1 2552 117 EPIGENETICS IN PRIMARY SJOGREN'S SYNDROME. PRIMARY SJOGREN'S SYNDROME (SJS) IS A CHRONIC AND SYSTEMIC AUTOIMMUNE EPITHELITIS WITH PREDOMINANT FEMALE INCIDENCE, WHICH IS CHARACTERIZED BY EXOCRINE GLAND DYSFUNCTION. INCOMPLETELY UNDERSTOOD, THE ETIOLOGY OF SJS IS MULTI-FACTORIAL AND EVIDENCE IS GROWING TO CONSIDER THAT EPIGENETIC FACTORS ARE PLAYING A CRUCIAL ROLE IN ITS DEVELOPMENT. INDEPENDENT FROM DNA SEQUENCE MUTATIONS, EPIGENETICS IS DESCRIBED AS INHERITABLE AND REVERSIBLE PROCESSES THAT MODIFY GENE EXPRESSION. EPIGENETIC MODIFICATIONS REPORTED IN MINOR SALIVARY GLAND AND LYMPHOCYTES FROM SJS PATIENTS ARE RELATED TO (I) AN ABNORMAL DNA METHYLATION PROCESS INDUCING IN TURN DEFECTIVE CONTROL OF NORMALLY REPRESSED GENES INVOLVING SUCH MATTERS AS AUTOANTIGENS, RETROTRANSPOSONS, AND THE X CHROMOSOME IN WOMEN; (II) ALTERED NUCLEOSOME POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION; AND (III) ALTERED CONTROL OF MICRORNA. RESULTS FROM EPIGENOME-WIDE ASSOCIATION STUDIES HAVE FURTHER REVEALED THE IMPORTANCE OF THE INTERFERON PATHWAY IN DISEASE PROGRESSION, THE CALCIUM SIGNALING PATHWAY FOR CONTROLLING FLUID SECRETIONS, AND A CELL-SPECIFIC CROSS TALK WITH RISK FACTORS ASSOCIATED WITH SJS. IMPORTANTLY, EPIGENETIC MODIFICATIONS ARE REVERSIBLE THUS OPENING OPPORTUNITIES FOR THERAPEUTIC PROCEDURES IN THIS CURRENTLY INCURABLE DISEASE. 2020 2 4457 37 MOLECULAR MECHANISMS MEDIATED BY HUMAN ENDOGENOUS RETROVIRUSES (HERVS) IN AUTOIMMUNITY. EIGHT PER CENT OF THE HUMAN GENOME IS DERIVED FROM THE INTEGRATION OF RETROVIRAL SEQUENCES THAT WERE INCORPORATED IN OUR DNA MORE THAN 25 MILLION YEARS AGO. ALTHOUGH SOME OF THESE ELEMENTS SHOW MUTATIONS AND DELETIONS, SOME HERVS ARE TRANSCRIPTIONALLY ACTIVE AND PRODUCE FUNCTIONAL PROTEINS. DIFFERENT MECHANISMS HAVE BEEN DESCRIBED WHICH LINK HERVS TO SOME CHRONIC DISEASES SUCH AS SEVERAL CANCERS, NERVOUS SYSTEM DISEASES AND AUTOIMMUNE RHEUMATIC AND CONNECTIVE TISSUE DISEASES. THEY COULD CAUSE DISEASE BECAUSE OF THEIR CAPACITY FOR BEING MOVED AND INSERTED NEXT TO CERTAIN GENES WHOSE EXPRESSION WOULD BE CONSEQUENTIALLY ALTERED. ANOTHER WAY IN WHICH DISEASE COULD POTENTIALLY ARISE IS WHEN HERV-ENCODED PROTEINS ARE EXPRESSED. THESE PROTEINS WOULD BE CONSIDERED AS [FOREIGN] AND THEY COULD TRIGGER B-CELLS TO PRODUCE ANTIBODIES AGAINST THEM, WHICH, IN TURN, MIGHT CROSS-REACT WITH OTHER PROTEINS OF OUR BODIES. THIS MECHANISM COULD GIVE RISE TO AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS (RA), LUPUS ERYTHEMATOSUS, SJOGREN'S SYNDROME (SJS), MIXED CONNECTIVE TISSUE DISEASES AND INFLAMMATORY NEUROLOGICAL DISEASE. FURTHERMORE, IT SHOULD BE POINTED OUT THAT HERV-PROTEINS MAY ACT AS SUPERANTIGENS. INTERESTINGLY, SOME ENVIRONMENTAL