1 104 129 A REVIEW OF CYTOKINE-BASED PATHOPHYSIOLOGY OF LONG COVID SYMPTOMS. THE LONG COVID/POST ACUTE SEQUELAE OF COVID-19 (PASC) GROUP INCLUDES PATIENTS WITH INITIAL MILD-TO-MODERATE SYMPTOMS DURING THE ACUTE PHASE OF THE ILLNESS, IN WHOM RECOVERY IS PROLONGED, OR NEW SYMPTOMS ARE DEVELOPED OVER MONTHS. HERE, WE PROPOSE A DESCRIPTION OF THE PATHOPHYSIOLOGY OF THE LONG COVID PRESENTATION BASED ON INFLAMMATORY CYTOKINE CASCADES AND THE P38 MAP KINASE SIGNALING PATHWAYS THAT REGULATE CYTOKINE PRODUCTION. IN THIS MODEL, THE SARS-COV-2 VIRAL INFECTION IS HYPOTHESIZED TO TRIGGER A DYSREGULATED PERIPHERAL IMMUNE SYSTEM ACTIVATION WITH SUBSEQUENT CYTOKINE RELEASE. CHRONIC LOW-GRADE INFLAMMATION LEADS TO DYSREGULATED BRAIN MICROGLIA WITH AN EXAGGERATED RELEASE OF CENTRAL CYTOKINES, PRODUCING NEUROINFLAMMATION. IMMUNOTHROMBOSIS LINKED TO CHRONIC INFLAMMATION WITH MICROCLOT FORMATION LEADS TO DECREASED TISSUE PERFUSION AND ISCHEMIA. INTERMITTENT FATIGUE, POST EXERTIONAL MALAISE (PEM), CNS SYMPTOMS WITH "BRAIN FOG," ARTHRALGIAS, PARESTHESIAS, DYSAUTONOMIA, AND GI AND OPHTHALMIC PROBLEMS CAN CONSEQUENTLY ARISE AS RESULT OF THE ELEVATED PERIPHERAL AND CENTRAL CYTOKINES. THERE ARE ABUNDANT SIMILARITIES BETWEEN SYMPTOMS IN LONG COVID AND MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS). DNA POLYMORPHISMS AND VIRAL-INDUCED EPIGENETIC CHANGES TO CYTOKINE GENE EXPRESSION MAY LEAD TO CHRONIC INFLAMMATION IN LONG COVID PATIENTS, PREDISPOSING SOME TO DEVELOP AUTOIMMUNITY, WHICH MAY BE THE GATEWAY TO ME/CFS. 2023 2 3021 31 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 3 6576 27 TREATMENT OF PRIMARY SJOGREN SYNDROME. PRIMARY SJOGREN SYNDROME (PSS) IS A PROGRESSIVE AUTOIMMUNE DISEASE CHARACTERIZED BY SICCA AND SYSTEMIC MANIFESTATIONS. IN THIS REVIEW, WE SUMMARIZE THE AVAILABLE DATA ON TOPICAL AND SYSTEMIC MEDICATIONS, ACCORDING TO CLINICAL SIGNS AND DISEASE ACTIVITY, AND WE DESCRIBE THE ONGOING STUDIES USING BIOLOGIC DRUGS IN THE TREATMENT OF PSS. EXPANDING KNOWLEDGE ABOUT THE EPIDEMIOLOGY, CLASSIFICATION CRITERIA, SYSTEMIC ACTIVITY SCORING (ESSDAI) AND PATIENT-REPORTED OUTCOMES (ESSPRI) IS DRIVING ACTIVE RESEARCH. TREATMENT DECISIONS ARE BASED ON THE EVALUATION OF SYMPTOMS AND EXTRAGLANDULAR MANIFESTATIONS. SYMPTOMATIC TREATMENT IS USUALLY APPROPRIATE, WHEREAS SYSTEMIC TREATMENT IS RESERVED FOR SYSTEMIC MANIFESTATIONS. SICCA IS MANAGED BY EDUCATION, ENVIRONMENT MODIFICATION, ELIMINATION OF CONTINGENT OFFENDING DRUGS, ARTIFICIAL TEARS, SECRETAGOGUES AND TREATMENTS FOR COMPLICATIONS. MILD SYSTEMIC SIGNS SUCH AS FATIGUE ARE TREATED BY EXERCISE. PAIN CAN REQUIRE SHORT-TERM MODERATE-DOSE GLUCOCORTICOID THERAPY AND, IN SOME CASES, DISEASE-MODIFYING DRUGS. SEVERE AND ACUTE SYSTEMIC MANIFESTATIONS INDICATE TREATMENT WITH GLUCOCORTICOIDS AND/OR IMMUNOSUPPRESSANT DRUGS. THE ROLE FOR BIOLOGIC AGENTS IS PROMISING, BUT NO DOUBLE-BLIND RANDOMIZED CONTROLLED TRIALS (RCTS) PROVING THE EFFICACY OF THESE DRUGS ARE AVAILABLE. TARGETS FOR NEW TREATMENTS DIRECTED AGAINST THE IMMUNOPATHOLOGICAL MECHANISMS OF PSS INCLUDE EPITHELIAL CELLS, T CELLS, B-CELL OVERACTIVITY, THE INTERFERON SIGNATURE, PROINFLAMMATORY CYTOKINES, ECTOPIC GERMINAL CENTRE FORMATION, CHEMOKINES INVOLVED IN LYMPHOID CELL HOMING, AND EPIGENETIC MODIFICATIONS. 