1 6727 143 VITILIGO AND CHRONIC AUTOIMMUNE THYROIDITIS. VITILIGO, THE DISCOLORATION OF THE SKIN, HAS DIFFERENT AUTOIMMUNE MECHANISMS REFLECTED BY MANY BIOMARKERS AS SHOWN BY SKIN HISTOLOGY, STAINING FOR CD4 AND CD8 T LYMPHOCYTES, CHEMOKINE LIGAND 9 OR CIRCULATING CYTOKINES SUCH AS INTERLEUKIN (IL)-1 BETA, INTERFERON (IFN)-GAMMA, TRANSFORMING GROWTH FACTOR (TGF)-BETA, ANTIBODIES, MARKERS OF OXIDATIVE STRESS, CHEMOKINES, AND OTHERS. IN THIS NARRATIVE REVIEW, WE AIM TO OVERVIEW VITILIGO IN RELATIONSHIP WITH CHRONIC AUTOIMMUNE THYROIDITIS. REGARDING VITILIGO, MORE THAN 50 DIFFERENT GENETIC LOCI HAVE BEEN ASSOCIATED WITH THIS DISEASE, AND THE HERITABILITY IS HIGH. THERE IS A 20% RISK OF AN ENVIRONMENTAL CONNECTION WHICH MAY ALSO ACT AS A TRIGGER; MOREOVER, THE ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN (HLA) EXPRESSION IS WELL RECOGNIZED. THE SPECIFIC LESIONS DISPLAY CD8+ TISSUE-RESIDENT MEMORY T CELLS AS CONTINUOUS KEY ACTIVATORS OF MELANOCYTES. THE ASSOCIATION WITH CHRONIC THYROIDITIS IS BASED ON COMMON AUTOIMMUNE BACKGROUND AND EXCESSIVE REACTIVE OXYGEN SPECIES THAT DESTROY MELANOCYTES AND THYROCYTES (OXIDATIVE STRESS HYPOTHESIS) WITH THYROXINE AND MELANIN AS TARGET MOLECULES, THUS SHARING A COMMON ORIGIN: TYROSINE. MOREOVER, COMMON EPIGENETIC ANOMALIES OR MUTATIONS OF THE FORKHEAD TRANSCRIPTION FACTOR D3 (FOXD3) HAVE BEEN DESCRIBED. SINCE VITILIGO AFFECTS UP TO 1-2% OF THE POPULATION WORLDWIDE AND 34% OF PATIENTS HAVE POSITIVE THYROID ANTIBODIES, APART FROM COMMON AUTOIMMUNITY BACKGROUND AND OXIDATIVE STRESS TOXICITY, THE ASSOCIATION IS CLINICALLY RELEVANT FOR DIFFERENT PRACTITIONERS. 2021 2 6038 27 THE CHEMICAL DEFENSIVE SYSTEM IN THE PATHOBIOLOGY OF IDIOPATHIC ENVIRONMENT-ASSOCIATED DISEASES. CHEMICAL DEFENSIVE SYSTEM CONSISTING OF BIO-SENSORING, TRANSMITTING, AND RESPONSIVE ELEMENTS HAS BEEN EVOLVED TO PROTECT MULTI-CELLULAR ORGANISMS AGAINST ENVIRONMENTAL CHEMICAL INSULTS (XENOBIOTICS) AND TO MAINTAIN HOMEOSTASIS OF ENDOGENOUS LOW MOLECULAR WEIGHT METABOLITES (ENDOBIOTICS). BOTH GENETIC AND EPIGENETIC DEFECTS OF THE SYSTEM IN ASSOCIATION WITH CARCINOGENESIS AND INDIVIDUAL SENSITIVITY TO ANTI-TUMOR THERAPIES HAVE BEEN INTENSELY STUDIED. RECENTLY, SEVERAL NON-TUMOR HUMAN PATHOLOGIES WITH EVIDENT ENVIRONMENTAL COMPONENTS SUCH AS RATHER RARE FUNCTIONAL SYNDROMES (MULTIPLE CHEMICAL SENSITIVITY, CHRONIC FATIGUE, PERSIAN GULF, AND FIBROMYALGIA NOW COLLECTIVELY LABELED AS IDIOPATHIC ENVIRONMENTAL INTOLERANCES) AND COMMON DISEASES (VITILIGO AND SYSTEMIC LUPUS ERYTHEMATOSUS) HAVE BECOME SUBJECTS OF THE RESEARCH ON THE IMPAIRED METABOLISM AND DETOXIFICATION OF XENOBIOTICS AND ENDOGENOUS TOXINS. HERE, WE COLLECTED AND CRITICALLY REVIEWED EPIDEMIOLOGICAL, GENETIC, AND BIOCHEMICAL DATA ON THE INVOLVEMENT AND POSSIBLE ROLE OF CYTOCHROME P450 SUPER FAMILY ENZYMES, GLUTATHIONE-S-TRANSFERASE ISOZYMES, CATECHOL-O-METHYL-TRANSFERASE, UDP-GLUCURONOSYL TRANSFERASES, AND PROTEINS DETOXIFYING INORGANIC AND ORGANIC PEROXIDES (CATALASE, GLUTATHIONE PEROXIDASE, AND PEROXIREDOXIN) IN THE ABOVE PATHOLOGIES. GENETIC PREDISPOSITION ASSESSED MAINLY BY SINGLE NUCLEOTIDE POLYMORPHISM AND GENE EXPRESSION ANALYSES REVEALED CORRELATIONS BETWEEN DEFECTS IN GENES ENCODING XENOBIOTIC-METABOLIZING AND/OR DETOXIFYING ENZYMES AND RISK/SEVERITY OF THESE SYNDROMES/DISEASES. PROTEOME ANALYSIS IDENTIFIED ABNORMAL EXPRESSION OF THE ENZYMES. THEIR FUNCTIONS WERE AFFECTED EPIGENETICALLY LEADING TO METABOLIC IMPAIRMENT AND, AS A CONSEQUENCE, TO THE NEGATIVE HEALTH OUTCOMES SHARED BY SOME OF THESE PATHOLOGIES. DATA OBTAINED SO FAR SUGGEST THAT DISTINCT COMPONENTS OF THE CHEMICAL DEFENSIVE SYSTEM COULD BE SUITABLE MOLECULAR TARGETS FOR FUTURE PATHOGENIC THERAPIES. 