AGENTS SEEM TO INDUCE THE EXPRESSION OF HERVS. THUS, ULTRAVIOLET LIGHT AND SEVERAL CHEMICAL AGENTS COULD REACTIVATE SUCH SEQUENCES BY ALTERING THEIR STRUCTURE WITHOUT MODIFYING THEIR NUCLEOTIDE COMPOSITION WHEN THE METHYLATION PATTERN IS CHANGED. THEREFORE, THE EPIGENETIC CHANGES OBSERVED IN PATHOLOGICAL CONDITIONS SUCH AS SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) OR CANCER COULD BE TRANSLATED INTO AN EFFECT ON THE ACTIVATION OF SOME OF THE RETROELEMENTS PRESENT IN OUR GENOME WHICH ULTIMATELY COULD HAVE A DIRECT OR INDIRECT ROLE ON THE INITIATION AND CLINICAL EVOLUTION OF CERTAIN CHRONIC DISEASES. 2009 3 6262 42 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 4 4030 18 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 5 1985 41 EPIGENETIC ALTERATIONS IN PRIMARY SJOGREN'S SYNDROME - AN OVERVIEW. PRIMARY SJOGREN'S SYNDROME (PSS) IS A CHRONIC AUTOIMMUNE RHEUMATIC DISEASE CHARACTERIZED BY INFLAMMATION OF EXOCRINE GLANDS, MAINLY SALIVARY AND LACRIMAL GLANDS. IN ADDITION, PSS MAY AFFECT MULTIPLE OTHER ORGANS RESULTING IN SYSTEMIC MANIFESTATIONS. ALTHOUGH THE PRECISE ETIOLOGY OF PSS REMAINS ELUSIVE, PSS IS CONSIDERED TO BE A MULTI-FACTORIAL DISEASE, WHERE UNDERLYING GENETIC PREDISPOSITION, ENVIRONMENTAL FACTORS AND EPIGENETIC MECHANISMS CONTRIBUTE TO DISEASE DEVELOPMENT. EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS, MAY CONSTITUTE A DYNAMIC LINK BETWEEN GENOME, ENVIRONMENT AND PHENOTYPIC MANIFESTATION BY THEIR MODULATING EFFECTS ON GENE EXPRESSION. A GROWING BODY OF STUDIES REPORTING ALTERED EPIGENETIC LANDSCAPES IN PSS SUGGESTS THAT EPIGENETIC MECHANISMS PLAY A ROLE IN THE PATHOGENESIS OF PSS, AND THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS SUGGESTS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC DYSREGULATION IN PSS. THIS ARTICLE REVIEWS OUR CURRENT UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSS AND DISCUSSES IMPLICATIONS FOR NOVEL DIAGNOSTIC AND THERAPEUTIC APPROACHES. 2018 6 3209 23 HEALTH DISPARITIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC MULTISYSTEM AUTOIMMUNE DISEASE CHARACTERIZED BY AUTOANTIBODY PRODUCTION AND DIVERSE CLINICAL MANIFESTATIONS. THE MANY COMPLEX, OVERLAPPING, AND CLOSELY ASSOCIATED FACTORS THAT INFLUENCE SLE SUSCEPTIBILITY AND OUTCOMES INCLUDE ETHNIC DISPARITIES, LOW ADHERENCE TO MEDICATIONS, AND POVERTY, AND GEOGRAPHY. EPIGENETIC MECHANISMS MAY PROVIDE THE LINK BETWEEN THESE ENVIRONMENTAL EXPOSURES AND BEHAVIORS AND THE DISPROPORTIONATE BURDEN OF SLE SEEN IN ETHNIC MINORITIES. ATTENTION TO THESE MODIFIABLE SOCIAL DETERMINANTS OF HEALTH WOULD NOT ONLY IMPROVE OUTCOMES FOR VULNERABLE PATIENTS WITH SLE BUT LIKELY REDUCE SUSCEPTIBILITY TO SLE AS WELL THROUGH EPIGENETIC CHANGES. 