2016 4 1985 26 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 5 1261 30 CURRENT VIEWS ON THE PATHOGENESIS OF SJOGREN'S SYNDROME. PURPOSE OF REVIEW: THE PURPOSE OF THIS REVIEW IS TO PROVIDE AN INSIGHT INTO THE PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE PATHOGENESIS OF PRIMARY SJOGREN'S SYNDROME (PSS), HIGHLIGHTING RECENT FINDINGS WITH POTENTIAL THERAPEUTIC REPERCUSSIONS. RECENT FINDINGS: IN THE LAST 2 YEARS, EPIGENETIC ANALYSES PROVIDED NEW INSIGHTS INTO PSS PATHOGENESIS. CHARACTERIZATION OF DNA METHYLATION PATTERNS, CHROMATIN STRUCTURES AND MICRORNA CONFIRMED THE IMPORTANCE OF ABERRANT INTERFERON AND B-CELL RESPONSES IN THE DEVELOPMENT OF THE DISEASE. THE FORMATION OF ECTOPIC B-CELL FOLLICLES WITH GERMINAL CENTERS IS NOW A WELL RECOGNIZED PATHOGENIC MECHANISM WITHIN SALIVARY GLANDS OF PSS. IN THE CONTEXT OF ECTOPIC GERMINAL CENTERS REACTION, T/B-CELL INTERACTIONS, THAT IS REGARDING T-HELPER 17 AND T-FOLLICULAR HELPER CELLS, AND THEIR RESPECTIVE COUNTERPARTS, T-REGULATORY AND T-FOLLICULAR REGULATORY CELLS, APPEAR PARTICULARLY RELEVANT IN PSS PATHOGENESIS AS THEIR IMBALANCE IS ASSOCIATED WITH A DYSREGULATION OF B-CELL DYNAMICS AND THE PRODUCTION OF AUTOANTIBODIES. SUMMARY: ADVANCES IN THE UNDERSTANDING OF PSS PATHOGENESIS HAVE PAVED THE WAY FOR CLINICAL TRIALS WITH NOVEL BIOLOGIC AGENTS TARGETING IMMUNE PATHWAYS REGULATING T/B-CELL INTERACTIONS AND DOWNSTREAM B-CELL ACTIVATION. REVERSE TRANSLATION FROM THESE STUDIES PROVIDES INVALUABLE NOVEL INFORMATION OF THE MECHANISMS SUSTAINING AUTOIMMUNITY AND CHRONIC INFLAMMATION IN PSS. 2018 6 5518 23 RISK FACTORS AND FUTURE DIRECTIONS FOR PREVENTING AND DIAGNOSING EXERTIONAL RHABDOMYOLYSIS. EXERTIONAL RHABDOMYOLYSIS MAY OCCUR WHEN AN INDIVIDUAL IS SUBJECTED TO STRENUOUS PHYSICAL EXERCISE. IT IS OCCASIONALLY ASSOCIATED WITH MYOGLOBINURIA (I.E. "COLA-COLORED" URINE) ALONGSIDE MUSCLE PAIN AND WEAKNESS. THE PATHOPHYSIOLOGY OF EXERTIONAL RHABDOMYOLYSIS INVOLVES STRIATED MUSCLE DAMAGE AND THE RELEASE OF CELLULAR COMPONENTS INTO EXTRACELLULAR FLUID AND BLOODSTREAM. THIS CAN CAUSE ACUTE RENAL FAILURE, ELECTROLYTE ABNORMALITIES, ARRHYTHMIAS AND POTENTIALLY DEATH. EXERTIONAL RHABDOMYOLYSIS IS OBSERVED IN HIGH-PERFORMANCE ATHLETES WHO ARE SUBJECTED TO INTENSE, REPETITIVE AND/OR PROLONGED EXERCISE BUT IS ALSO OBSERVED IN UNTRAINED INDIVIDUALS AND HIGHLY TRAINED OR ELITE GROUPS OF MILITARY PERSONNEL. SEVERAL RISK FACTORS HAVE BEEN REPORTED TO INCREASE THE LIKELIHOOD OF THE CONDITION IN ATHLETES, INCLUDING: VIRAL INFECTION, DRUG AND ALCOHOL ABUSE, EXERCISE IN INTENSELY HOT AND HUMID ENVIRONMENTS, GENETIC POLYMORPHISMS (E.G. SICKLE CELL TRAIT AND MCARDLE DISEASE) AND EPIGENETIC MODIFICATIONS. THIS ARTICLE REVIEWS SEVERAL OF THESE RISK FACTORS AND PROPOSES SCREENING PROTOCOLS TO IDENTIFY INDIVIDUAL SUSCEPTIBILITY TO EXERTIONAL RHABDOMYOLYSIS AS WELL AS THE RELEVANCE OF PROTEOMICS FOR THE EVALUATION OF POTENTIAL BIOMARKERS OF MUSCLE DAMAGE. 