1 6275 153 THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS: HARNESSING BIG DATA TO UNDERSTAND THE MOLECULAR BASIS OF LUPUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, SYSTEMIC AUTOIMMUNE DISEASE THAT CAUSES DAMAGE TO MULTIPLE ORGAN SYSTEMS. DESPITE DECADES OF RESEARCH AND AVAILABLE MURINE MODELS THAT CAPTURE SOME ASPECTS OF THE HUMAN DISEASE, NEW TREATMENTS FOR SLE LAG BEHIND OTHER AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS AND CROHN'S DISEASE. BIG DATA GENOMIC ASSAYS HAVE TRANSFORMED OUR UNDERSTANDING OF SLE BY PROVIDING IMPORTANT INSIGHTS INTO THE MOLECULAR HETEROGENEITY OF THIS MULTIGENIC DISEASE. GENE WIDE ASSOCIATION STUDIES HAVE DEMONSTRATED MORE THAN 100 RISK LOCI, SUPPORTING A MODEL OF MULTIPLE GENETIC HITS INCREASING SLE RISK IN A NON-LINEAR FASHION, AND PROVIDING EVIDENCE OF ANCESTRAL DIVERSITY IN SUSCEPTIBILITY LOCI. EPIGENETIC STUDIES TO DETERMINE THE ROLE OF METHYLATION, ACETYLATION AND NON-CODING RNAS HAVE PROVIDED NEW UNDERSTANDING OF THE MODULATION OF GENE EXPRESSION IN SLE PATIENTS AND IDENTIFIED NEW DRUG TARGETS AND BIOMARKERS FOR SLE. GENE EXPRESSION PROFILING HAS LED TO A GREATER UNDERSTANDING OF THE ROLE OF MYELOID CELLS IN THE PATHOGENESIS OF SLE, CONFIRMED ROLES FOR T AND B CELLS IN SLE, PROMOTED CLINICAL TRIALS BASED ON THE PROMINENT INTERFERON SIGNATURE FOUND IN SLE PATIENTS, AND IDENTIFIED CANDIDATE BIOMARKERS AND CELLULAR SIGNATURES TO FURTHER DRUG DEVELOPMENT AND DRUG REPURPOSING. GENE EXPRESSION STUDIES ARE ADVANCING OUR UNDERSTANDING OF THE UNDERLYING MOLECULAR HETEROGENEITY IN SLE AND PROVIDING HOPE THAT PATIENT STRATIFICATION WILL EXPEDITE NEW THERAPIES BASED ON PERSONAL MOLECULAR SIGNATURES. ALTHOUGH BIG DATA ANALYSES PRESENT UNIQUE INTERPRETATION CHALLENGES, BOTH COMPUTATIONALLY AND BIOLOGICALLY, ADVANCES IN MACHINE LEARNING APPLICATIONS MAY FACILITATE THE ABILITY TO PREDICT CHANGES IN SLE DISEASE ACTIVITY AND OPTIMIZE THERAPEUTIC STRATEGIES. 2020 2 2516 48 EPIGENETICS AND SYSTEMIC LUPUS ERYTHEMATOSUS: UNMET NEEDS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC RELAPSING-REMITTING AUTOIMMUNE DISEASE AFFECTING SEVERAL ORGANS. ALTHOUGH THE MANAGEMENT OF LUPUS PATIENTS HAS IMPROVED IN THE LAST YEARS, SEVERAL ASPECTS STILL REMAIN CHALLENGING. MORE SENSITIVE AND SPECIFIC BIOMARKERS FOR AN EARLY DIAGNOSIS AS WELL AS FOR MONITORING DISEASE ACTIVITY AND TISSUE DAMAGE ARE NEEDED. GENOME-WIDE ASSOCIATION AND GENE MAPPING STUDIES HAVE SUPPORTED THE GENETIC BACKGROUND FOR SLE SUSCEPTIBILITY. HOWEVER, THE RELATIVELY MODEST RISK ASSOCIATION AND THE STUDIES IN TWINS HAVE SUGGESTED