)/PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY IN CLINICAL TREATMENTS HAVE ACHIEVED REMARKABLE SUCCESS IN TREATING MULTIPLE TYPES OF CANCER. HOWEVER, OWING TO THE HETEROGENEITY OF TUMORS AND INDIVIDUAL IMMUNE SYSTEMS, PD-L1/PD-1 BLOCKADE STILL SHOWS SLOW RESPONSE RATES IN CONTROLLING MALIGNANCIES IN MANY PATIENTS. ACCUMULATING EVIDENCE HAS SHOWN THAT AN EFFECTIVE RESPONSE TO ANTI-PD-L1/ANTI-PD-1 THERAPY REQUIRES ESTABLISHING AN INTEGRATED IMMUNE CYCLE. DAMAGE IN ANY STEP OF THE IMMUNE CYCLE IS ONE OF THE MOST IMPORTANT CAUSES OF IMMUNOTHERAPY FAILURE. IMPAIRMENTS IN THE IMMUNE CYCLE CAN BE RESTORED BY EPIGENETIC MODIFICATION, INCLUDING REPROGRAMMING THE ENVIRONMENT OF TUMOR-ASSOCIATED IMMUNITY, ELICITING AN IMMUNE RESPONSE BY INCREASING THE PRESENTATION OF TUMOR ANTIGENS, AND BY REGULATING T CELL TRAFFICKING AND REACTIVATION. THUS, A RATIONAL COMBINATION OF PD-L1/PD-1 BLOCKADE AND EPIGENETIC AGENTS MAY OFFER GREAT POTENTIAL TO RETRAIN THE IMMUNE SYSTEM AND TO IMPROVE CLINICAL OUTCOMES OF CHECKPOINT BLOCKADE THERAPY. 2020 3 5899 41 T-CELL DYSFUNCTION IN CHRONIC LYMPHOCYTIC LEUKEMIA FROM AN EPIGENETIC PERSPECTIVE. CELLULAR IMMUNOTHERAPEUTIC APPROACHES SUCH AS CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) THUS FAR HAVE NOT MET THE HIGH EXPECTATIONS. THEREFORE IT IS ESSENTIAL TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS OF CLLINDUCED T-CELL DYSFUNCTION. EVEN THOUGH A SIGNIFICANT NUMBER OF STUDIES ARE AVAILABLE ON T-CELL FUNCTION AND DYSFUNCTION IN CLL PATIENTS, NONE EXAMINE DYSFUNCTION AT THE EPIGENOMIC LEVEL. IN NON-MALIGNANT T-CELL RESEARCH, EPIGENOMICS IS WIDELY EMPLOYED TO DEFINE THE DIFFERENTIATION PATHWAY INTO T-CELL EXHAUSTION. ADDITIONALLY, METABOLIC RESTRICTIONS IN THE TUMOR MICROENVIRONMENT THAT CAUSE T-CELL DYSFUNCTION ARE OFTEN MEDIATED BY EPIGENETIC CHANGES. WITH THIS REVIEW PAPER WE ARGUE THAT UNDERSTANDING THE EPIGENETIC (DYS)REGULATION IN T CELLS OF CLL PATIENTS SHOULD BE LEVELED TO THE KNOWLEDGE WE CURRENTLY HAVE OF THE NEOPLASTIC B CELLS THEMSELVES. THIS WILL PERMIT A COMPLETE UNDERSTANDING OF HOW THESE IMMUNE CELL INTERACTIONS REGULATE T- AND B-CELL FUNCTION. HERE WE RELATE THE CELLULAR AND PHENOTYPIC CHARACTERISTICS OF CLL-INDUCED T-CELL DYSFUNCTION TO EPIGENETIC STUDIES OF T-CELL REGULATION EMERGING FROM CHRONIC VIRAL INFECTION AND TUMOR MODELS. THIS PAPER PROPOSES A FRAMEWORK FOR FUTURE STUDIES INTO THE EPIGENETIC REGULATION OF CLL-INDUCED TCELL DYSFUNCTION, KNOWLEDGE THAT WILL HELP TO GUIDE IMPROVEMENTS IN THE UTILITY OF AUTOLOGOUS T-CELL BASED THERAPIES IN CLL. 2021 4 5059 38 PHENOTYPIC AND IMMUNOMETABOLIC ASPECTS ON STEM CELL