2009 3 6406 28 THE SEARCH FOR RELIABLE BIOMARKERS OF DISEASE IN MULTIPLE CHEMICAL SENSITIVITY AND OTHER ENVIRONMENTAL INTOLERANCES. WHILST FACING A WORLDWIDE FAST INCREASE OF FOOD AND ENVIRONMENTAL ALLERGIES, THE MEDICAL COMMUNITY IS ALSO CONFRONTED WITH ANOTHER INHOMOGENEOUS GROUP OF ENVIRONMENT-ASSOCIATED DISABLING CONDITIONS, INCLUDING MULTIPLE CHEMICAL SENSITIVITY (MCS), FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, ELECTRIC HYPERSENSITIVITY, AMALGAM DISEASE AND OTHERS. THESE SHARE THE FEATURES OF POLY-SYMPTOMATIC MULTI-ORGAN CUTANEOUS AND SYSTEMIC MANIFESTATIONS, WITH POSTULATED INHERITED/ACQUIRED IMPAIRED METABOLISM OF CHEMICAL/PHYSICAL/NUTRITIONAL XENOBIOTICS, TRIGGERING ADVERSE REACTIONS AT EXPOSURE LEVELS FAR BELOW TOXICOLOGICALLY-RELEVANT VALUES, OFTEN IN THE ABSENCE OF CLEAR-CUT ALLERGOLOGIC AND/OR IMMUNOLOGIC INVOLVEMENT. DUE TO THE LACK OF PROVEN PATHOGENIC MECHANISMS GENERATING MEASURABLE DISEASE BIOMARKERS, THESE ENVIRONMENTAL HYPERSENSITIVITIES ARE GENERALLY IGNORED BY SANITARY AND SOCIAL SYSTEMS, AS PSYCHOGENIC OR "MEDICALLY UNEXPLAINED SYMPTOMS". THE UNCONTROLLED APPLICATION OF DIAGNOSTIC AND TREATMENT PROTOCOLS NOT CORRESPONDING TO ACCEPTABLE LEVELS OF VALIDATION, SAFETY, AND CLINICAL EFFICACY, TO A STEADILY INCREASING NUMBER OF PATIENTS DEMANDING ASSISTANCE, OCCURS IN MANY COUNTRIES IN THE ABSENCE OF EVIDENCE-BASED GUIDELINES. HERE WE REVISE AVAILABLE INFORMATION SUPPORTING THE ORGANIC NATURE OF THESE CLINICAL CONDITIONS. FOLLOWING INTENSE RESEARCH ON GENE POLYMORPHISMS OF PHASE I/II DETOXIFICATION ENZYME GENES, SO FAR STATISTICALLY INCONCLUSIVE, EPIGENETIC AND METABOLIC FACTORS ARE UNDER INVESTIGATION, IN PARTICULAR FREE RADICAL/ANTIOXIDANT HOMEOSTASIS DISTURBANCES. THE FINDING OF RELEVANT ALTERATIONS OF CATALASE, GLUTATHIONE-TRANSFERASE AND PEROXIDASE DETOXIFYING ACTIVITIES SIGNIFICANTLY CORRELATING WITH CLINICAL MANIFESTATIONS OF MCS, HAS RECENTLY REGISTERED SOME PROGRESS TOWARDS THE IDENTIFICATION OF RELIABLE BIOMARKERS OF DISEASE ONSET, PROGRESSION, AND TREATMENT OUTCOMES. 2011 4 6438 22 THERAPEUTIC AND PREVENTIVE INTERVENTIONS FOR POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE FATIGUE-RELATED DISORDERS. MAJOR ADVANCES HAVE BEEN MADE IN UNDERSTANDING THE RELATIVELY NOVEL GROUP OF VASOACTIVE (VASODILATORY) NEUROPEPTIDES (VNS) IN HUMANS. VNS COMPRISE A NOVEL BUT EXPANDING GROUP OF SUBSTANCES HAVING IMMUNOREGULATION, INFLAMMATION MODULATION, NEUROTRANSMITTER, NEUROTROPHIC, HORMONAL AND METABOLIC FUNCTIONS. THESE SUBSTANCES MAY CONTROL GENE EXPRESSION FOR MRNA FOR THEMSELVES AND THEIR RECEPTORS. THEY HAVE COMPLEX RELATIONSHIPS WITH GASEOUS AND OTHER NEUROTRANSMITTERS AND XENOBIOTIC SUBSTANCES. THEORETICAL ARGUMENTS HAVE IMPLICATED THESE SUBSTANCES IN AUTOIMMUNE PHENOMENA RESULTING IN FATIGUE-RELATED CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME (CFS), SUDDEN INFANT DEATH SYNDROME (SIDS), FIBROMYALGIA (FM) AND GULF WAR SYNDROME (GWS) BUT REMAIN UNPROVEN. AS WELL AS POSSIBLY SPONTANEOUS ONSET, THE PRECIPITATING CAUSES OF VN AUTOIMMUNE DYSFUNCTION ARE LIKELY TO BE A COMBINATION OF GENETIC PREDISPOSITION, INFECTION AND XENOBIOTIC SUBSTANCES. THERAPEUTIC AND PREVENTIVE POSSIBILITIES FOR POSTULATED VN AUTOIMMUNE CONDITIONS WILL BE INFLUENCED BY THE COMPLEX PATHOLOPHYSIOLOGY UNDERPINNING THEM. SOME SPECULATIVE POSSIBILITIES ARE VN SUBSTITUTION/REPLACEMENT, PRESERVATION OF BIOLOGICAL EFFECT, EPIGENETIC DNA MODIFICATIONS, PLASMA EXCHANGE, ANTI-CHOLINESTERASES, E.G., PYRIDOSTIGMINE, CORTICOSTEROIDS AND OTHER DRUG TREATMENTS, THYMECTOMY, INTRAVENOUS IMMUNOGLOBULIN AND ANTI-IDIOTYPE ANTIBODIES, AND CPG/DNA VACCINES. PREVENTION AND TREATMENT OF POSSIBLE VN AUTOIMMUNE FATIGUE-RELATED DISORDERS MAY PROVE TO BE IMPORTANT AREAS FOR FUTURE RESEARCH AND DEVELOPMENT. 2005 5 6908 20 [THYROID AND HEPATITIS C]. AUTOIMMUNE THYROID DISEASES ARE COMPLEX DISEASES THAT DEVELOP AS A RESULT OF INTERACTIONS BETWEEN GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. IFNA THERAPY OF CHRONIC HCV INFECTION IS ASSOCIATED WITH SUBCLINICAL OR CLINICAL THYROIDITIS, WHILE THE RELATIONSHIP BETWEEN THYROIDITIS AND VIRUS C INFECTION IS STILL DEBATED. 2012 6 5451 35 REPROGRAMMING CELLS FROM GULF WAR VETERANS INTO NEURONS TO STUDY GULF WAR ILLNESS. GULF WAR ILLNESS (GWI), WHICH AFFLICTS AT LEAST 25% OF VETERANS WHO SERVED IN THE 1990-1991 WAR IN THE PERSIAN GULF, IS THOUGHT TO BE CAUSED BY DEPLOYMENT EXPOSURES TO VARIOUS NEUROTOXICANTS, INCLUDING PESTICIDES, ANTI-NERVE GAS PILLS, AND LOW-LEVEL NERVE AGENTS INCLUDING SARIN/CYCLOSARIN. GWI IS A MULTISYMPTOM DISORDER CHARACTERIZED BY FATIGUE, JOINT PAIN, COGNITIVE PROBLEMS, AND GASTROINTESTINAL COMPLAINTS. THE MOST PROMINENT SYMPTOMS OF GWI (MEMORY PROBLEMS, POOR ATTENTION/CONCENTRATION, CHRONIC HEADACHES, MOOD ALTERATIONS, AND IMPAIRED SLEEP) SUGGEST THAT THE DISEASE PRIMARILY AFFECTS THE CNS. DEVELOPMENT OF URGENTLY NEEDED TREATMENTS DEPENDS ON EXPERIMENTAL MODELS APPROPRIATE FOR TESTING MECHANISTIC HYPOTHESES AND FOR SCREENING THERAPEUTIC COMPOUNDS. RODENT MODELS HAVE BEEN USEFUL THUS FAR, BUT ARE LIMITED BY THEIR INABILITY TO ASSESS THE CONTRIBUTION OF GENETIC OR EPIGENETIC BACKGROUND TO THE DISEASE, AND BECAUSE DISEASE-VULNERABLE PROTEINS AND PATHWAYS MAY BE DIFFERENT IN HUMANS RELATIVE TO RODENTS. AS OF YET, NO POSTMORTEM TISSUE FROM THE VETERANS HAS BECOME AVAILABLE FOR RESEARCH. WE ARE MOVING FORWARD WITH A PARADIGM SHIFT IN THE STUDY OF GWI, WHICH UTILIZES CONTEMPORARY STEM CELL TECHNOLOGY TO CONVERT SOMATIC CELLS FROM GULF WAR VETERANS INTO PLURIPOTENT CELL LINES THAT CAN BE DIFFERENTIATED INTO VARIOUS CELL TYPES, INCLUDING NEURONS, GLIA, MUSCLE, OR OTHER RELEVANT CELL TYPES. SUCH CELL LINES ARE IMMORTAL AND WILL BE A RESOURCE FOR GWI RESEARCHERS TO PURSUE MECHANISTIC HYPOTHESES AND THERAPEUTICS. 