1 3209 74 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 2 2990 28 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 3 6194 29 THE IMPACT OF PROTEIN ACETYLATION/DEACETYLATION ON SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE IN WHICH THE BODY'S IMMUNE SYSTEM MISTAKENLY ATTACKS HEALTHY CELLS. ALTHOUGH THE EXACT CAUSE OF SLE HAS NOT BEEN IDENTIFIED, IT IS CLEAR THAT BOTH GENETICS AND ENVIRONMENTAL FACTORS TRIGGER THE DISEASE. IDENTICAL TWINS HAVE A 24% CHANCE OF GETTING LUPUS DISEASE IF THE OTHER ONE IS AFFECTED. INTERNAL FACTORS SUCH AS FEMALE GENDER AND SEX HORMONES, THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) LOCUS AND OTHER GENETIC POLYMORPHISMS HAVE BEEN SHOWN TO AFFECT SLE, AS WELL AS EXTERNAL, ENVIRONMENTAL INFLUENCES SUCH AS SUNLIGHT EXPOSURE, SMOKING, VITAMIN D DEFICIENCY, AND CERTAIN INFECTIONS. SEVERAL STUDIES HAVE REPORTED AND PROPOSED MULTIPLE ASSOCIATIONS BETWEEN THE ALTERATION OF THE EPIGENOME AND THE PATHOGENESIS OF AUTOIMMUNE DISEASE. EPIGENETIC FACTORS CONTRIBUTING TO SLE INCLUDE MICRORNAS, DNA METHYLATION STATUS, AND THE ACETYLATION/DEACETYLATION OF HISTONE PROTEINS. ADDITIONALLY, THE ACETYLATION OF NON-HISTONE PROTEINS CAN ALSO INFLUENCE CELLULAR FUNCTION. A BETTER UNDERSTANDING OF NON-GENOMIC FACTORS THAT REGULATE SLE WILL PROVIDE INSIGHT INTO THE MECHANISMS THAT INITIATE AND FACILITATE DISEASE AND ALSO CONTRIBUTE TO THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT CAN SPECIFICALLY TARGET PATHOGENIC MOLECULAR PATHWAYS. 2018 4 2516 33 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 5 6275 26 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 6 1463 28 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 7 2192 29 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 8 4411 26 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 9 398 27 AN UPDATE ON GENETIC SUSCEPTIBILITY IN LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY MULTIPLE SYSTEM INVOLVEMENT AND POSITIVE SERUM AUTOANTIBODIES. LUPUS NEPHRITIS (LN) IS THE MOST COMMON AND SERIOUS COMPLICATION OF SLE, AND IT IS THE MAIN CAUSE OF DEATH IN PATIENTS WITH SLE. ABNORMALITIES IN THE IMMUNE SYSTEM LEAD TO LN AND INVOLVE A VARIETY OF CELLS (T CELLS, B CELLS, MACROPHAGES, NK CELLS, ETC.), CYTOKINES (INTERLEUKIN, TUMOR NECROSIS FACTOR ALPHA, ETC.) AND THEIR RELATED PATHWAYS. PREVIOUS STUDIES HAVE SHOWN THAT THE INTERACTIONS OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS CONTRIBUTE TO THE PATHOGENESIS AND DEVELOPMENT OF LN. IN RECENT YEARS, ONE GENOME-WIDE ASSOCIATION STUDY (GWAS) AND A NUMBER OF GENE ASSOCIATION STUDIES HAVE EXPLORED THE SUSCEPTIBILITY GENES OF LN, INCLUDING IMMUNIZATION-, INFLAMMATION-, ADHESION- AND OTHER PATHWAY-RELATED GENES. THESE GENES PARTICIPATE IN OR SUGGEST THE PATHOGENESIS AND PROGRESSION OF LN. IN THIS REVIEW, WE SUMMARIZE THE GENETIC SUSCEPTIBILITY OF LN AND DISCUSS THE POSSIBLE MECHANISM