2021 7 2 32 "DRY MOUTH" AND "FLAMMER" SYNDROMES-NEGLECTED RISKS IN ADOLESCENTS AND NEW CONCEPTS BY PREDICTIVE, PREVENTIVE AND PERSONALISED APPROACH. BACKGROUND: "DRY MOUTH" SYNDROME (CHRONIC HYPOSALIVATION) CAN BE CAUSED BY A NUMBER OF PATHOPHYSIOLOGICAL CONDITIONS SUCH AS ACUTE AND CHRONIC STRESS EXPOSURE, ABNORMAL BODY WEIGHT (BOTH TOO HIGH AND TOO LOW ONES), EATING DISORDERS (SUCH AS ANOREXIA NERVOSA), METABOLIC SYNDROME(S), SJOGREN'S AND SICCA SYNDROMES, DRUGS AND HEAD/NECK RADIOTHERAPY APPLICATION. IN TURN, THE CHRONIC HYPOSALIVATION AS A SUBOPTIMAL HEALTH CONDITION SIGNIFICANTLY REDUCES QUALITY OF LIFE, MAY INDICATE A SYSTEMIC DEHYDRATION, PROVOKES AND CONTRIBUTES TO A NUMBER OF PATHOLOGIES SUCH AS A STRONGLY COMPROMISED PROTECTION OF THE ORAL CAVITY, CHRONIC INFECTIONS AND INFLAMMATORY PROCESSES, PERIODONTITIS, VOICE AND DIGESTIVE DISORDERS. CONSEQUENTLY, "DRY MOUTH" SYNDROME MIGHT BE EXTREMELY USEFUL AS AN INDICATOR FOR AN IN-DEPTH DIAGNOSTICS OF BOTH-CO-EXISTING AND SNOWBALLING HEALTH-THREATING CONDITIONS. HOWEVER, PREDICTIVE DIAGNOSTICS, TARGETED PREVENTION AND PERSONALISATION OF TREATMENTS ARE EVIDENTLY UNDERDEVELOPED FOR INDIVIDUALS AT HIGH RISK SUFFERING FROM THE "DRY MOUTH" SYNDROME. WORKING HYPOTHESIS AND METHODOLOGY: IN THE CURRENT STUDY, WE HAVE HYPOTHESISED THAT INDIVIDUALS DEMONSTRATING "FLAMMER SYNDROME" (FS) PHENOTYPE MAY SUFFER FROM THE "DRY MOUTH" SYNDROME MORE FREQUENTLY, DUE TO DISTURBED MICROCIRCULATION, PSYCHOLOGICAL FACTORS (OBSESSIONAL PERSONALITY/PERFECTIONISM), AND DIMINISHED FEELING OF THIRST WITH CONSEQUENTLY INSUFFICIENT DAILY LIQUID INTAKE POTENTIALLY RESULTING IN THE SYSTEMIC DEHYDRATION WITH INDIVIDUALLY PRONOUNCED LEVEL OF SEVERITY. IF CONFIRMED, FS PHENOTYPING LINKED TO THE CHRONIC HYPOSALIVATION MIGHT BE PREDICTIVE FOR INDIVIDUALS AT RISK IDENTIFIED BY INNOVATIVE SCREENING PROGRAMMES. TO VERIFY THE WORKING HYPOTHESIS, HEALTHY INDIVIDUALS (NEGATIVE CONTROL GROUP) VERSUS INDIVIDUALS WITH EVIDENT HYPOSALIVATION AS WELL AS PATIENTS DIAGNOSED WITH PERIODONTITIS (POSITIVE CONTROL GROUP) OBSERVED AND TREATED AT THE DENTAL CLINIC WERE INVESTIGATED. THE DEGREE TO WHICH AN INDIVIDUAL IS AFFECTED BY HYPOSALIVATION WAS DETERMINED BY THE BOTHER XEROSTOMIA INDEX UTILISING A QUESTIONNAIRE OF 10 ISSUE-SPECIFIC ITEMS AND MONITORING OF A TYPICALLY MATT ROOF OF THE MOUTH IN DENTAL PRACTICE. AN EXTENT TO WHICH INDIVIDUALS INCLUDED IN THE STUDY ARE THE CARRIERS OF THE FS PHENOTYPE WAS ESTIMATED BY THE SPECIALISED 15-ITEM QUESTIONNAIRE. RESULTS AND CONCLUSIONS: FOR BOTH-THE TARGET GROUP (HYPOSALIVATION) AND POSITIVE CONTROL GROUP (PERIODONTITIS)-FS PHENOTYPE WAS DEMONSTRATED TO BE MORE SPECIFIC COMPARED TO THE DISEASE-FREE (NEGATIVE CONTROL) GROUP. MOREOVER, SELF-REPORTS PROVIDED BY INTERVIEWED ADOLESCENTS OF THE TARGET GROUP FREQUENTLY RECORDED REMARKABLE DISCOMFORT RELATED TO "DRY MOUTH" SYNDROME, ACUTE AND CHRONIC OTORHINOLARYNGOLOGICAL INFECTIONS AND EVEN DELAYED WOUND HEALING. FURTHER, INTERVIEWED ADOLESCENTS DO WORRY ABOUT THE SYMPTOMS WHICH MIGHT BE INDICATIVE FOR POTENTIAL DISEASES; THEY ARE ALSO