2017 7 1637 31 DOES DYSREGULATION OF KEY EPIGENETIC AND BIOCHEMICAL PATHWAYS OCCUR IN POSTULATED VASOACTIVE NEUROPEPTIDE AUTOIMMUNE DISORDERS? AUTOIMMUNE DYSFUNCTION OF CERTAIN VASOACTIVE NEUROPEPTIDES (VNS) HAS BEEN POSTULATED AS A CONTRIBUTING CAUSE OF SUDDEN INFANT DEATH SYNDROME (SIDS), CHRONIC FATIGUE SYNDROME (CFS), GULF WAR SYNDROME (GWS) AND OTHER FATIGUE-RELATED DISORDERS. THIS FAMILY OF VNS INCLUDES PITUITARY ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE (PACAP), VASOACTIVE INTESTINAL PEPTIDE (VIP) AND CALCITONIN GENE RELATED PEPTIDE (CGRP). THE POSTULATED MECHANISM IS COMPROMISE OF ADENYLATE CYCLASE ACTIVATION, A VITAL AND UNIQUE STEP IN CYCLIC AMP PRODUCTION FROM ATP, THROUGH AUTOIMMUNE DYSFUNCTION OF VNS, THEIR RECEPTORS OR THEIR GENES POSSIBLY INVOLVING CYTOSINE-PHOSPHATE-GUANINE (CPG) FRAGMENTS. CPG FRAGMENTS ARE IMMUNOMODULATORY DINUCLEOTIDES SERVING AS 'FRIEND OR FOE' RECOGNITION SYSTEMS TO DIFFERENTIATE BACTERIAL AND VIRAL (HYPOMETHYLATED CPG) FROM MAMMALIAN (METHYLATED CPG) DNA. HOWEVER HYPOMETHYLATION DISORDERS AFFECTING THESE FRAGMENTS IN MAMMALS MAY CONVERT THEM TO DYSFUNCTIONAL STATES BY PROMOTING AUTOIMMUNE INFLAMMATORY REACTIONS. EPIGENETIC MECHANISMS ACTING ON GENE PROMOTER REGIONS MAY CONTRIBUTE TO THE DEVELOPMENT OF VN AUTOIMMUNE FATIGUE-RELATED DISORDERS THROUGH CPG FRAGMENTS LOCATED IN VITAL SEGMENTS OF VN/RECEPTOR GENES BY CAUSING SIGNALLING DEFECTS WITH PROFOUND IMPLICATIONS FOR VN FUNCTION. NEUROTRANSMITTER DYSFUNCTION PARTICULARLY GLUTAMATERGIC TRANSMISSION COULD ALSO RESULT WITH DISRUPTION OF NEURONAL CELLULAR BIOCHEMICAL FUNCTIONS SUCH AS AMMONIA REGULATION. ENDOSOMAL ACIDITY AND MITOCHONDRIAL MEMBRANE POTENTIAL MODIFIERS SUCH AS CHLOROQUINE, TOGETHER WITH IMMUNOREGULATORY THERAPIES, MAY HAVE THERAPEUTIC IMPLICATIONS IN PROTECTING AGAINST THESE APPARENT AUTOIMMUNE DISORDERS. THIS PAPER EXAMINES SPECIFIC EPIGENETIC AND BIOCHEMICAL MECHANISMS POSSIBLY MEDIATED BY VN OR RECEPTOR GENES RESULTING IN POSTULATED VN AUTOIMMUNE FATIGUE-RELATED DISORDERS. THESE MECHANISMS MAY HAVE IMPLICATIONS FOR TREATMENT AND PREVENTION OPTIONS FOR VN AUTOIMMUNE DISORDERS. VN AUTOIMMUNE PROCESSES HAVE IMPLICATIONS FOR MILITARY MEDICINE WHERE RADIOLOGICAL, CHEMICAL AND BIOLOGICAL AGENTS MAY PLAY AN IMPORTANT ROLE IN PATHOGENESIS. 2005 8 336 26 ALTERATIONS IN DNA METHYLATION STATUS ASSOCIATED WITH GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) AFFECTS ABOUT 25% OF PERSIAN GULF VETERANS WITH A CLUSTER OF CHRONIC SYMPTOMS, INCLUDING IMMUNE DYSFUNCTION AND NEUROLOGICAL ISSUES. RECENT STUDIES IMPLICATE GENE EXPRESSION CHANGES IN IMMUNE FUNCTION TO BE ASSOCIATED WITH GWI. SINCE DNA METHYLATION CAN REGULATE SUCH CHANGES IN GENE EXPRESSION, AND DISRUPTION OF DNA METHYLATION PATTERN IS IMPLICATED IN VARIOUS IMMUNE AND NEUROLOGICAL DISEASES, WE AIMED TO STUDY THE DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM GWI PATIENTS. GLOBAL DNA METHYLATION LEVELS WERE SIMILAR IN GWI PATIENTS AND CONTROLS. HOWEVER, THE GENOME-WIDE MICROARRAY TECHNOLOGY DETECTED 10,767 DIFFERENTIALLY METHYLATED CPG SITES ACROSS GENE REGULATORY ELEMENTS AND WITHIN CODING REGIONS. APPROXIMATELY 88% OF THEM WERE HYPERMETHYLATED IN GWI PATIENTS. THE SEPARATE ANALYSIS FOUND 776 DIFFERENTIALLY METHYLATED GENE PROMOTERS (DMP), WHICH WERE PREDOMINANTLY HYPERMETHYLATED. PYROSEQUENCING VALIDATION CONFIRMED MICROARRAY RESULTS. FUNCTIONAL ANALYSIS REVEALED THAT MAJORITY OF THE DMPS BELONGED TO GENES RESPONSIBLE FOR METABOLISM AND IMMUNE SYSTEM. THIS IS THE FIRST PILOT HUMAN STUDY CHARACTERIZING GENOME-WIDE EPIGENETIC CHANGES ASSOCIATED WITH GWI. IT SUGGESTS A SIGNIFICANT CONTRIBUTION OF EPIGENETIC DYSFUNCTION IN GWI. MOREOVER, IT SUPPORTS THE DYSREGULATION OF IMMUNE FUNCTION IN GWI. LASTLY, IT SUGGESTS STUDIES WITH THE LARGER COHORT TO VALIDATE OUR FINDINGS. 