2020 7 2257 24 EPIGENETIC PERSPECTIVES IN SYSTEMIC LUPUS ERYTHEMATOSUS: PATHOGENESIS, BIOMARKERS, AND THERAPEUTIC POTENTIALS. SYSTEM LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRODUCTION OF AUTOANTIBODIES THAT CAUSE WIDESPREAD TISSUE DAMAGE. THE UNDERLYING ETIOLOGY REMAINS LARGELY UNKNOWN. ABERRANT EPIGENETICS PLAYS ESSENTIAL ROLES IN THE PATHOGENESIS OF SLE. THIS REVIEW EXPLORES THE LINKS BETWEEN DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNAS IN SLE AND HIGHLIGHTS HOW THESE FACTORS MAY INTERACT IN SLE PATHOGENESIS. WE ALSO DISCUSS HOW FURTHERING OUR KNOWLEDGE OF EPIGENETICS IN LUPUS PROVIDES HOPE FOR FINDING NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS AND NOVEL THERAPEUTIC TARGETS AND STRATEGIES. 2010 8 2731 24 EXPLORING THE COMPLEX RELATIONSHIP BETWEEN MICROBIOTA AND SYSTEMIC LUPUS ERYTHEMATOSUS. PURPOSE OF REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY VARIOUS AUTOANTIBODIES AND MULTI-ORGAN. MICROBIOTA DYSBIOSIS IN THE GUT, SKIN, ORAL, AND OTHER SURFACES HAS A SIGNIFICANT IMPACT ON SLE DEVELOPMENT. THIS ARTICLE SUMMARIZES RELEVANT RESEARCH AND PROVIDES NEW MICROBIOME-RELATED STRATEGIES FOR EXPLORING THE MECHANISMS AND TREATING PATIENTS WITH SLE. RECENT FINDINGS: SLE PATIENTS HAVE DISRUPTIONS IN MULTIPLE MICROBIOMES, WITH THE GUT MICROBIOTA (BACTERIA, VIRUSES, AND FUNGI) AND THEIR METABOLITES BEING THE MOST THOROUGHLY RESEARCHED. THIS DYSBIOSIS CAN PROMOTE SLE PROGRESSION THROUGH MECHANISMS SUCH AS THE LEAKY GUT, MOLECULAR MIMICRY, AND EPIGENETIC REGULATION. NOTWITHSTANDING STUDY CONSTRAINTS ON THE RELATIONSHIP BETWEEN MICROBIOTA AND SLE, SPECIFIC INTERVENTIONS TARGETING THE GUT MICROBIOTA, SUCH AS PROBIOTICS, DIETARY MANAGEMENT, AND FECAL MICROBIOTA TRANSPLANTATION, HAVE EMERGED AS PROMISING SLE THERAPEUTICS. 2023 9 6050 45 THE CONTRIBUTION OF EPIGENETICS IN SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS) IS A CHRONIC AUTOIMMUNE EPITHELITIS THAT COMBINES EXOCRINE GLAND DYSFUNCTIONS AND LYMPHOCYTIC INFILTRATIONS. WHILE THE PATHOGENESIS OF SS REMAINS UNCLEAR, ITS ETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC PREDISPOSITIONS, ENVIRONMENTAL FACTORS, AND EPIGENETIC FACTORS. RECENTLY, INTEREST HAS GROWN IN THE INVOLVEMENT OF EPIGENETICS IN AUTOIMMUNE DISEASES. EPIGENETICS IS DEFINED AS CHANGES IN GENE EXPRESSION, THAT ARE INHERITABLE AND THAT DO NOT ENTAIL CHANGES IN THE DNA SEQUENCE. IN SS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION THAT PREDOMINATES IN EPITHELIAL CELLS, AN ABNORMAL EXPRESSION OF MICRORNAS, AND ABNORMAL CHROMATIN POSITIONING-ASSOCIATED WITH AUTOANTIBODY PRODUCTION. LAST BUT NOT LEAST, EPIGENETIC MODIFICATIONS ARE REVERSIBLE AS OBSERVED IN MINOR SALIVARY GLANDS FROM SS PATIENTS AFTER B CELL DEPLETION USING RITUXIMAB. THUS EPIGENETIC FINDINGS IN SS OPEN NEW PERSPECTIVES FOR THERAPEUTIC APPROACHES AS WELL AS THE POSSIBLE IDENTIFICATION OF NEW BIOMARKERS. 