AMAZED THAT TOO LITTLE ATTENTION IS CURRENTLY PAID TO THE ISSUE BY CAREGIVERS. IN CONCLUSION, FS QUESTIONNAIRE LINKED TO THE "DRY MOUTH" SYNDROME IS STRONGLY RECOMMENDED FOR APPLICATION IN PRIMARY HEALTHCARE. CONSEQUENTLY, TARGETED PREVENTIVE MEASURES CAN BE TRIGGERED EARLY IN LIFE. FOR EXAMPLE, TRADITIONAL, COMPLEMENTARY AND ALTERNATIVE MEDICINE DEMONSTRATES POSITIVE THERAPEUTIC EFFECTS IN INDIVIDUALS SUFFERING FROM XEROSTOMIA. FOR IN-DEPTH DIAGNOSTICS, EPI/GENETIC REGULATIONS INVOLVED INTO PATHOPHYSIOLOGIC MECHANISMS OF HYPOSALIVATION IN FS-AFFECTED INDIVIDUALS SHOULD BE THOROUGHLY INVESTIGATED AT MOLECULAR LEVEL. IDENTIFIED BIOMARKER PANELS MIGHT BE OF GREAT CLINICAL UTILITY FOR PREDICTIVE DIAGNOSTICS AND PATIENT STRATIFICATION THAT, FURTHER, WOULD SUFFICIENTLY IMPROVE PERSONALISED CARE TO THE PATIENT. 2018 8 4909 31 PAIN AND STRESS IN A SYSTEMS PERSPECTIVE: RECIPROCAL NEURAL, ENDOCRINE, AND IMMUNE INTERACTIONS. THIS PAPER ADVANCES A PSYCHOPHYSIOLOGICAL SYSTEMS VIEW OF PAIN IN WHICH PHYSICAL INJURY, OR WOUNDING, GENERATES A COMPLEX STRESS RESPONSE THAT EXTENDS BEYOND THE NERVOUS SYSTEM AND CONTRIBUTES TO THE EXPERIENCE OF PAIN. THROUGH A COMMON CHEMICAL LANGUAGE COMPRISING NEUROTRANSMITTERS, PEPTIDES, ENDOCANNABINOIDS, CYTOKINES, AND HORMONES, AN ENSEMBLE OF INTERDEPENDENT NERVOUS, ENDOCRINE, AND IMMUNE PROCESSES OPERATES IN CONCERT TO COPE WITH THE INJURY. THESE PROCESSES ACT AS A SINGLE AGENT AND COMPRISE A SUPERSYSTEM. ACUTE PAIN IN ITS MULTIPLE DIMENSIONS, AND THE RELATED SYMPTOMS THAT COMMONLY OCCUR WITH IT, ARE PRODUCTS OF THE SUPERSYSTEM. CHRONIC PAIN CAN DEVELOP AS A RESULT OF UNUSUAL STRESS. SOCIAL STRESSORS CAN COMPOUND THE STRESS RESULTING FROM A WOUND OR ACT ALONE TO DYSREGULATE THE SUPERSYSTEM. WHEN THE SUPERSYSTEM SUFFERS DYSREGULATION, HEALTH, FUNCTION, AND SENSE OF WELL-BEING SUFFER. SOME CHRONIC PAIN CONDITIONS ARE THE PRODUCT OF SUPERSYSTEM DYSREGULATION. INDIVIDUALS VARY AND ARE VULNERABLE TO DYSREGULATION AND DYSFUNCTION IN PARTICULAR ORGAN SYSTEMS DUE TO THE UNIQUE INTERACTIONS OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS, AS WELL AS THE PAST EXPERIENCES THAT CHARACTERIZE EACH PERSON. PERSPECTIVE: ACUTE TISSUE INJURY ACTIVATES AN ENSEMBLE OF INTERDEPENDENT NERVOUS, ENDOCRINE, AND IMMUNE PROCESSES THAT OPERATE IN CONCERT AND COMPRISE A SUPERSYSTEM. SOME CHRONIC PAIN CONDITIONS RESULT FROM SUPERSYSTEM DYSREGULATION. INDIVIDUALS VARY AND ARE VULNERABLE TO DYSREGULATION DUE TO THE UNIQUE INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AND PAST EXPERIENCES THAT CHARACTERIZE EACH PERSON. THIS PERSPECTIVE CAN POTENTIALLY ASSIST CLINICIANS IN ASSESSING AND MANAGING CHRONIC PAIN PATIENTS. 