MEMORY AND RESIDENT MEMORY CD8(+) T CELLS. THE IMMUNE SYSTEM, SMARTLY AND SURPRISINGLY, SAVES THE EXPOSURE OF A PARTICULAR PATHOGEN IN ITS MEMORY AND REACTS TO THE PATHOGEN VERY RAPIDLY, PREVENTING SERIOUS DISEASES. IMMUNOLOGISTS HAVE LONG BEEN FASCINATED BY UNDERSTANDING THE ABILITY TO RECALL AND RESPOND FASTER AND MORE VIGOROUSLY TO A PATHOGEN, KNOWN AS "MEMORY". T-CELL POPULATIONS CAN BE BETTER DESCRIBED BY USING MORE SOPHISTICATED TECHNIQUES TO DEFINE PHENOTYPE, TRANSCRIPTIONAL AND EPIGENETIC SIGNATURES AND METABOLIC PATHWAYS (SINGLE-CELL RESOLUTION), WHICH UNCOVERED THE HETEROGENEITY OF THE MEMORY T-COMPARTMENT. PHENOTYPE, EFFECTOR FUNCTIONS, MAINTENANCE, AND METABOLIC PATHWAYS HELP IDENTIFY THESE DIFFERENT SUBSETS. HERE, WE EXAMINE RECENT DEVELOPMENTS IN THE CHARACTERIZATION OF THE HETEROGENEITY OF THE MEMORY T CELL COMPARTMENT. IN PARTICULAR, WE FOCUS ON THE EMERGING ROLE OF CD8(+) T(RM) AND T(SCM) CELLS, PROVIDING EVIDENCE ON HOW THEIR IMMUNOMETABOLISM OR MODULATION CAN PLAY A VITAL ROLE IN THEIR GENERATION AND MAINTENANCE IN CHRONIC CONDITIONS SUCH AS INFECTIONS OR AUTOIMMUNE DISEASES. 2022 5 5359 39 REBOOTING REGULATORY T CELL AND DENDRITIC CELL FUNCTION IN IMMUNE-MEDIATED INFLAMMATORY DISEASES: BIOMARKER AND THERAPY DISCOVERY UNDER A MULTI-OMICS LENS. IMMUNE-MEDIATED INFLAMMATORY DISEASES (IMIDS) ARE A GROUP OF AUTOIMMUNE AND CHRONIC INFLAMMATORY DISORDERS WITH CONSTANTLY INCREASING PREVALENCE IN THE MODERN WORLD. THE VAST MAJORITY OF IMIDS DEVELOP AS A CONSEQUENCE OF COMPLEX MECHANISMS DEPENDENT ON GENETIC, EPIGENETIC, MOLECULAR, CELLULAR, AND ENVIRONMENTAL ELEMENTS, THAT LEAD TO DEFECTS IN IMMUNE REGULATORY GUARDIANS OF TOLERANCE, SUCH AS DENDRITIC (DCS) AND REGULATORY T (TREGS) CELLS. AS A RESULT OF THIS DYSFUNCTION, IMMUNE TOLERANCE COLLAPSES AND PATHOGENESIS EMERGES. DEEPER UNDERSTANDING OF SUCH DISEASE DRIVING MECHANISMS REMAINS A MAJOR CHALLENGE FOR THE PREVENTION OF INFLAMMATORY DISORDERS. THE RECENT RENAISSANCE IN HIGH THROUGHPUT TECHNOLOGIES HAS ENABLED THE INCREASE IN THE AMOUNT OF DATA COLLECTED THROUGH MULTIPLE OMICS LAYERS, WHILE ADDITIONALLY NARROWING THE RESOLUTION DOWN TO THE SINGLE CELL LEVEL. IN LIGHT OF THE AFOREMENTIONED, THIS REVIEW FOCUSES ON DCS AND TREGS AND DISCUSSES HOW MULTI-OMICS APPROACHES CAN BE HARNESSED TO CREATE ROBUST CELL-BASED IMID BIOMARKERS IN HOPE OF LEADING TO MORE EFFICIENT AND PATIENT-TAILORED THERAPEUTIC INTERVENTIONS. 