2019 9 4411 27 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 10 3980 33 LONG-TERM EPIGENETIC ALTERATIONS IN A RAT MODEL OF GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC, MULTISYMPTOM ILLNESS THAT AFFECTS 25% OF THE 700,000 US VETERANS DEPLOYED TO THE PERSIAN GULF DURING THE 1990-1991 GULF WAR. CENTRAL NERVOUS SYSTEM IMPAIRMENTS ARE AMONG THE MOST COMMON SYMPTOMS REPORTED, INCLUDING MEMORY DYSFUNCTION AND DEPRESSION. AFTER 25 YEARS, THE DIAGNOSIS REMAINS ELUSIVE, USEFUL TREATMENTS ARE LACKING, AND THE CAUSE IS POORLY UNDERSTOOD, ALTHOUGH EXPOSURES TO PYRIDOSTIGMINE BROMIDE (PB) AND PESTICIDES ARE CONSISTENTLY IDENTIFIED TO BE AMONG THE STRONGEST RISK FACTORS. EPIGENETIC CHANGES INCLUDING ALTERED MICRORNA (MIRNA) EXPRESSION AND DNA METHYLATION PLAY AN IMPORTANT ROLE IN LEARNING, MEMORY, AND EMOTION REGULATION AND HAVE BEEN IMPLICATED IN VARIOUS NEUROLOGICAL DISORDERS. IN THIS STUDY, WE USED AN ESTABLISHED RAT MODEL OF GWI TO DETERMINE WHETHER 1) CHRONIC ALTERATIONS IN MIRNA EXPRESSION AND GLOBAL DNA METHYLATION AND DNA HYDROXYMETHYLATION ARE MECHANISMS INVOLVED IN THE PATHOBIOLOGY OF GWI, AND 2) PLASMA EXOSOME SMALL RNAS MAY SERVE AS POTENTIAL NONINVASIVE BIOMARKERS OF THIS DEBILITATING DISEASE. ONE YEAR AFTER A 28-DAY EXPOSURE REGIMEN OF PB, DEET (N,N-DIETHYL-3-METHYLBENZAMIDE), PERMETHRIN, AND MILD STRESS, EXPRESSION OF 84 MATURE MIRNAS AND GLOBAL 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) CONTENT WERE ANALYZED IN THE BRAINS OF GWI RATS AND VEHICLE CONTROLS BY PCR ARRAY AND ENZYME-LINKED IMMUNOSORBENT ASSAY, RESPECTIVELY. PLASMA EXOSOME RNA NEXT-GENERATION SEQUENCING ANALYSIS WAS PERFORMED IN POOLED SAMPLES TO DISCOVER POTENTIAL NONINVASIVE BIOMARKERS. WE FOUND THAT COMBINED EXPOSURE TO LOW DOSES OF GW-RELATED CHEMICALS AND MILD STRESS CAUSED EPIGENETIC MODIFICATIONS IN THE BRAIN THAT PERSISTED ONE YEAR AFTER EXPOSURE, INCLUDING INCREASED EXPRESSION OF MIR-124-3P AND MIR-29B-3P IN THE HIPPOCAMPUS AND REGIONAL ALTERATIONS IN GLOBAL 5MC AND 5HMC CONTENT. GW-RELEVANT EXPOSURES ALSO INDUCED THE DIFFERENTIAL EXPRESSION OF TWO PIWI-INTERACTING RNAS (PIRNAS) IN CIRCULATION (PIR-007899 AND PIR-019162). RESULTS FROM THIS STUDY IMPLICATE A ROLE FOR EPIGENETIC ALTERATIONS IN GWI. EVALUATION OF THE DIAGNOSTIC POTENTIAL OF PLASMA EXOSOME RNAS IN VETERANS WITH GWI IS WARRANTED. 2016 11 2123 37 EPIGENETIC IMPACTS OF STRESS PRIMING OF THE NEUROINFLAMMATORY RESPONSE TO SARIN SURROGATE IN MICE: A MODEL OF GULF WAR ILLNESS. BACKGROUND: GULF WAR ILLNESS (GWI) IS AN ARCHETYPAL, MEDICALLY UNEXPLAINED, CHRONIC CONDITION CHARACTERISED BY PERSISTENT SICKNESS BEHAVIOUR AND NEUROIMMUNE AND NEUROINFLAMMATORY COMPONENTS. AN ESTIMATED 25-32% OF THE OVER 900,000 VETERANS OF THE 1991 GULF WAR FULFIL THE REQUIREMENTS OF A GWI DIAGNOSIS. IT HAS BEEN HYPOTHESISED THAT THE HIGH PHYSICAL AND PSYCHOLOGICAL STRESS OF COMBAT MAY HAVE INCREASED VULNERABILITY TO IRREVERSIBLE ACETYLCHOLINESTERASE (ACHE) INHIBITORS LEADING TO A PRIMING OF THE NEUROIMMUNE SYSTEM. A NUMBER OF