2014 10 2192 27 EPIGENETIC METHODS AND TWIN STUDIES. GENOMIC PREDISPOSITION FAILS TO FULLY EXPLAIN THE ONSET OF COMPLEX DISEASES, WHICH IS WELL ILLUSTRATED BY THE LARGELY INCOMPLETE CONCORDANCE AMONG MONOZYGOTIC TWINS. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CHROMATIN REMODELING, AND NON-CODING RNA, ARE THE LINK BETWEEN ENVIRONMENTAL STIMULI AND DISEASE ONSET ON A PERMISSIVE GENETIC BACKGROUND IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASES. AUTOIMMUNE DISEASES NOW INCLUDE ALMOST 100 CONDITIONS AND ARE ESTIMATED TO CUMULATIVELY AFFECT UP TO 5% OF THE WORLD POPULATION WITH A HEALTHCARE EXPENDITURE SUPERIOR TO CANCER WORLDWIDE. MANY ADVANCES IN MEDICINE HAVE BEEN MADE TO TREAT THESE CONDITIONS BUT THERE ARE STILL GAPS, AND AN INNOVATIVE AND EFFICIENT THERAPY IS NEEDED. SYSTEMIC AUTOIMMUNE DISEASES INCLUDE RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, SYSTEMIC SCLEROSIS, SJOGREN SYNDROME, POLYMYOSITIS, AND DERMATOMYOSITIS. MONOZYGOTIC TWINS DISCORDANT FOR ANY DISEASE OFFER AN IDEAL STUDY DESIGN AS THEY ARE MATCHED FOR MANY FACTORS, INCLUDING GENETIC VARIATION AND THIS IS A REAL ADVANTAGE FOR EPIGENETICS STUDY. WE WILL HEREIN DISCUSS THE AVAILABLE DATA IN THE EPIGENETIC DIFFERENCES LEADING TO DISEASE DISCORDANCE IN MZ TWINS FOR SYSTEMIC LUPUS ERYTHEMATOSUS, RHEUMATOID ARTHRITIS, AND SYSTEMIC SCLEROSIS. 2020 11 2515 44 EPIGENETICS AND SJOGREN'S SYNDROME. THERE IS GROWING EVIDENCE THAT EPIGENETICS, THE STUDY OF HERITABLE CHANGES IN GENE EXPRESSION THAT DO NOT INVOLVE MUTATIONS IN THE DNA ITSELF, MAY PLAY AN ESSENTIAL ROLE IN AUTOIMMUNE DISEASES (AID). IN SJOGREN'S SYNDROME (SS), A CHRONIC AID CHARACTERIZED BY AN EPITHELIS OF THE EXOCRINE GLANDS, EPIGENETIC STUDIES HAVE FOCUSED ON THREE MECHANISMS: DNA METHYLATION AND ITS CONSEQUENCES INCLUDING HUMAN ENDOGENOUS RETROVIRUS (HERV) EXPRESSION; MICRORNA EXPRESSION; AND PROTEIN POST-TRANSLATIONAL MODIFICATIONS ASSOCIATED WITH AUTOANTIBODY PRODUCTION. ALTHOUGH IN ITS INFANCY, COMPREHENSION OF THE EPIGENETIC (DYS)REGULATION IN SS MAY HELP US TO UNDERSTAND: WHY SS AFFECTS PREDOMINANTLY MIDDLE-AGED WOMEN; WHY GENETICALLY PREDISPOSED INDIVIDUALS DEVELOP SS BUT NOT OTHERS; WHY FLARE-UPS OCCUR; WHY TREATMENT RESPONSES DIFFER BETWEEN PATIENTS; AND WHY SOME PATIENTS DEVELOP LYMPHOMA. FROM THESE STUDIES WILL ARISE A BETTER COMPREHENSION OF THE PATHOPHYSIOLOGY OF SS AS WELL AS DEVELOPMENT OF NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS, AND NOVEL THERAPEUTICS FOR PREVENTION AND PERHAPS EARLY INTERVENTION. 