2022 6 2461 39 EPIGENETIC THERAPY AS A PUTATIVE MOLECULAR TARGET TO MODULATE B CELL BIOLOGY AND BEHAVIOR IN THE CONTEXT OF IMMUNOLOGICAL DISORDERS. HISTONE DEACETYLASE- (HDAC-) DEPENDENT EPIGENETIC MECHANISMS HAVE BEEN WIDELY EXPLORED IN THE LAST DECADE IN DIFFERENT TYPES OF MALIGNANCIES IN PRECLINICAL STUDIES. THIS EFFORT LED TO THE DISCOVERY AND DEVELOPMENT OF A RANGE OF NEW HDAC INHIBITORS (IHDAC) WITH DIFFERENT CHEMICAL PROPERTIES AND SELECTIVE ABILITIES. IN FACT, HEMATOLOGICAL MALIGNANCIES WERE THE FIRST ONES TO HAVE NEW IHDACS APPROVED FOR CLINICAL USE, SUCH AS VORINOSTAT AND ROMIDEPSIN FOR CUTANEOUS T CELL LYMPHOMA AND PANOBINOSTAT FOR MULTIPLE MYELOMA. BESIDES THESE PROMISING ALREADY APPROVED IHDACS, WE HIGHLIGHT A RANGE OF STUDIES FOCUSING ON THE HDAC-DEPENDENT EPIGENETIC CONTROL OF B CELL DEVELOPMENT, BEHAVIOR, AND/OR FUNCTION. HERE, WE HIGHLIGHT 21 IHDACS WHICH HAVE BEEN STUDIED IN THE LITERATURE IN THE CONTEXT OF B CELL DEVELOPMENT AND/OR DYSFUNCTION MOSTLY FOCUSED ON B CELL LYMPHOMAGENESIS. REGARDLESS, WE HAVE IDENTIFIED 55 CLINICAL TRIALS USING 6 OUT OF 21 IHDACS TO APPROACH THEIR PUTATIVE ROLES ON B CELL MALIGNANCIES; NONE OF THEM FOCUSES ON PERITONEAL B CELL POPULATIONS. SINCE CELLS BELONGING TO THIS PECULIAR BODY COMPARTMENT, NAMED B1 CELLS, MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTOIMMUNE PATHOLOGIES, SUCH AS LUPUS, A BETTER UNDERSTANDING OF THE HDAC-DEPENDENT EPIGENETIC MECHANISMS THAT CONTROL ITS BIOLOGY AND BEHAVIOR MIGHT SHED LIGHT ON IHDAC USE TO MANAGE THESE IMMUNOLOGICAL DYSFUNCTIONS. IN THIS SENSE, IHDACS MIGHT EMERGE AS A PROMISING NEW APPROACH FOR TRANSLATIONAL STUDIES IN THIS FIELD. IN THIS REVIEW, WE DISCUSS A PUTATIVE ROLE OF IHDACS IN THE MODULATION OF PERITONEAL B CELL SUBPOPULATION'S BALANCE AS WELL AS THEIR ROLE AS THERAPEUTIC AGENTS IN THE CONTEXT OF CHRONIC DISEASES MEDIATED BY PERITONEAL B CELLS. 2020 7 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 8 5248 39 PROGRAMMED CELL DEATH 1-DIRECTED IMMUNOTHERAPY FOR ENHANCING T-CELL FUNCTION. T-CELL EXHAUSTION IS A UNIQUE STATE THAT APPEARS DURING MANY CHRONIC INFECTIONS AND CANCER AND IS CHARACTERIZED BY LOSS OF PROLIFERATIVE CAPACITY AND EFFECTOR FUNCTION. COMPLEX MECHANISMS ARE INVOLVED IN THIS T-CELL DYSFUNCTION BUT AN INHIBITORY RECEPTOR, PD-1, HAS BEEN IDENTIFIED AS A MAJOR REGULATOR OF T-CELL EXHAUSTION. BLOCKADE OF THE PD-1 PATHWAY CAN REINVIGORATE EXHAUSTED T CELLS, RESULTING IN BETTER CONTROL OF CHRONIC INFECTIONS AND CANCER. NOTABLY, RECENT CLINICAL STUDIES HAVE REVEALED THAT PD-1-DIRECTED IMMUNOTHERAPY IS HIGHLY EFFECTIVE IN CANCER PATIENTS, DEMONSTRATING THAT PD-1 IS A PROMISING THERAPEUTIC TARGET IN HUMANS. IN THIS REVIEW, WE SUMMARIZE OUR CURRENT UNDERSTANDING OF THE EPIGENETIC REGULATION OF PD-1 EXPRESSION IN T CELLS AND DISCUSS POTENTIAL COMBINATION THERAPY WITH PD-1 BLOCKADE TOWARD DEVELOPING MORE EFFECTIVE TREATMENT FOR CHRONIC INFECTIONS AND CANCER. 