STUDIES HAVE LINKED HIGH LEVELS OF PSYCHOPHYSIOLOGICAL STRESS AND TOXICANT EXPOSURES TO EPIGENETIC MODIFICATIONS THAT REGULATE GENE EXPRESSION. RECENT RESEARCH IN A MOUSE MODEL OF GWI HAS SHOWN THAT PRE-EXPOSURE WITH THE STRESS HORMONE CORTICOSTERONE (CORT) CAUSES AN INCREASE IN EXPRESSION OF SPECIFIC CHEMOKINES AND CYTOKINES IN RESPONSE TO DIISOPROPYL FLUOROPHOSPHATE (DFP), A SARIN SURROGATE AND IRREVERSIBLE ACHE INHIBITOR. METHODS: C57BL/6J MICE WERE EXPOSED TO CORT FOR 4 DAYS, AND EXPOSED TO DFP ON DAY 5, BEFORE SACRIFICE 6 H LATER. THE TRANSCRIPTOME WAS EXAMINED USING RNA-SEQ, AND THE EPIGENOME WAS EXAMINED USING REDUCED REPRESENTATION BISULFITE SEQUENCING AND H3K27AC CHIP-SEQ. RESULTS: WE SHOW TRANSCRIPTIONAL, HISTONE MODIFICATION (H3K27AC) AND DNA METHYLATION CHANGES IN GENES RELATED TO THE IMMUNE AND NEURONAL SYSTEM, POTENTIALLY RELEVANT TO NEUROINFLAMMATORY AND COGNITIVE SYMPTOMS OF GWI. FURTHER EVIDENCE SUGGESTS ALTERED PROPORTIONS OF MYELINATING OLIGODENDROCYTES IN THE FRONTAL CORTEX, PERHAPS CONNECTED TO WHITE MATTER DEFICITS SEEN IN GWI SUFFERERS. CONCLUSIONS: OUR FINDINGS MAY REFLECT THE EARLY CHANGES WHICH OCCURRED IN GWI VETERANS, AND WE OBSERVE ALTERATIONS IN SEVERAL PATHWAYS ALTERED IN GWI SUFFERERS. THESE CLOSE LINKS TO CHANGES SEEN IN VETERANS WITH GWI INDICATES THAT THIS MODEL REFLECTS THE ENVIRONMENTAL EXPOSURES RELATED TO GWI AND MAY PROVIDE A MODEL FOR BIOMARKER DEVELOPMENT AND TESTING FUTURE TREATMENTS. 2018 12 2731 27 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 13 4030 25 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 14 3511 33 IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI): FROM MOLECULAR EPIDEMIOLOGY TO MOLECULAR MEDICINE. INHERITED OR ACQUIRED IMPAIRMENT OF XENOBIOTICS METABOLISM IS A POSTULATED MECHANISM UNDERLYING ENVIRONMENT-ASSOCIATED PATHOLOGIES SUCH AS MULTIPLE CHEMICAL SENSITIVITY, FIBROMYALGIA, CHRONIC FATIGUE SYNDROME, DENTAL AMALGAM DISEASE, AND OTHERS, ALSO COLLECTIVELY NAMED IDIOPATHIC ENVIRONMENTAL INTOLERANCES (IEI). IN VIEW OF THE POOR CURRENT KNOWLEDGE OF THEIR ETIOLOGY AND PATHOGENESIS, AND THE ABSENCE OF RECOGNISED GENETIC AND METABOLIC MARKERS OF THE DISEASES. THEY ARE OFTEN CONSIDERED "MEDICALLY UNEXPLAINED SYNDROMES",. THESE DISABLING CONDITIONS SHARE THE FEATURES OF POLYSYMPTOMATIC MULTI-ORGAN SYNDROMES, CONSIDERED BY PART OF THE MEDICAL COMMUNITY TO BE ABERRANT RESPONSES TRIGGERED BY EXPOSURE TO LOW-DOSE ORGANIC AND INORGANIC CHEMICALS AND METALS, IN CONCENTRATIONS FAR BELOW AVERAGE REFERENCE LEVELS ADMITTED FOR ENVIRONMENTAL TOXICANTS. A GENETIC PREDISPOSITION TO ALTERED BIOTRANSFORMATION OF ENVIRONMENTAL CHEMICALS, DRUGS, AND METALS, AND OF ENDOGENOUS LOW-MOLECULAR WEIGHT METABOLITES, CAUSED BY POLYMORPHISMS OF GENES CODING FOR XENOBIOTIC METABOLIZING ENZYMES, THEIR RECEPTORS AND TRANSCRIPTION FACTORS APPEARS TO BE INVOLVED IN THE SUSCEPTIBILITY TO THESE ENVIRONMENT-ASSOCIATED PATHOLOGIES, ALONG WITH EPIGENETIC FACTORS. FREE RADICAL/ANTIOXIDANT HOMEOSTASIS MAY ALSO BE HEAVILY IMPLICATED, INDIRECTLY BY AFFECTING THE REGULATION OF XENOBIOTIC METABOLIZING ENZYMES, AND DIRECTLY BY CAUSING INCREASED LEVELS OF OXIDATIVE PRODUCTS, IMPLICATED IN THE CHRONIC DAMAGE OF CELLS AND TISSUES, WHICH IS IN PART CORRELATED WITH CLINICAL SYMPTOMS. MORE SYSTEMATIC STUDIES OF MOLECULAR EPIDEMIOLOGY, TOXICO- AND PHARMACO-GENOMICS, ELUCIDATING THE MECHANISMS OF REGULATION, EXPRESSION, INDUCTION, AND ACTIVITY OF ANTIOXIDANT/DETOXIFYING ENZYMES, AND THE POSSIBLE ROLE OF INFLAMMATORY MEDIATORS, PROMISE A BETTER UNDERSTANDING OF THIS PATHOLOGICALLY INCREASED SENSITIVITY TO LOW-LEVEL CHEMICAL STIMULI, AND A SOLID BASIS FOR EFFECTIVE INDIVIDUALIZED ANTIOXIDANT- AND/OR CHELATOR-BASED TREATMENTS. 