2012 12 1033 34 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 13 2990 29 GENETIC FACTORS PREDISPOSING TO SYSTEMIC LUPUS ERYTHEMATOSUS AND LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY A LOSS OF TOLERANCE TO SELF-ANTIGENS AND THE PRODUCTION OF HIGH TITERS OF SERUM AUTOANTIBODIES. LUPUS NEPHRITIS CAN AFFECT UP TO 74% OF SLE PATIENTS, PARTICULARLY THOSE OF HISPANIC AND AFRICAN ANCESTRIES, AND REMAINS A MAJOR CAUSE OF MORBIDITY AND MORTALITY. A GENETIC ETIOLOGY IN SLE IS NOW WELL SUBSTANTIATED. THANKS TO EXTENSIVE COLLABORATIONS, EXTRAORDINARY PROGRESS HAS BEEN MADE IN THE PAST FEW YEARS AND THE NUMBER OF CONFIRMED GENES PREDISPOSING TO SLE HAS CATAPULTED TO APPROXIMATELY 30. STUDIES OF OTHER FORMS OF GENETIC VARIATION, SUCH AS COPY NUMBER VARIANTS AND EPIGENETIC ALTERATIONS, ARE EMERGING AND PROMISE TO REVOLUTIONIZE OUR KNOWLEDGE ABOUT DISEASE MECHANISMS. HOWEVER, TO DATE LITTLE PROGRESS HAS BEEN MADE ON THE IDENTIFICATION OF GENETIC FACTORS SPECIFIC TO LUPUS NEPHRITIS. ON THE NEAR HORIZON, TWO LARGE-SCALE EFFORTS, A COLLABORATIVE META-ANALYSIS OF LUPUS NEPHRITIS BASED ON ALL GENOME-WIDE ASSOCIATION DATA IN CAUCASIANS AND PARALLEL SCANS IN FOUR OTHER ETHNICITIES, ARE POISED TO MAKE FUNDAMENTAL DISCOVERIES IN THE GENETICS OF LUPUS NEPHRITIS. COLLECTIVELY, THESE FINDINGS WILL SHOW THAT A BROAD ARRAY OF PATHWAYS UNDERLINES THE GENETIC HETEROGENEITY OF SLE AND LUPUS NEPHRITIS, AND PROVIDE POTENTIAL AVENUES FOR THE DEVELOPMENT OF NOVEL THERAPIES. 2010 14 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 15 4411 28 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 16 2294 34 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 17 207 45 ACTIVATION OF THE TYPE I INTERFERON PATHWAY IN PRIMARY SJOGREN'S SYNDROME. SJOGREN'S SYNDROME (SS), A CHRONIC AUTOIMMUNE SYSTEMIC DISEASE AFFECTING MIDDLE AGED WOMEN, IS CHARACTERIZED BY LYMPHOCYTIC INFILTRATION OF THE SALIVARY AND LACHRYMAL GLANDS RESULTING IN DRY EYES AND DRY MOUTH. RECENT ADVANCES HAVE REVEALED A MAJOR ROLE FOR ACTIVATION OF THE TYPE I INTERFERON (IFN) PATHWAY IN THE PATHOGENESIS OF THE SYNDROME, AS EVIDENCED BY THE INCREASED CIRCULATING TYPE I IFN ACTIVITY AND AN IFN "SIGNATURE" IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND MINOR SALIVARY GLAND (MSG) BIOPSIES FROM THESE PATIENTS. POLYMORPHISMS IN GENES INVOLVED IN THE IFNALPHA PATHWAY, SUCH AS IRF5 AND STAT4, HAVE BEEN FOUND TO BE ASSOCIATED WITH DISEASE SUSCEPTIBILITY. WHILE THE INITIAL TRIGGERS OF THE INNATE IMMUNE RESPONSE IN SS REMAIN ELUSIVE, PRELIMINARY EVIDENCE SUPPORTS THE ROLE OF INAPPROPRIATELY EXPRESSED ENDOGENOUS LINE-1 (L1) RETROELEMENTS AS POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION IN SS, POSSIBLY THROUGH TOLL-LIKE RECEPTOR (TLR) DEPENDENT OR