2013 9 4012 29 LOW-DENSITY GRANULOCYTES IN SYSTEMIC AUTOIMMUNITY AND AUTOINFLAMMATION. A BODY OF EVIDENCE HAS RE-ENERGIZED THE INTEREST ON THE ROLE NEUTROPHILS IN INFLAMMATORY AND AUTOIMMUNE CONDITIONS. FOR DECADES, NEUTROPHILS HAVE BEEN CONSIDERED A HOMOGENOUS POPULATION. NEVERTHELESS, ACCUMULATING EVIDENCE SUGGESTS THAT NEUTROPHILS ARE MORE VERSATILE AND HETEROGENEOUS THAN INITIALLY CONSIDERED. THE NOTION OF NEUTROPHIL HETEROGENEITY HAS BEEN SUPPORTED BY THE IDENTIFICATION OF LOW-DENSITY GRANULOCYTES (LDGS) IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND OTHER SYSTEMIC AUTOIMMUNE AND AUTOINFLAMMATORY CONDITIONS. TRANSCRIPTOMIC, EPIGENETIC, PROTEOMIC, AND FUNCTIONAL ANALYSES SUPPORT THAT LDGS ARE A DISTINCT SUBSET OF PROINFLAMMATORY NEUTROPHILS IMPLICATED IN THE PATHOGENESIS OF SLE AND OTHER AUTOIMMUNE DISEASES. IMPORTANTLY, IT REMAINS INCOMPLETELY CHARACTERIZED WHETHER LDGS DETECTED IN OTHER INFLAMMATORY/AUTOIMMUNE CONDITIONS DISPLAY THE SAME PHENOTYPE THAT THOSE PRESENT IN SLE. A SHARED FEATURE OF LDGS ACROSS DISEASES IS THEIR ASSOCIATION WITH VASCULAR DAMAGE, AN IMPORTANT CONTRIBUTOR TO MORBIDITY AND MORTALITY IN CHRONIC INFLAMMATORY CONDITIONS. ADDITIONALLY, THE LACK OF SPECIFIC MARKERS TO IDENTIFY LDGS IN CIRCULATION OR IN TISSUE, MAKES IT A CHALLENGE TO ELUCIDATE THEIR ROLE IN THE PATHOGENESIS OF INFLAMMATORY AND AUTOIMMUNE CONDITIONS. IN THIS REVIEW, WE AIM TO EXAMINE THE EVIDENCE ON THE BIOLOGY AND THE PUTATIVE PATHOGENIC ROLE OF LDGS IN SYSTEMIC AUTOIMMUNE DISEASES. 2023 10 6584 33 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 11 1763 36 EARLY TRANSCRIPTIONAL AND EPIGENETIC DIVERGENCE OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTION. DURING A MICROBIAL INFECTION, RESPONDING CD8+ T CELLS GIVE RISE TO EFFECTOR CELLS THAT PROVIDE ACUTE HOST DEFENSE AND MEMORY CELLS THAT PROVIDE SUSTAINED PROTECTION. AN ALTERNATIVE OUTCOME IS EXHAUSTION, A STATE OF T CELL DYSFUNCTION THAT OCCURS IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCER. ALTHOUGH IT IS EVIDENT THAT EXHAUSTED CD8+ T (TEX) CELLS ARE PHENOTYPICALLY AND MOLECULARLY DISTINCT FROM EFFECTOR AND MEMORY CD8+ T CELLS, THE FACTORS REGULATING THE EARLIEST EVENTS IN THE DIFFERENTIATION PROCESS OF TEX CELLS REMAIN INCOMPLETELY UNDERSTOOD. HERE, WE PERFORMED SINGLE-CELL RNA-SEQUENCING AND SINGLE-CELL ATAC-SEQUENCING OF CD8+ T CELLS RESPONDING TO LCMV-ARMSTRONG (LCMV-ARM) OR LCMV-CLONE 13 (LCMV-CL13), WHICH RESULT IN ACUTE OR CHRONIC INFECTIONS, RESPECTIVELY. COMPARED TO CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-ARM (DIV1ARM) CELLS, CD8+ T CELLS THAT HAD UNDERGONE THEIR FIRST DIVISION IN RESPONSE TO LCMV-CL13 (DIV1CL13) EXPRESSED HIGHER LEVELS OF GENES ENCODING TRANSCRIPTION FACTORS PREVIOUSLY ASSOCIATED WITH EXHAUSTION, ALONG WITH HIGHER LEVELS OF EZH2, THE CATALYTIC COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) COMPLEX, WHICH MEDIATES EPIGENETIC SILENCING. MODULATION OF EZH2 RESULTED IN ALTERED EXPRESSION OF EXHAUSTION-ASSOCIATED MOLECULES BY CD8+ T CELLS RESPONDING TO LCMV-CL13, THOUGH THE SPECIFIC CELLULAR AND INFECTIOUS CONTEXTS, RATHER THAN SIMPLY THE LEVEL OF EZH2 EXPRESSION, LIKELY DETERMINE THE EVENTUAL OUTCOME. TAKEN TOGETHER, THESE FINDINGS SUGGEST THAT THE DIFFERENTIATION PATHS OF CD8+ T CELLS RESPONDING TO ACUTE VERSUS CHRONIC INFECTIONS MAY DIVERGE EARLIER THAN PREVIOUSLY APPRECIATED. 2023 12 6496 50 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 13 6642 36 UNRAVELING THE PATHOGENESIS OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE OVERLAP: FOCUSING ON EPIGENETIC MECHANISMS. ASTHMA AND COPD OVERLAP (ACO) IS CHARACTERIZED BY PATIENTS PRESENTING WITH PERSISTENT AIRFLOW LIMITATION AND FEATURES OF BOTH ASTHMA AND COPD. IT IS ASSOCIATED WITH A HIGHER FREQUENCY AND SEVERITY OF EXACERBATIONS, A FASTER LUNG FUNCTION DECLINE, AND A HIGHER HEALTHCARE COST. SYSTEMIC INFLAMMATION IN COPD AND ASTHMA IS DRIVEN BY TYPE 1 T HELPER (TH1) AND TH2 IMMUNE RESPONSES, RESPECTIVELY, BOTH OF WHICH MAY CONTRIBUTE TO AIRWAY REMODELING IN ACO. ACO-RELATED BIOMARKERS CAN BE CLASSIFIED INTO FOUR CATEGORIES: NEUTROPHIL-MEDIATED INFLAMMATION, TH2 CELL RESPONSES, ARACHIDONIC ACID-EICOSANOIDS PATHWAY, AND METABOLITES. GENE-ENVIRONMENT INTERACTIONS ARE KEY CONTRIBUTORS TO THE COMPLEXITY OF ACO AND ARE REGULATED BY EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS. THUS, THIS REVIEW FOCUSES ON THE LINK BETWEEN EPIGENETICS AND ACO, AND OUTLINES THE FOLLOWING: (I) INHERITING EPIGENOTYPES WITHOUT CHANGE WITH ENVIRONMENTAL STIMULI, OR EPIGENETIC CHANGES IN RESPONSE TO LONG-TERM EXPOSURE TO INHALED PARTICLES PLUS INTERMITTENT EXPOSURE TO SPECIFIC ALLERGENS; (II) EPIGENETIC MARKERS DISTINGUISHING ACO FROM COPD AND ASTHMA; (III) POTENTIAL EPIGENETIC DRUGS THAT CAN REVERSE OXIDATIVE STRESS, GLUCOCORTICOID INSENSITIVITY, AND CELL INJURY. IMPROVED UNDERSTANDING OF THE EPIGENETIC REGULATIONS HOLDS GREAT VALUE TO GIVE DEEPER INSIGHT INTO THE MECHANISMS, AND CLARIFY THEIR IMPLICATIONS FOR BIOMEDICAL RESEARCH IN ACO. 2022 14 4558 36 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006 15 6334 33 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019 16 1260 41 