2008 9 6438 26 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 10 3041 23 GENOME-EPIGENOME INTERACTIONS ASSOCIATED WITH MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) IS A COMPLEX DISEASE OF UNKNOWN ETIOLOGY. MULTIPLE STUDIES POINT TO DISRUPTIONS IN IMMUNE FUNCTIONING IN ME/CFS PATIENTS AS WELL AS SPECIFIC GENETIC POLYMORPHISMS AND ALTERATIONS OF THE DNA METHYLOME IN LYMPHOCYTES. HOWEVER, POTENTIAL INTERACTIONS BETWEEN DNA METHYLATION AND GENETIC BACKGROUND IN RELATION TO ME/CFS HAVE NOT BEEN EXAMINED. IN THIS STUDY WE EXPLORED THIS ASSOCIATION BY CHARACTERIZING THE EPIGENETIC (~480 THOUSAND CPG LOCI) AND GENETIC (~4.3 MILLION SNPS) VARIATION BETWEEN COHORTS OF ME/CFS PATIENTS AND HEALTHY CONTROLS. WE FOUND SIGNIFICANT ASSOCIATIONS OF DNA METHYLATION STATES IN T-LYMPHOCYTES AT SEVERAL CPG LOCI AND REGIONS WITH ME/CFS PHENOTYPE. THESE METHYLATION ANOMALIES ARE IN CLOSE PROXIMITY TO GENES INVOLVED WITH IMMUNE FUNCTION AND CELLULAR METABOLISM. FINALLY, WE FOUND SIGNIFICANT CORRELATIONS OF GENOTYPES WITH METHYLATION MODIFICATIONS ASSOCIATED WITH ME/CFS. THE FINDINGS FROM THIS STUDY HIGHLIGHT THE ROLE OF EPIGENETIC AND GENETIC INTERACTIONS IN COMPLEX DISEASES, AND SUGGEST SEVERAL GENETIC AND EPIGENETIC ELEMENTS POTENTIALLY INVOLVED IN THE MECHANISMS OF DISEASE IN ME/CFS. 2018 11 823 25 CHARACTERIZATION OF COMPREHENSIVE DYNAMIC EPIGENETIC CHANGES DURING HUMAN PRIMARY SJOGREN'S SYNDROME PROGRESSION. BACKGROUND: PRIMARY SJOGREN'S SYNDROME (PSS) IS A SYSTEMIC AUTOIMMUNE DISEASE CHARACTERIZED BY REDUCED EXOCRINE GLAND (PRINCIPALLY THE SALIVARY AND LACRIMAL GLANDS) ACTIVITY CAUSED BY CHRONIC LYMPHOCYTIC INFILTRATION. ALTHOUGH PSS HAS BEEN CLOSELY ASSOCIATED WITH AN INCREASED RISK OF MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA, THE DYNAMIC EPIGENETIC CHANGES IN THE GLAND CELLS THAT ACCOMPANY THE PATHOGENESIS ARE NOT ENTIRELY UNDERSTOOD. METHODS: IN THIS STUDY, WE HARVESTED TISSUE SAMPLES FROM THE LABIAL GLAND WITH (LG_PSS) OR WITHOUT PSS (LG_NC) BEFORE MALT DEVELOPMENT, AS WELL AS THE PAROTID GLAND WITH TUMOR TISSUES (PG_MALT) AND PARACANCEROUS TISSUES (PG_NC) OF TWO PSS PATIENTS WITH MALT LYMPHOMA, AND CONDUCTED RNA-SEQ AND CHIP-SEQ FOR TRI-METHYLATED HISTONE 3 LYSINE 4, 9, 27, 36, AND 79 (H3K4/9/27/36/79ME3). RESULTS: TRANSCRIPTOME LANDSCAPES INDICATED TWO OUTCOMES OF PSS PROGRESSION WITH OR WITHOUT MALT LYMPHOMA REPRESENTED BY DISTINCT POPULATIONS OF DIFFERENTIALLY EXPRESSED GENES AND THEIR FUNCTIONS. FURTHERMORE, THE EPIGENETIC ATLAS OF GENOME-WIDE H3K4/9/27/36/79ME3 WAS IN DIFFERENT STAGES FOR VARIOUS SAMPLES, INDICATING THAT THE VARIANCE OF H3K4ME3 WAS THE EARLIEST EVENT, FOLLOWED BY SELECTIVE ALTERATIONS OF H3K9/27/36/79ME3. THESE FOUR EPIGENETIC MODIFICATIONS DETERMINE THE FINAL OUTCOME OF PSS PROGRESSION. CONCLUSIONS: OUR RESULTS NOT ONLY ADVANCE THE UNDERSTANDING OF THE DYNAMICS OF PSS PROGRESSION AND HIGHLIGHT THE IMPORTANCE OF EPIGENETIC ALTERATIONS IN REGULATING TRANSCRIPTION DURING THIS PATHOLOGICAL PROCESS, BUT ALSO IDENTIFY POTENTIAL THERAPEUTIC TARGETS FOR PSS TREATMENT AND LYMPHOMA INTERVENTION. 