A ROLE FOR ENVIRONMENTAL AND EPIGENETIC FACTORS, AS WELL AS GENETIC-EPIGENETIC INTERACTION. ACCORDINGLY, THERE IS EVIDENCE THAT DIFFERENCES IN DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNA PROFILING CAN BE FOUND IN LUPUS PATIENTS VERSUS NORMAL SUBJECTS. MOREOVER, IMPAIRED DNA METHYLATION ON THE INACTIVE X-CHROMOSOME WAS SUGGESTED TO EXPLAIN, AT LEAST IN PART, THE FEMALE PREVALENCE OF THE DISEASE. EPIGENETIC MARKERS MAY BE HELP IN FULFILLING THE UNMET NEEDS FOR SLE BY OFFERING NEW DIAGNOSTIC TOOLS, NEW BIOMARKERS FOR MONITORING DISEASE ACTIVITY, OR TO BETTER CHARACTERIZE PATIENTS WITH A SILENT CLINICAL DISEASE BUT WITH AN ACTIVE SEROLOGY. ANTI-DNA, ANTI-PHOSPHOLIPID, AND ANTI-RO/SSA AUTOANTIBODIES ARE THOUGHT TO BE PATHOGENIC FOR GLOMERULONEPHRITIS, RECURRENT THROMBOSIS AND MISCARRIAGES, AND NEONATAL LUPUS, RESPECTIVELY. HOWEVER, TISSUE DAMAGE OCCURS OCCASIONALLY OR, IN SOME PATIENTS, ONLY IN SPITE OF THE PERSISTENT PRESENCE OF THE ANTIBODIES. PRELIMINARY STUDIES SUGGEST THAT EPIGENETIC MECHANISMS MAY EXPLAIN WHY THE DAMAGE TAKES PLACE IN SOME PATIENTS ONLY OR AT A GIVEN TIME. 2016 3 398 34 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 4 6194 41 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 5 2990 38 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 6 1719 43 DYSREGULATED MICRORNAS IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS: A COMPREHENSIVE REVIEW. SYSTEMIC LUPUS ERYTHEMATOSUS IS A CHRONIC AUTOIMMUNE DISEASE OF WHICH CLINICAL PRESENTATION IS VASTLY HETEROGENEOUS, RANGING FROM MILD SKIN RASHES TO SEVERE RENAL DISEASES. TREATMENT GOAL OF THIS ILLNESS IS TO MINIMIZE DISEASE ACTIVITY AND PREVENT FURTHER ORGAN DAMAGE. IN RECENT YEARS, MUCH RESEARCH HAS BEEN DONE ON THE EPIGENETIC ASPECTS OF SLE PATHOGENESIS, FOR AMONG THE VARIOUS FACTORS KNOWN TO CONTRIBUTE TO THE PATHOGENIC PROCESS, EPIGENETIC FACTORS, ESPECIALLY MICRORNAS, BEAR THE MOST THERAPEUTIC POTENTIAL THAT CAN BE ALTERED UNLIKE CONGENITAL GENETIC FACTORS. THIS ARTICLE REVIEWS AND UPDATES WHAT HAS BEEN DISCOVERED SO FAR ABOUT THE PATHOGENESIS OF LUPUS, WHILE FOCUSING ON THE DYSREGULATION OF MICRORNAS IN LUPUS PATIENTS IN COMPARISON TO HEALTHY CONTROLS ALONG WITH THE POTENTIALLY PATHOGENIC ROLES OF THE MICRORNAS COMMONLY REPORTED TO BE EITHER UPREGULATED OR DOWNREGULATED. FURTHERMORE, THIS REVIEW INCLUDES MICRORNAS OF WHICH RESULTS ARE CONTROVERSIAL, SUGGESTING POSSIBLE EXPLANATIONS FOR SUCH DISCREPANCIES AND DIRECTIONS FOR FUTURE RESEARCH. MOREOVER, WE AIMED TO EMPHASIZE THE POINT THAT HAD BEEN OVERLOOKED SO FAR IN STUDIES REGARDING MICRORNA