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021 17 5901 28 T-CELL HETEROGENEITY, PROGENITOR-PROGENY RELATIONSHIPS, AND FUNCTION DURING LATENT AND CHRONIC VIRAL INFECTIONS. UPON RESOLUTION OF AN ACUTE VIRAL INFECTION, DURING LATENT-REACTIVATING INFECTION AND DURING CHRONIC ACTIVE INFECTIONS VIRUS-SPECIFIC T-CELLS DIFFERENTIATE INTO DISTINCT SUBSETS THAT DIFFER IN PHENOTYPE, LONGEVITY, TRANSCRIPTIONAL, METABOLIC, AND EPIGENETIC PROFILES, AND EFFECTOR FUNCTIONS. WITH RECENT ADVANCES IN SINGLE-CELL PROFILING, THIS SUBSTANTIAL HETEROGENEITY HAS BECOME APPARENT AND NEW SUBSETS OF VIRUS-SPECIFIC T CELLS, EITHER OF STABLE OR TRANSITORY NATURE, ARE BEING IDENTIFIED. A UNIFYING PRINCIPLE OF T CELLS EMERGING IN THESE DIFFERENT CONDITIONS IS THEIR PRECURSOR-PROGENY RELATIONSHIP. FOR ACUTE AND RESOLVED VIRAL INFECTIONS, THIS RELATIONSHIP BECOMES APPARENT DURING RE-CHALLENGE, WHEREAS A CONSTANT DIFFERENTIATION OF PROGENITOR T CELLS INTO MORE DIFFERENTIATED CELLS OCCURS DURING LATENT-REACTIVATING AND ACTIVE CHRONIC VIRAL INFECTIONS. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS CURRENT KNOWLEDGE ABOUT T-CELL HETEROGENEITY AND PROGENITOR-PROGENY RELATIONSHIPS IN THE SETTING OF PERSISTENT VIRAL INFECTIONS. 2023 18 2568 38 EPIGENETICS OF ALCOHOL-RELATED LIVER DISEASES. ALCOHOL-RELATED LIVER DISEASE (ARLD) IS A PRIMARY CAUSE OF CHRONIC LIVER DISEASE IN THE UNITED STATES. DESPITE ADVANCES IN THE DIAGNOSIS AND MANAGEMENT OF ARLD, IT REMAINS A MAJOR PUBLIC HEALTH PROBLEM ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY, EMPHASISING THE NEED TO ADOPT NOVEL APPROACHES TO THE STUDY OF ARLD AND ITS COMPLICATIONS. EPIGENETIC CHANGES ARE INCREASINGLY BEING RECOGNISED AS CONTRIBUTING TO THE PATHOGENESIS OF MULTIPLE DISEASE STATES. HARNESSING THE POWER OF INNOVATIVE TECHNOLOGIES FOR THE STUDY OF EPIGENETICS (E.G., NEXT-GENERATION SEQUENCING, DNA METHYLATION ASSAYS, HISTONE MODIFICATION PROFILING AND COMPUTATIONAL TECHNIQUES LIKE MACHINE LEARNING) HAS RESULTED IN A SEISMIC SHIFT IN OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ARLD. KNOWLEDGE OF THESE TECHNIQUES AND ADVANCES IS OF PARAMOUNT IMPORTANCE FOR THE PRACTICING HEPATOLOGIST AND RESEARCHERS ALIKE. ACCORDINGLY, IN THIS REVIEW ARTICLE WE WILL SUMMARISE THE CURRENT KNOWLEDGE ABOUT ALCOHOL-INDUCED EPIGENETIC ALTERATIONS IN THE CONTEXT OF ARLD, INCLUDING BUT NOT LIMITED TO, DNA HYPER/HYPO METHYLATION, HISTONE MODIFICATIONS, CHANGES IN NON-CODING RNA, 3D CHROMATIN ARCHITECTURE AND ENHANCER-PROMOTER INTERACTIONS. ADDITIONALLY, WE WILL DISCUSS THE STATE-OF-THE-ART TECHNIQUES USED IN THE STUDY OF ARLD (E.G. SINGLE-CELL SEQUENCING). WE