2021 12 5317 32 PSYCHOLOGICAL STRESS, INTESTINAL BARRIER DYSFUNCTIONS, AND AUTOIMMUNE DISORDERS: AN OVERVIEW. AUTOIMMUNE DISORDERS (ADS) ARE MULTIFACTORIAL DISEASES INVOLVING, GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS CHARACTERIZED BY AN INAPPROPRIATE IMMUNE RESPONSE TOWARD SELF-ANTIGENS. IN THE PAST DECADES, THERE HAS BEEN A CONTINUOUS RISE IN THE INCIDENCE OF ADS, WHICH CANNOT BE EXPLAINED BY GENETIC FACTORS ALONE. INFLUENCE OF PSYCHOLOGICAL STRESS ON THE DEVELOPMENT OR THE COURSE OF AUTOIMMUNE DISORDERS HAS BEEN DISCUSSED FOR A LONG TIME. INDEED, BASED ON EPIDEMIOLOGICAL STUDIES, STRESS HAS BEEN SUGGESTED TO PRECEDE AD OCCURRENCE AND TO EXACERBATE SYMPTOMS. FURTHERMORE, COMPILING DATA SHOWED THAT MOST OF ADS ARE ASSOCIATED WITH GASTROINTESTINAL SYMPTOMS, THAT IS, MICROBIOTA DYSBIOSIS, INTESTINAL HYPERPERMEABILITY, AND INTESTINAL INFLAMMATION. INTERESTINGLY, SOCIAL STRESS (ACUTE OR CHRONIC, IN ADULT OR IN NEONATE) IS A WELL-DESCRIBED INTESTINAL DISRUPTING FACTOR. TAKEN TOGETHER, THOSE OBSERVATIONS QUESTION A POTENTIAL ROLE OF STRESS-INDUCED DEFECT OF THE INTESTINAL BARRIER IN THE ONSET AND/OR THE COURSE OF ADS. IN THIS REVIEW, WE AIM TO PRESENT EVIDENCES SUPPORTING THE HYPOTHESIS FOR A ROLE OF STRESS-INDUCED INTESTINAL BARRIER DISRUPTION IN THE ONSET AND/OR THE COURSE OF ADS. WE WILL MAINLY FOCUS ON AUTOIMMUNE TYPE 1 DIABETES, MULTIPLE SCLEROSIS AND SYSTEMIC LUPUS ERYTHEMATOSUS, ADS FOR WHICH WE COULD FIND SUFFICIENT CIRCUMSTANTIAL DATA TO SUPPORT THIS HYPOTHESIS. WE EXCLUDED GASTROINTESTINAL (GI) ADS LIKE COELIAC DISEASE TO PRIVILEGE ADS NOT FOCUSED ON INTESTINAL DISORDERS TO AVOID CONFOUNDING FACTORS. INDEED, GIADS ARE CHARACTERIZED BY ANTIBODIES DIRECTED AGAINST INTESTINAL BARRIER ACTORS. 2020 13 207 34 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 14 2294 37 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 15 5104 14 POLYCYSTIC OVARIAN SYNDROME. WOMEN WITH PCOS PRESENT WITH SIGNS OF CHRONIC ANOVULATION, HYPERANDROGENISM, AND METABOLIC ABNORMALITIES. THE NIH RECENTLY EMBRACED THE ROTTERDAM CRITERIA TO BROADLY IDENTIFY ALL THE PHENOTYPES OF PCOS. WOMEN WITH PCOS ARE OFTEN OBESE WITH INSULIN RESISTANCE AND HENCE HAVE AN INCREASED SUSCEPTIBILITY TO GLUCOSE INTOLERANCE AND TYPE 2 DIABETES. FUTURE RESEARCH SHOULD FOCUS ON THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS OF PCOS TO DEVELOP NEW THERAPIES TO ADDRESS THE PREVENTION OF THIS DISORDER AND ITS LONG-TERM COMPLICATIONS. 2015 16 3701 26 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022 17 5885 31 SYSTEMIC LUPUS ERYTHEMATOSUS FOLLOWING HUMAN PAPILLOMAVIRUS VACCINATION: A CASE-BASED REVIEW. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A HETEROGENEOUS SYSTEMIC AUTOIMMUNE DISEASES (AIDS) WITH MANY PATHOGENIC FACTORS, RANGING FROM GENETIC TO EPIGENETIC TO ENVIRONMENTAL. THE HUMAN PAPILLOMAVIRUS (HPV), A VIRAL INFECTIOUS AGENT, IS A COMMON CONTRIBUTOR TO THE ONSET AND EXACERBATION OF SLE. HPV INFECTIONS ARE MORE PREVALENT AMONG SLE PATIENTS THAN HEALTHY INDIVIDUALS, BRINGING ABOUT A SUBSTANTIAL NEED FOR TREATMENT. WHILE HPV RECOMBINANT GENE VACCINES ARE ACCEPTED AS A UNIVERSAL METHOD FOR INFECTION PREVENTION, THEY POSE A RISK FOR ADVERSE EVENTS SUCH AS FEVER, JOINT PAIN, AND RASHES. IN RARE CASES, THEY MIGHT EVEN TRIGGER AIDS SUCH AS SLE, ESPECIALLY IN PATIENTS WITH A PERSONAL OR FAMILY HISTORY OF SUCH DISEASES. IN THIS ARTICLE, WE PROVIDE A REPORT OF A CASE OF SLE ONSET FOLLOWING HPV VACCINATION AND A REVIEW OF 11 SIMILAR CASES. AN ANALYSIS OF 12 PATIENTS