EXPRESSION LEVELS; THAT IS, WHICH SPECIMEN WAS USED TO ASSESS THE DYSREGULATION OF MICRORNAS. TO OUR SURPRISE, A VAST NUMBER OF STUDIES HAVE NOT CONSIDERED THIS FACTOR AND HAVE ANALYZED THE POTENTIAL ROLE OF MICRORNAS IN GENERAL. DESPITE EXTENSIVE INVESTIGATIONS DONE ON MICRORNA LEVELS, THEIR SIGNIFICANCE AND POTENTIAL ROLE REMAIN A MYSTERY, WHICH CALLS FOR FURTHER STUDIES ON THIS PARTICULAR SUBJECT IN REGARD OF WHICH SPECIMEN IS USED FOR ASSESSMENT. 2023 7 1463 40 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 8 6800 38 [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 9 549 27 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 10 3038 37 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 11 2257 32 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 12 3039 35 GENOME ENGINEERING FOR PERSONALIZED ARTHRITIS THERAPEUTICS. ARTHRITIS REPRESENTS A FAMILY OF COMPLEX JOINT PATHOLOGIES RESPONSIBLE FOR THE MAJORITY OF MUSCULOSKELETAL CONDITIONS. NEARLY ALL DISEASES WITHIN THIS FAMILY, INCLUDING OSTEOARTHRITIS, RHEUMATOID ARTHRITIS, AND JUVENILE IDIOPATHIC ARTHRITIS, ARE CHRONIC CONDITIONS WITH FEW OR NO DISEASE-MODIFYING THERAPEUTICS AVAILABLE. ADVANCES IN GENOME ENGINEERING TECHNOLOGY, MOST RECENTLY WITH CRISPR-CAS9, HAVE REVOLUTIONIZED OUR ABILITY TO INTERROGATE AND VALIDATE GENETIC AND EPIGENETIC ELEMENTS ASSOCIATED WITH CHRONIC DISEASES SUCH AS ARTHRITIS. THESE TECHNOLOGIES, TOGETHER WITH CELL REPROGRAMMING METHODS, INCLUDING THE USE OF INDUCED PLURIPOTENT STEM CELLS, PROVIDE A PLATFORM FOR HUMAN DISEASE MODELING. WE SUMMARIZE NEW EVIDENCE FROM GENOME-WIDE ASSOCIATION STUDIES AND GENOMICS THAT SUBSTANTIATES A GENETIC BASIS FOR ARTHRITIS PATHOGENESIS. WE ALSO REVIEW THE POTENTIAL CONTRIBUTIONS OF GENOME ENGINEERING IN THE DEVELOPMENT OF NEW ARTHRITIS THERAPEUTICS. 2017 13 4958 36 PATHOGENESIS OF HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS: A CELLULAR PERSPECTIVE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE AFFECTING MULTIPLE ORGANS. A COMPLEX INTERACTION OF GENETICS, ENVIRONMENT, AND HORMONES LEADS TO IMMUNE DYSREGULATION AND BREAKDOWN OF TOLERANCE TO SELF-ANTIGENS, RESULTING IN AUTOANTIBODY PRODUCTION, INFLAMMATION, AND DESTRUCTION OF END-ORGANS. EMERGING EVIDENCE ON THE ROLE OF THESE FACTORS HAS INCREASED OUR KNOWLEDGE OF THIS COMPLEX DISEASE, GUIDING THERAPEUTIC STRATEGIES AND IDENTIFYING PUTATIVE BIOMARKERS. RECENT FINDINGS INCLUDE THE CHARACTERIZATION OF GENETIC/EPIGENETIC FACTORS LINKED TO SLE, AS WELL AS CELLULAR EFFECTORS. NOVEL OBSERVATIONS HAVE PROVIDED AN IMPROVED UNDERSTANDING OF THE CONTRIBUTION OF TISSUE-SPECIFIC FACTORS AND ASSOCIATED DAMAGE, T AND B LYMPHOCYTES, AS WELL AS INNATE IMMUNE CELL SUBSETS AND THEIR CORRESPONDING ABNORMALITIES. THE INTRICATE WEB OF INVOLVED FACTORS AND PATHWAYS DICTATES THE ADOPTION OF TAILORED THERAPEUTIC APPROACHES TO CONQUER THIS DISEASE. 