UNDERLYING THE SUSCEPTIBILITY GENES OF LN. 2020 10 4958 25 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 11 5371 25 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 12 549 26 AUTOANTIGENS: NOVEL FORMS AND PRESENTATION TO THE IMMUNE SYSTEM. IT IS CLEAR THAT LUPUS AUTOIMMUNITY IS MARKED BY A VARIETY OF ABNORMALITIES, INCLUDING THOSE FOUND AT A MACROSCOPIC SCALE, CELLS AND TISSUES, AS WELL AS MORE MICROENVIRONMENTAL INFLUENCES, ORIGINATING AT THE INDIVIDUAL CELL SURFACE THROUGH TO THE NUCLEUS. THE CONVERGENCE OF GENETIC, EPIGENETIC, AND PERHAPS ENVIRONMENTAL INFLUENCES ALL LEAD TO THE OVERT CLINICAL EXPRESSION OF DISEASE, REFLECTED BY THE PRESENCES OF AUTOANTIBODIES AND TISSUE PATHOLOGY. THIS REVIEW WILL ADDRESS SEVERAL SPECIFIC AREAS THAT FALL AMONG THE NON-GENETIC FACTORS THAT CONTRIBUTE TO LUPUS AUTOIMMUNITY AND RELATED SYNDROMES. IN PARTICULAR, WE WILL DISCUSS THE IMPORTANCE OF UNDERSTANDING VARIOUS PROTEIN POST-TRANSLATIONAL MODIFICATIONS (PTMS), MECHANISMS THAT MEDIATE THE ABILITY OF "MODIFIED SELF" TO TRIGGER AUTOIMMUNITY, AND HOW THESE PTMS INFLUENCE LUPUS DIAGNOSIS. FINALLY, WE WILL DISCUSS ALTERED PATHWAYS OF AUTOANTIGEN PRESENTATION THAT MAY CONTRIBUTE TO THE PERPETUATION OF CHRONIC AUTOIMMUNE DISEASE. 2014 13 2731 25 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 14 5886 27 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 15 4216 31 METHYL DONOR MICRONUTRIENTS: A POTENTIAL DIETARY EPIGENETIC TARGET IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY AN ABERRANT IMMUNE RESPONSE AND PERSISTENT INFLAMMATION. ITS PATHOGENESIS REMAINS UNKNOWN; HOWEVER, A COMPLEX INTERACTION BETWEEN ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN SUGGESTED TO CAUSE DISEASE ONSET. SEVERAL STUDIES HAVE DEMONSTRATED THAT EPIGENETIC ALTERATIONS, SUCH AS DNA HYPOMETHYLATION, MIRNA OVEREXPRESSION, AND ALTERED HISTONE ACETYLATION, MAY CONTRIBUTE TO SLE ONSET AND THE DISEASE'S CLINICAL MANIFESTATIONS. EPIGENETIC CHANGES, ESPECIALLY METHYLATION PATTERNS, ARE MODIFIABLE AND SUSCEPTIBLE TO ENVIRONMENTAL FACTORS SUCH AS DIET. IT IS WELL KNOWN THAT METHYL DONOR NUTRIENTS, SUCH AS FOLATE, METHIONINE, CHOLINE, AND SOME B VITAMINS, PLAY A RELEVANT ROLE IN DNA METHYLATION BY PARTICIPATING AS METHYL DONORS OR COENZYMES IN ONE-CARBON METABOLISM. BASED ON THIS KNOWLEDGE, THIS CRITICAL LITERATURE REVIEW AIMED TO INTEGRATE THE EVIDENCE IN ANIMAL MODELS AND HUMANS REGARDING THE ROLE OF NUTRIENTS IN EPIGENETIC HOMEOSTASIS AND THEIR IMPACT ON IMMUNE SYSTEM REGULATION TO SUGGEST A POTENTIAL EPIGENETIC DIET THAT COULD SERVE AS ADJUVANT THERAPY IN SLE. 2023 16 1719 22 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 17 5643 23 SEX AND AUTOIMMUNITY: PROPOSED MECHANISMS OF DISEASE ONSET AND SEVERITY. CHRONIC AUTOIMMUNE DISEASES AFFECT 5-10% OF THE POPULATION WORLDWIDE AND ARE LARGELY PREDOMINANT IN WOMEN. SEX HORMONE CHANGES HAVE BEEN WIDELY INVESTIGATED