REVEALED THAT 7 CASES OF SLE DEVELOPED BETWEEN 3 WEEKS AND 2 MONTHS POST-VACCINATION. SYMPTOMS OF SLE GENERALLY MANIFEST AS FATIGUE, FEVER, JOINT PAIN, AND MYALGIA. TWO PATIENTS HAD LUPUS NEPHRITIS, 2 SHOWED CENTRAL NERVOUS SYSTEM INVOLVEMENT, INCLUDING ABNORMAL BEHAVIOR AND EPILEPTIC SEIZURES, AND 1 HAD INTESTINAL PSEUDO-OBSTRUCTION. ALL PATIENTS SHOWED RAPID REMISSION WITH GLUCOCORTICOID AND IMMUNOSUPPRESSIVE THERAPY AND REMAINED STABLE DURING SEVERAL MONTHS OF FOLLOW-UP. 2022 18 4973 41 PATHOPHYSIOLOGICAL EFFECTS OF CONTEMPORARY LIFESTYLE ON EVOLUTIONARY-CONSERVED SURVIVAL MECHANISMS IN POLYCYSTIC OVARY SYNDROME. POLYCYSTIC OVARY SYNDROME (PCOS) IS INCREASINGLY BEING CHARACTERIZED AS AN EVOLUTIONARY MISMATCH DISORDER THAT PRESENTS WITH A COMPLEX MIXTURE OF METABOLIC AND ENDOCRINE SYMPTOMS. THE EVOLUTIONARY MODEL PROPOSES THAT PCOS ARISES FROM A COLLECTION OF INHERITED POLYMORPHISMS THAT HAVE BEEN CONSISTENTLY DEMONSTRATED IN A VARIETY OF ETHNIC GROUPS AND RACES. IN UTERO DEVELOPMENTAL PROGRAMMING OF SUSCEPTIBLE GENOMIC VARIANTS ARE THOUGHT TO PREDISPOSE THE OFFSPRING TO DEVELOP PCOS. POSTNATAL EXPOSURE TO LIFESTYLE AND ENVIRONMENTAL RISK FACTORS RESULTS IN EPIGENETIC ACTIVATION OF DEVELOPMENTALLY PROGRAMMED GENES AND DISTURBANCE OF THE HALLMARKS OF HEALTH. THE RESULTING PATHOPHYSIOLOGICAL CHANGES REPRESENT THE CONSEQUENCES OF POOR-QUALITY DIET, SEDENTARY BEHAVIOUR, ENDOCRINE DISRUPTING CHEMICALS, STRESS, CIRCADIAN DISRUPTION, AND OTHER LIFESTYLE FACTORS. EMERGING EVIDENCE SUGGESTS THAT LIFESTYLE-INDUCED GASTROINTESTINAL DYSBIOSIS PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF PCOS. LIFESTYLE AND ENVIRONMENTAL EXPOSURES INITIATE CHANGES THAT RESULT IN DISTURBANCE OF THE GASTROINTESTINAL MICROBIOME (DYSBIOSIS), IMMUNE DYSREGULATION (CHRONIC INFLAMMATION), ALTERED METABOLISM (INSULIN RESISTANCE), ENDOCRINE AND REPRODUCTIVE IMBALANCE (HYPERANDROGENISM), AND CENTRAL NERVOUS SYSTEM DYSFUNCTION (NEUROENDOCRINE AND AUTONOMIC NERVOUS SYSTEM). PCOS CAN BE A PROGRESSIVE METABOLIC CONDITION THAT LEADS TO OBESITY, GESTATIONAL DIABETES, TYPE TWO DIABETES, METABOLIC-ASSOCIATED FATTY LIVER DISEASE, METABOLIC SYNDROME, CARDIOVASCULAR DISEASE, AND CANCER. THIS REVIEW EXPLORES THE MECHANISMS THAT UNDERPIN THE EVOLUTIONARY MISMATCH BETWEEN ANCIENT SURVIVAL PATHWAYS AND CONTEMPORARY LIFESTYLE FACTORS INVOLVED IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF PCOS. 2023 19 6375 36 THE ROLE OF NEURO-IMMUNE INTERACTION IN CHRONIC PAIN CONDITIONS; FUNCTIONAL SOMATIC SYNDROME, NEUROGENIC INFLAMMATION, AND PERIPHERAL NEUROPATHY. FUNCTIONAL SOMATIC SYNDROMES ARE INCREASINGLY DIAGNOSED IN CHRONICALLY ILL PATIENTS PRESENTING WITH AN ARRAY OF SYMPTOMS NOT ATTRIBUTED TO PHYSICAL AILMENTS. CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, OR IRRITABLE BOWEL SYNDROME ARE COMMON DISORDERS THAT BELONG IN THIS BROAD CATEGORY. SUCH SYNDROMES ARE CHARACTERISED BY THE PRESENCE OF ONE OR MULTIPLE CHRONIC SYMPTOMS INCLUDING WIDESPREAD MUSCULOSKELETAL PAIN, FATIGUE, SLEEP DISORDERS, AND ABDOMINAL PAIN, AMONGST OTHER ISSUES. SYMPTOMS ARE BELIEVED TO RELATE