WILL ALSO HIGHLIGHT THE EPIGENETIC REGULATION OF CHEMOKINES AND THEIR PROINFLAMMATORY ROLE IN THE CONTEXT OF ARLD. LASTLY, WE WILL EXAMINE THE CLINICAL APPLICATIONS OF EPIGENETICS IN THE DIAGNOSIS AND MANAGEMENT OF ARLD. 2022 19 6057 25 THE DARK SIDE OF REGULATORY T CELLS IN PSORIASIS. PSORIASIS IS A HEREDITARY DISEASE ELICITED BY CHRONIC ACTIVATION OF CUTANEOUS T CELLS. DELINEATING THE MECHANISTIC INTERPLAY OF THE CELL SUBSETS INVOLVED IS KEY TO DEVELOPING THE NEXT GENERATION OF EFFECTIVE TREATMENTS. IN THIS ISSUE, BOVENSCHEN ET AL. REPORT THAT REGULATORY T CELLS MAINTAIN A FINE BALANCE BETWEEN THE TRANSCRIPTION FACTORS FOXP3 AND RORGAMMAT. IN PATIENTS WITH PSORIASIS, TREGS READILY TURN INTO IL-17-EXPRESSING CELLS, THUS POTENTIALLY PERPETUATING THE INFLAMMATORY PROCESS THAT CHARACTERIZES THE DISEASE. RESULTS DEMONSTRATING THAT THE HISTONE/PROTEIN DEACETYLATION INHIBITOR TRICHOSTATIN A CAN BLOCK THIS CONVERSION SUGGEST THAT AN EPIGENETIC MODIFICATION MAY UNDERLIE REGULATORY T-CELL PLASTICITY. 2011 20 5476 39 RESTORING T CELL TOLERANCE, EXPLORING THE POTENTIAL OF HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS CHARACTERIZED BY A LOSS OF IMMUNE TOLERANCE. HERE, THE BALANCE BETWEEN THE ACTIVITY OF EFFECTOR T (TEFF) CELLS AND REGULATORY T (TREG) CELLS IS DISTURBED RESULTING IN CHRONIC INFLAMMATION IN THE JOINTS. PRESENTLY, THERAPEUTIC STRATEGIES ARE PREDOMINANTLY AIMED AT SUPPRESSING IMMUNE ACTIVATION AND PRO-INFLAMMATORY EFFECTOR MECHANISMS, IGNORING THE OPPORTUNITY TO ALSO PROMOTE TOLERANCE BY BOOSTING THE REGULATORY SIDE OF THE IMMUNE BALANCE. HISTONE DEACETYLASES (HDACS) CAN DEACETYLATE BOTH HISTONE AND NON-HISTONE PROTEINS AND HAVE BEEN DEMONSTRATED TO MODULATE EPIGENETIC REGULATION AS WELL AS CELLULAR SIGNALING IN VARIOUS CELL TYPES. IMPORTANTLY, HDACS ARE POTENT REGULATORS OF BOTH TEFF CELL AND TREG CELL FUNCTION AND CAN THUS BE REGARDED AS ATTRACTIVE THERAPEUTIC TARGETS IN CHRONIC INFLAMMATORY ARTHRITIS. HDAC INHIBITORS (HDACI) HAVE PROVEN THERAPEUTIC POTENTIAL IN THE CANCER FIELD, AND ARE PRESENTLY BEING EXPLORED FOR THEIR POTENTIAL IN THE TREATMENT OF AUTOIMMUNE DISEASES. SPECIFIC HDACI HAVE ALREADY BEEN DEMONSTRATED TO REDUCE THE SECRETION OF PRO-INFLAMMATORY CYTOKINES BY TEFF CELLS, AND PROMOTE TREG NUMBERS AND SUPPRESSIVE CAPACITY IN VITRO AND IN VIVO. IN THIS REVIEW, WE OUTLINE THE ROLE OF THE DIFFERENT CLASSES OF HDACS IN BOTH TEFF CELL AND TREG CELL FUNCTION. FURTHERMORE, WE WILL REVIEW THE EFFECT OF DIFFERENT HDACI ON T CELL TOLERANCE AND EXPLORE THEIR POTENTIAL AS A THERAPEUTIC STRATEGY FOR THE TREATMENT OF OLIGOARTICULAR AND POLYARTICULAR JIA. 2019