2010 15 3025 36 GENETICS AND PATHOPHYSIOLOGY OF GRANULOMATOSIS WITH POLYANGIITIS (GPA) AND ITS MAIN AUTOANTIGEN PROTEINASE 3. GRANULOMATOSIS WITH POLYANGIITIS (GPA) IS A SEVERE AUTOIMMUNE DISEASE AND ONE OF THE SMALL VESSEL ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIDES. ALTHOUGH ITS ETIOLOGY AND PATHOPHYSIOLOGY ARE STILL WIDELY UNKNOWN, IT IS ACCEPTED THAT INFECTIONS, ENVIRONMENTAL FACTORS, EPIGENETIC MODIFICATIONS, AND A GENETIC PREDISPOSITION PROVIDE THE BASIS FOR THIS SYSTEMIC DISORDER. GPA TYPICALLY EVOLVES INTO TWO PHASES: AN INITIAL PHASE CHARACTERIZED BY EAR, NOSE AND THROAT (ENT) MANIFESTATIONS, SUCH AS CHRONIC SINUSITIS AND OTITIS, ULCERATION OF THE ORAL CAVITY AND PHARYNX, AS WELL AS PULMONARY NODULES AND A SEVERE GENERALIZED PHASE, DEFINED BY THE OCCURRENCE OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS, PULMONARY HEMORRHAGE, AND ARTHRITIS. ANCAS, DIRECTED AGAINST THE NEUTROPHILIC ENZYMES PROTEINASE 3 AND MYELOPEROXIDASE, ARE PRESENT IN UP TO 90% OF THE AFFECTED PATIENTS IN THE SYSTEMIC PHASE. AS THE HUMORAL IMMUNITY IS PREDOMINANTLY DIRECTED AGAINST NEUTROPHILIC ANTIGENS, IT IS APPARENT THAT NEUTROPHILS PLAY A CRITICAL ROLE IN GPA BOTH AS TARGET AND EFFECTOR CELLS. ALTHOUGH GPA PATHOGENESIS IS NOT WELL KNOWN, SOME SUSCEPTIBILITY GENES AND LOCI HAVE BEEN IDENTIFIED BY CANDIDATE GENE APPROACHES, GENOME-WIDE ASSOCIATION STUDIES, AND META-ANALYSES, AS WELL AS FAMILIAL ASSOCIATION STUDIES. SUCH GENES ARE CTLA4, PTPN22, COL11A2, SERPINA1, AND THE MHC CLASS II GENE CLUSTER. THIS REVIEW HIGHLIGHTS THE CLINICAL, PATHOPHYSIOLOGICAL, AND GENETIC BACKGROUND OF GPA AND AIMS TO GIVE AN OVERVIEW OF RECENT EFFORTS TO IDENTIFY GPA SUSCEPTIBILITY GENES. WE POINT OUT THE GENETIC BASIS OF THE MAIN AUTOANTIGEN PR3 AND WHY IT IS SO DIFFICULT TO ESTABLISH A MURINE GPA MODEL. 2016 16 3209 25 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 17 107 35 A REVIEW OF PRE-CLINICAL MODELS FOR GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC MULTISYMPTOMATIC DISORDER THAT AFFLICTS OVER 1/3RD OF THE 1991 GW VETERANS. IT SPANS MULTIPLE BODILY SYSTEMS AND PRESENTS ITSELF AS A SYNDROME EXHIBITING DIVERSE SYMPTOMS INCLUDING FATIGUE, DEPRESSION, MOOD, AND MEMORY AND CONCENTRATION DEFICITS, MUSCULOSKELETAL PAIN AND GASTROINTESTINAL DISTRESS IN GW VETERANS. THE ETIOLOGY OF GWI IS COMPLEX AND MANY FACTORS, INCLUDING CHEMICAL, PHYSIOLOGICAL, AND ENVIRONMENTAL STRESSORS PRESENT IN THE GW ARENA, HAVE BEEN IMPLICATED FOR ITS DEVELOPMENT. IT HAS BEEN OVER 30 YEARS SINCE THE END OF THE GW BUT, GWI HAS BEEN PERSISTENT IN SUFFERING VETERANS WHO ARE ALSO DEALING WITH PAUCITY OF EFFECTIVE TREATMENTS. THE MULTIFACTORIAL ASPECT OF GWI ALONG WITH GENETIC HETEROGENEITY AND LACK OF AVAILABLE DATA SURROUNDING WAR-TIME EXPOSURES HAVE PROVED TO BE CHALLENGING IN DEVELOPING