2017 14 6262 43 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 15 5886 43 SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC MULTISYSTEM AUTOIMMUNE DISEASE THAT IS HIGHLY HETEROGENEOUS IN ITS PRESENTATION. THIS CAN POSE SIGNIFICANT CHALLENGES FOR PHYSICIANS RESPONSIBLE FOR THE DIAGNOSIS AND TREATMENT OF SUCH PATIENTS. SLE ARISES FROM A COMBINATION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. PATHOLOGICALLY, THE DISEASE IS PRIMARILY DRIVEN BY LOSS OF IMMUNE TOLERANCE AND ABNORMAL B- AND T-CELL FUNCTION. MAJOR ORGAN INVOLVEMENT MAY LEAD TO SIGNIFICANT MORBIDITY AND MORTALITY. CLASSIFICATION CRITERIA FOR SLE HAVE BEEN DEVELOPED LARGELY FOR RESEARCH PURPOSES; HOWEVER, THESE ARE ALSO WIDELY USED IN CLINICAL PRACTICE. ANTINUCLEAR ANTIBODIES ARE THE HALLMARK SEROLOGICAL FEATURE, OCCURRING IN OVER 95% OF PATIENTS WITH SLE AT SOME POINT DURING THEIR DISEASE. THE MAINSTAY OF TREATMENT IS ANTIMALARIAL DRUGS SUCH AS HYDROXYCHLOROQUINE, COMBINED WITH CORTICOSTEROIDS AND CONVENTIONAL IMMUNOSUPPRESSIVE DRUGS. AN INCREASING UNDERSTANDING OF PATHOGENESIS HAS FACILITATED A MOVE TOWARDS THE DEVELOPMENT OF TARGETED BIOLOGIC THERAPIES, WITH THE INTRODUCTION OF RITUXIMAB AND BELIMUMAB INTO CLINICAL PRACTICE. 2017 16 5371 46 RECENT ADVANCES IN UNDERSTANDING THE GENETIC BASIS OF SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A POLYGENIC CHRONIC AUTOIMMUNE DISEASE LEADING TO MULTIPLE ORGAN DAMAGE. A LARGE HERITABILITY OF UP TO 66% IS ESTIMATED IN SLE, WITH ROUGHLY 180 REPORTED SUSCEPTIBILITY LOCI THAT HAVE BEEN IDENTIFIED MOSTLY BY GENOME-WIDE ASSOCIATION STUDIES (GWASS) AND ACCOUNT FOR APPROXIMATELY 30% OF GENETIC HERITABILITY. A VAST MAJORITY OF RISK VARIANTS RESIDE IN NON-CODING REGIONS, WHICH MAKES IT QUITE CHALLENGING TO INTERPRET THEIR FUNCTIONAL IMPLICATIONS IN THE SLE-AFFECTED IMMUNE SYSTEM, SUGGESTING THE IMPORTANCE OF UNDERSTANDING CELL TYPE-SPECIFIC EPIGENETIC REGULATION AROUND SLE GWAS VARIANTS. THE LATEST GENETIC STUDIES HAVE BEEN HIGHLY FRUITFUL AS SEVERAL DOZENS OF SLE LOCI WERE NEWLY DISCOVERED IN THE LAST FEW YEARS AND MANY LOCI HAVE COME TO BE UNDERSTOOD IN SYSTEMIC APPROACHES INTEGRATING GWAS SIGNALS WITH OTHER BIOLOGICAL RESOURCES. IN THIS REVIEW, WE SUMMARIZE SLE-ASSOCIATED GENETIC VARIANTS IN BOTH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) AND