BASED ON CHANGES IN THE CLINICAL PHENOTYPES OBSERVED DURING PREGNANCY AND MENOPAUSE. IT IS KNOWN THAT FEMALES WITH AUTOIMMUNE DISEASES MANIFEST A HIGHER RATE OF CIRCULATING LEUKOCYTES WITH A SINGLE X CHROMOSOME, AND THERE HAVE BEEN SEVERAL REPORTS ON THE ROLE OF X CHROMOSOME GENE DOSAGE THROUGH INACTIVATION OR DUPLICATION IN AUTOIMMUNITY. HOWEVER, IT IS ALSO IMPORTANT NOT TO OVERLOOK MEN WITH AUTOIMMUNE DISEASES, WHO MIGHT MANIFEST A MORE FREQUENT LOSS OF THE Y CHROMOSOME IN CIRCULATING LEUKOCYTES. AREAS COVERED: IN THE PRESENT REVIEW, WE WILL DISCUSS THE CURRENT EVIDENCE SUPPORTING THE MECHANISMS OF FEMALE PREDOMINANCE IN RHEUMATIC DISEASES, BY DISCUSSING THE ROLE OF REPRODUCTIVE HISTORY, SEX HORMONES AND ABNORMALITIES RELATED TO THEM, CLINICAL DIFFERENCES BETWEEN MALE AND FEMALE PATIENTS, AND EPIGENETIC CHANGES THAT HAVE BEEN EVALUATED THROUGH TWIN STUDIES ON GENETIC AND ENVIRONMENTAL CHANGES IN RHEUMATIC PATIENTS. EXPERT OPINION: THE INFLUENCE OF SEX HORMONES AND CHROMOSOMES ON THE FUNCTION OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS NEEDS TO BE CLARIFIED, TO BETTER UNDERSTAND THE RISK OF AUTOIMMUNE DISEASES, EARLY DIAGNOSTIC TOOLS, AND THERAPEUTIC RESPONSE. 2019 18 3402 28 HOW DOES AGE DETERMINE THE DEVELOPMENT OF HUMAN IMMUNE-MEDIATED ARTHRITIS? DOES AGE SUBSTANTIALLY AFFECT THE EMERGENCE OF HUMAN IMMUNE-MEDIATED ARTHRITIS? CHILDREN DO NOT USUALLY DEVELOP IMMUNE-MEDIATED ARTICULAR INFLAMMATION DURING THEIR FIRST YEAR OF LIFE. IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS, THIS APPARENT 'IMMUNE PRIVILEGE' DISINTEGRATES, AND CHRONIC INFLAMMATION IS ASSOCIATED WITH VARIABLE AUTOANTIBODY SIGNATURES AND PATTERNS OF DISEASE THAT RESEMBLE ADULT ARTHRITIS PHENOTYPES. NUMEROUS MECHANISMS MIGHT BE INVOLVED IN THIS SHIFT, INCLUDING GENETIC AND EPIGENETIC PREDISPOSING FACTORS, MATURATION OF THE IMMUNE SYSTEM WITH A PROGRESSIVE MODULATION OF PUTATIVE TOLEROGENIC CONTROLS, PARALLEL DEVELOPMENT OF MICROBIAL DYSBIOSIS, ACCUMULATION OF A PRO-INFLAMMATORY BURDEN DRIVEN BY ENVIRONMENTAL EXPOSURES (THE EXPOSOME) AND COMORBIDITY-RELATED DRIVERS. BY EXPLORING THESE MECHANISMS, WE EXPAND THE DISCUSSION OF THREE (NOT MUTUALLY EXCLUSIVE) HYPOTHESES ON HOW THESE FACTORS CAN CONTRIBUTE TO THE DIFFERENCES AND SIMILARITIES BETWEEN THE LOSS OF IMMUNE TOLERANCE IN CHILDREN AND THE DEVELOPMENT OF ESTABLISHED IMMUNE-MEDIATED ARTHRITIS IN ADULTS. THESE THREE HYPOTHESES RELATE TO A CRITICAL WINDOW IN GENETICS AND EPIGENETICS, IMMUNE MATURATION, AND THE ACCUMULATION OF BURDEN. THE VARIED MANIFESTATION OF THE UNDERLYING MECHANISMS AMONG INDIVIDUALS IS ONLY BEGINNING TO BE CLARIFIED, BUT THE ESTABLISHMENT OF A FRAMEWORK CAN FACILITATE THE DEVELOPMENT OF AN INTEGRATED UNDERSTANDING OF THE PATHOGENESIS OF ARTHRITIS ACROSS ALL AGES. 2022 19 4030 22 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 20 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