INDEPENDENT PATHWAYS. PROTEINS OF THE METHYLATION MACHINERY AND THE APOBEC FAMILY OF CYTIDINE DEAMINASES ARE COORDINATELY OVEREXPRESSED, SUGGESTING THAT THOSE PROTEINS MIGHT CONTRIBUTE TO REGULATION OF THE INAPPROPRIATELY EXPRESSED L1 ENDOGENOUS RETROELEMENTS IN SS. GIVEN THE APPARENT CENTRAL ROLE OF IFNALPHA IN THE PATHOGENESIS OF SS, BLOCKADE OF THIS CYTOKINE MAY BE A RATIONAL THERAPEUTIC APPROACH. IN THE CURRENT REVIEW WE SUMMARIZE THE CURRENT EVIDENCE REGARDING THE POTENTIAL TRIGGERS OF TYPE I IFN ACTIVATION AS WELL AS THE DATA SUPPORTING GENETIC AND EPIGENETIC REGULATION OF THE TYPE I IFN SYSTEM IN SS. 2010 18 3545 25 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 19 2988 20 GENETIC FACTORS AND SYSTEMIC SCLEROSIS. SYSTEMIC SCLEROSIS (SSC) IS A RARE CONNECTIVE TISSUE DISEASE OF UNKNOWN ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND FIBROSIS OF THE SKIN, VASCULAR ABNORMALITIES, AND VARIABLE INVOLVEMENT OF ORGANS INCLUDING KIDNEYS, GASTROINTESTINAL TRACT, HEART, AND LUNGS. SSC SHOWS A COMPLEX ETIOLOGY IN WHICH BOTH ENVIRONMENTAL AND GENETIC FACTORS SEEM TO INFLUENCE THE ONSET AND OUTCOME OF THE DISEASE. WE PROVIDE AN EXTENSIVE OVERVIEW OF THE GENETIC FACTORS AND EPIGENETIC MODIFICATIONS AND WHAT THEIR KNOWLEDGE HAS REVEALED IN TERMS OF ETIOPATHOGENESIS OF SSC. 2016 20 3021 40 GENETICS AND EPIGENETICS OF PRIMARY SJOGREN SYNDROME: IMPLICATIONS FOR FUTURE THERAPIES. IN PRIMARY SJOGREN SYNDROME (PSS), CHRONIC INFLAMMATION OF EXOCRINE GLANDS RESULTS IN TISSUE DESTRUCTION AND SICCA SYMPTOMS, PRIMARILY OF THE MOUTH AND EYES. FATIGUE, ARTHRALGIA AND MYALGIA ARE ALSO COMMON SYMPTOMS, WHEREAS EXTRAGLANDULAR MANIFESTATIONS THAT INVOLVE THE RESPIRATORY, NERVOUS AND VASCULAR SYSTEMS OCCUR IN A SUBSET OF PATIENTS. THE DISEASE PREDOMINANTLY AFFECTS WOMEN, WITH AN ESTIMATED FEMALE TO MALE RATIO OF 14 TO 1. THE AETIOLOGY OF PSS, HOWEVER, REMAINS INCOMPLETELY UNDERSTOOD, AND EFFECTIVE TREATMENT IS LACKING. LARGE-SCALE GENETIC AND EPIGENETIC INVESTIGATIONS HAVE REVEALED ASSOCIATIONS BETWEEN PSS AND GENES IN BOTH INNATE AND ADAPTIVE IMMUNE PATHWAYS. THE GENETIC VARIANTS MEDIATE CONTEXT-DEPENDENT EFFECTS, AND BOTH SEX AND ENVIRONMENTAL FACTORS CAN INFLUENCE THE OUTCOME. AS SUCH, GENETIC AND EPIGENETIC STUDIES CAN PROVIDE INSIGHT INTO THE DYSREGULATED MOLECULAR MECHANISMS, WHICH IN TURN MIGHT REVEAL NEW THERAPEUTIC POSSIBILITIES. THIS REVIEW DISCUSSES THE GENETIC AND EPIGENETIC FEATURES THAT HAVE BEEN ROBUSTLY CONNECTED WITH PSS, PUTTING THEM INTO THE CONTEXT OF CELLULAR FUNCTION, CARRIER SEX AND ENVIRONMENTAL CHALLENGES. IN ALL, THE OBSERVATIONS POINT TO SEVERAL NOVEL OPPORTUNITIES FOR EARLY DETECTION, TREATMENT DEVELOPMENT AND THE PATHWAY TOWARDS PERSONALIZED MEDICINE. 2023