TO A COMPLEX INTERACTION OF BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WHERE A DEFINITE AETIOLOGY HAS NOT BEEN ESTABLISHED. THEORIES SUGGEST CAUSATIVE PATHWAYS BETWEEN THE IMMUNE AND NERVOUS SYSTEMS OF AFFECTED INDIVIDUALS WITH SEVERAL RISK FACTORS IDENTIFIED IN PATIENTS PRESENTING WITH ONE OR MORE FUNCTIONAL SYNDROMES. RISK FACTORS INCLUDING STRESS AND CHILDHOOD TRAUMA ARE NOW RECOGNISED AS IMPORTANT CONTRIBUTORS TO CHRONIC PAIN CONDITIONS. EMOTIONAL, PHYSICAL, AND SEXUAL ABUSE DURING CHILDHOOD IS CONSIDERED A SEVERE STRESSOR HAVING A HIGH PREVALENCE IN FUNCTIONAL SOMATIC SYNDROME SUFFERS. SUCH TRAUMA PERMANENTLY ALTERS THE BIOLOGICAL STRESS RESPONSE OF THE SUFFERS LEADING TO NEUROEXCITATORY AND OTHER NERVE ISSUES ASSOCIATED WITH CHRONIC PAIN IN ADULTS. TRAUMATIC AND CHRONIC STRESS RESULTS IN EPIGENETIC CHANGES IN STRESS RESPONSE GENES, WHICH ULTIMATELY LEADS TO DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY AXIS, THE AUTONOMIC NERVOUS SYSTEM, AND THE IMMUNE SYSTEM MANIFESTING IN A BROAD ARRAY OF SYMPTOMS. IMPORTANTLY, THESE SYSTEMS ARE KNOWN TO BE DYSREGULATED IN PATIENTS SUFFERING FROM FUNCTIONAL SOMATIC SYNDROME. FUNCTIONAL SOMATIC SYNDROMES ARE ALSO HIGHLY PREVALENT CO-MORBIDITIES OF PSYCHIATRIC CONDITIONS, MOOD DISORDERS, AND ANXIETY. CONSEQUENTLY, THIS REVIEW AIMS TO PROVIDE INSIGHT INTO THE ROLE OF THE NERVOUS SYSTEM AND IMMUNE SYSTEM IN CHRONIC PAIN DISORDERS ASSOCIATED WITH THE MUSCULOSKELETAL SYSTEM, AND CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. 2022 20 5221 26 PRIMARY BILIARY CHOLANGITIS: PATHOGENESIS AND THERAPEUTIC OPPORTUNITIES. PRIMARY BILIARY CHOLANGITIS IS A CHRONIC, SEROPOSITIVE AND FEMALE-PREDOMINANT INFLAMMATORY AND CHOLESTATIC LIVER DISEASE, WHICH HAS A VARIABLE RATE OF PROGRESSION TOWARDS BILIARY CIRRHOSIS. SUBSTANTIAL PROGRESS HAS BEEN MADE IN PATIENT RISK STRATIFICATION WITH THE GOAL OF PERSONALIZED CARE, INCLUDING EARLY ADOPTION OF NEXT-GENERATION THERAPY WITH LICENSED USE OF OBETICHOLIC ACID OR OFF-LABEL FIBRATE DERIVATIVES FOR THOSE WITH INSUFFICIENT BENEFIT FROM URSODEOXYCHOLIC ACID, THE CURRENT FIRST-LINE DRUG. THE DISEASE BIOLOGY SPANS GENETIC RISK, EPIGENETIC CHANGES, DYSREGULATED MUCOSAL IMMUNITY AND ALTERED BILIARY EPITHELIAL CELL FUNCTION, ALL OF WHICH INTERACT AND ARISE IN THE CONTEXT OF ILL-DEFINED ENVIRONMENTAL TRIGGERS. A CURRENT FOCUS OF RESEARCH ON NUCLEAR RECEPTOR PATHWAY MODULATION THAT SPECIFICALLY AND POTENTLY IMPROVES BILIARY EXCRETION, REDUCES INFLAMMATION AND ATTENUATES FIBROSIS IS REDEFINING THERAPY. PATIENTS ARE BENEFITING FROM PHARMACOLOGICAL AGONISTS OF FARNESOID X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS. IMMUNOTHERAPY REMAINS A CHALLENGE, WITH A LACK OF TARGET DEFINITION, PLEIOTROPIC IMMUNE PATHWAYS AND AN INTERPLAY BETWEEN HEPATIC IMMUNE RESPONSES AND CHOLESTASIS, WHEREIN BILE ACID-INDUCED INFLAMMATION AND FIBROSIS ARE DOMINANT CLINICALLY. THE MANAGEMENT OF PATIENT SYMPTOMS, PARTICULARLY PRURITUS, IS A NOTABLE GOAL REFLECTED IN THE DEVELOPMENT OF RATIONAL THERAPY WITH APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITORS. 2020