NON-MHC LOCI, EXAMINING POLYGENETIC RISK SCORES FOR SLE AND THEIR ASSOCIATIONS WITH CLINICAL FEATURES. FINALLY, VARIANT-DRIVEN PATHOGENETIC FUNCTIONS UNDERLYING GENETIC ASSOCIATIONS ARE DESCRIBED, COUPLED WITH DISCUSSION ABOUT CHALLENGES AND FUTURE DIRECTIONS IN GENETIC STUDIES ON SLE. 2022 17 2017 44 EPIGENETIC BIOMARKERS IN RHEUMATOLOGY - THE FUTURE? EPIGENETIC CHANGES ARE STABLE MODIFICATIONS OF DNA OR HISTONES THAT PROFOUNDLY ALTER GENE EXPRESSION. THEY CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES AND CAN THEN BE PASSED ON TO DAUGHTER CELLS OR VIA THE GERM LINE TO OFFSPRING. A VARIETY OF CHANGES IN EPIGENETIC MARKS AND IN THE EXPRESSION OF NONCODING RNA HAS BEEN FOUND IN CANCER AS WELL AS IN CHRONIC INFLAMMATORY DISEASES. INTERESTINGLY, IN BOTH DISEASES SIMILAR MECHANISMS AND PATHWAYS ARE AFFECTED ALBEIT OFTEN TO A DIFFERENT EXTENT. DNA METHYLATION IS OFTEN LOST IN REPETITIVE SEQUENCES, WHILE IN PROMOTER REGIONS HYPO- AS WELL AS HYPERMETHYLATION IS FOUND. CHANGES IN MICRORNA LEVELS TYPICALLY AFFECT MICRORNAS THAT ARE CHANGED BY AN INFLAMMATORY ENVIRONMENT, BUT DISEASE SPECIFIC CHANGES HAVE ALSO BEEN FOUND IN THE BLOOD AND VARIOUS CELL TYPES OF PATIENTS WITH RHEUMATOID ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER RHEUMATIC DISEASES. THEREFORE, CHANGES IN THE EXPRESSION OF MICRORNA IN PARTICULAR, BUT ALSO DEMETHYLATED GENE LOCI, HAVE BEEN PROPOSED AS POTENTIAL BIOMARKERS IN CHRONIC INFLAMMATORY DISEASES AND IN CANCER. POTENTIALLY, THESE CHANGES COULD BE USED FOR EARLY DIAGNOSIS AND ALSO TO PREDICT TREATMENT RESPONSE. UNFORTUNATELY MOST STUDIES IN RHEUMATOLOGY UP TO NOW WERE NOT DESIGNED TO VALIDATE THESE EPIGENETIC CHANGES AS BIOMARKERS. SINCE THE CANCER FIELD IS MUCH MORE ADVANCED IN THE USAGE OF BIOMARKERS FOR DISEASE SUBCLASSIFICATIONS AND SUBSEQUENT THERAPEUTIC DECISIONS, IT IS WORTHWHILE TO TAKE A CLOSER LOOK AT THE BIOMARKERS, METHODS AND PROCEDURES USED IN ONCOLOGY AND TO SEE WHICH OF THESE COULD ALSO BE APPLIED TO PREDICTING DISEASE SEVERITY AND THERAPEUTIC RESPONSE IN RHEUMATIC DISEASES. THIS ARTICLE WILL HIGHLIGHT COMMON EPIGENETIC PATHWAYS ACTIVATED IN CANCER AND VARIOUS RHEUMATIC DISEASES AND SUMMARISE EPIGENETIC CHANGES THAT HAVE THE POTENTIAL TO BECOME BIOMARKERS IN RHEUMATIC DISEASES. 2016 18 2404 42 EPIGENETIC RESEARCH IN MULTIPLE SCLEROSIS: PROGRESS, CHALLENGES, AND OPPORTUNITIES. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. MS LIKELY RESULTS FROM A COMPLEX INTERPLAY BETWEEN PREDISPOSING CAUSAL GENE VARIANTS (THE STRONGEST INFLUENCE COMING FROM HLA CLASS II LOCUS) AND ENVIRONMENTAL RISK FACTORS SUCH AS SMOKING, INFECTIOUS MONONUCLEOSIS, AND LACK OF SUN EXPOSURE/VITAMIN D. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS UNDERLYING MS DEVELOPMENT AND PROGRESSION. MOREOVER, THE CLINICAL HETEROGENEITY AND VARIABLE RESPONSE TO TREATMENT REPRESENT ADDITIONAL CHALLENGES TO A COMPREHENSIVE UNDERSTANDING AND EFFICIENT TREATMENT OF DISEASE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INTEGRATE INFLUENCES FROM THE GENES AND THE ENVIRONMENT TO REGULATE GENE EXPRESSION ACCORDINGLY. STUDYING EPIGENETIC MODIFICATIONS, WHICH ARE STABLE AND REVERSIBLE, MAY PROVIDE AN ALTERNATIVE APPROACH TO BETTER UNDERSTAND AND MANAGE DISEASE. WE HERE AIM TO REVIEW FINDINGS FROM EPIGENETIC STUDIES IN MS AND FURTHER DISCUSS THE CHALLENGES AND CLINICAL OPPORTUNITIES ARISING FROM EPIGENETIC RESEARCH, MANY OF WHICH APPLY TO OTHER DISEASES WITH SIMILAR COMPLEX ETIOLOGY. A GROWING BODY OF EVIDENCE SUPPORTS A ROLE OF EPIGENETIC PROCESSES IN THE MECHANISMS UNDERLYING IMMUNE PATHOGENESIS AND NERVOUS SYSTEM DYSFUNCTION IN MS. HOWEVER, DISPARITIES BETWEEN STUDIES SHED LIGHT ON THE NEED TO CONSIDER POSSIBLE CONFOUNDERS AND METHODOLOGICAL LIMITATIONS FOR A BETTER INTERPRETATION OF THE DATA. NEVERTHELESS, TRANSLATIONAL USE OF EPIGENETICS MIGHT OFFER NEW OPPORTUNITIES IN EPIGENETIC-BASED DIAGNOSTICS AND THERAPEUTIC TOOLS FOR A PERSONALIZED CARE OF MS PATIENTS. 2017 19 2529 29 EPIGENETICS CHANGES ASSOCIATED TO ENVIRONMENTAL TRIGGERS IN AUTOIMMUNITY. AUTOIMMUNE DISEASES (AIDS) ARE CHRONIC CONDITIONS INITIATED BY THE LOSS OF IMMUNOLOGICAL TOLERANCE TO SELF-ANTIGENS AND REPRESENT A HETEROGENEOUS GROUP OF DISORDERS THAT AFFECT SPECIFIC TARGET ORGANS OR MULTIPLE ORGANS IN DIFFERENT SYSTEMS. WHILE THE PATHOGENESIS OF AID REMAINS UNCLEAR, ITS AETIOLOGY IS MULTIFUNCTIONAL AND INCLUDES A COMBINATION OF GENETIC, EPIGENETIC, IMMUNOLOGICAL AND ENVIRONMENTAL FACTORS. IN AIDS, SEVERAL EPIGENETIC MECHANISMS ARE DEFECTIVE INCLUDING DNA DEMETHYLATION, ABNORMAL CHROMATIN POSITIONING ASSOCIATED WITH AUTOANTIBODY PRODUCTION AND ABNORMALITIES IN THE EXPRESSION OF RNA INTERFERENCE (RNAI). IT IS KNOWN THAT ENVIRONMENTAL FACTORS MAY INTERFERE WITH DNA METHYLATION AND HISTONE MODIFICATIONS, HOWEVER, LITTLE IS KNOWN ABOUT EPIGENETIC CHANGES DERIVED OF REGULATION OF RNAI. AN APPROACH TO THE KNOWN ENVIRONMENTAL FACTORS AND THE MECHANISMS THAT ALTER THE EPIGENETIC REGULATION IN AIDS (WITH EMPHASIS IN SYSTEMIC LUPUS ERYTHEMATOSUS, THE PROTOTYPE OF SYSTEMIC AID) ARE SHOWED IN THIS REVIEW. 2016 20 2192 34 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