PRE-CLINICAL MODELS OF GWI. DESPITE THIS, OVER A DOZEN GWI ANIMAL MODELS EXIST IN THE LITERATURE. IN THIS ARTICLE, FOLLOWING A BRIEF DISCUSSION OF GW HISTORY, GWI DEFINITIONS, AND PROBABLE CAUSES FOR ITS PATHOGENESIS, WE WILL EXPAND UPON VARIOUS EXPERIMENTAL MODELS USED IN GWI LABORATORY RESEARCH. THESE ANIMAL MODELS WILL BE DISCUSSED IN THE CONTEXT OF THEIR ATTEMPTS AT MIMICKING GW-RELATED EXPOSURES WITH REGARDS TO THE VARIATIONS IN CHEMICAL COMBINATIONS, DOSES, AND FREQUENCY OF EXPOSURES. WE WILL DISCUSS THEIR ADVANTAGES AND LIMITATIONS IN MODELING GWI FOLLOWED BY A DISCUSSION OF BEHAVIORAL AND MOLECULAR FINDINGS IN THESE MODELS. THE MECHANISTIC DATA OBTAINED FROM THESE PRECLINICAL STUDIES HAVE OFFERED MULTIPLE MOLECULAR PATHWAYS INCLUDING CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIPID DISTURBANCES, CALCIUM HOMEOSTATIC ALTERATIONS, CHANGES IN GUT MICROBIOTA, AND EPIGENETIC MODIFICATIONS, AMONGST OTHERS FOR EXPLAINING GWI DEVELOPMENT AND ITS PERSISTENCE. FINALLY, THESE FINDINGS HAVE ALSO INFORMED US ON NOVEL DRUGGABLE TARGETS IN GWI. WHILE, IT HAS BEEN DIFFICULT TO CONCEIVE A SINGLE PRE-CLINICAL MODEL THAT COULD EXPRESS ALL THE GWI SIGNS AND EXHIBIT BIOLOGICAL COMPLEXITY REFLECTIVE OF THE CLINICAL PRESENTATION IN GWI, ANIMAL MODELS HAVE BEEN CRITICAL FOR IDENTIFYING MOLECULAR UNDERPINNINGS OF GWI AND EVALUATING TREATMENT STRATEGIES FOR GWI. 2021 18 3545 26 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 4964 31 PATHOGENETIC AND CLINICAL ASPECTS OF ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIDES. ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODIES (ANCA) TARGETING PROTEINASE 3 (PR3) AND MYELOPEROXIDASE EXPRESSED BY INNATE IMMUNE CELLS (NEUTROPHILS AND MONOCYTES) ARE SALIENT DIAGNOSTIC AND PATHOGENIC FEATURES OF SMALL VESSEL VASCULITIS, COMPRISING GRANULOMATOSIS WITH POLYANGIITIS (GPA), MICROSCOPIC POLYANGIITIS, AND EOSINOPHILIC GPA. GENETIC STUDIES SUGGEST THAT ANCA-ASSOCIATED VASCULITIDES (AAV) CONSTITUTE SEPARATE DISEASES, WHICH SHARE COMMON IMMUNOLOGICAL AND PATHOLOGICAL FEATURES, BUT ARE OTHERWISE HETEROGENEOUS. THE SUCCESSFUL THERAPEUTIC USE OF ANTI-CD20 ANTIBODIES EMPHASIZES THE PROMINENT ROLE OF ANCA AND POSSIBLY OTHER AUTOANTIBODIES IN THE PATHOGENESIS OF AAV. HOWEVER, TO ELUCIDATE CAUSAL EFFECTS IN AAV, A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY LEADING TO THE EMERGENCE OF B LYMPHOCYTES THAT PRODUCE PATHOGENIC ANCA REMAINS A CHALLENGE. DIFFERENT SCENARIOS SEEM POSSIBLE; E.G., THE BREAK OF TOLERANCE INDUCED BY A SHIFT FROM NON-PATHOGENIC TOWARD PATHOGENIC AUTOANTIGEN EPITOPES IN INFLAMED TISSUE. THIS REVIEW GIVES A BRIEF OVERVIEW ON CURRENT KNOWLEDGE ABOUT GENETIC AND EPIGENETIC FACTORS, BARRIER DYSFUNCTION AND CHRONIC NON-RESOLVING INFLAMMATION, NECRO-INFLAMMATORY AUTO-AMPLIFICATION OF CELLULAR DEATH AND INFLAMMATION, ALTERED AUTOANTIGEN PRESENTATION, ALTERNATIVE COMPLEMENT PATHWAY ACTIVATION, ALTERATIONS WITHIN PERIPHERAL AND INFLAMED TISSUE-RESIDING T- AND B-CELL POPULATIONS, ECTOPIC LYMPHOID TISSUE NEOFORMATION, THE CHARACTERIZATION OF PR3-SPECIFIC T-CELLS, PROPERTIES OF ANCA, LINKS BETWEEN AUTOIMMUNE DISEASE AND INFECTION-TRIGGERED PATHOLOGY, AND ANIMAL MODELS IN AAV. 2018 20 4457 45 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