1 4667 148 NEW INSIGHTS INTO ADULT AND PAEDIATRIC CHRONIC NON-BACTERIAL OSTEOMYELITIS CNO. PURPOSE OF REVIEW: TO DESCRIBE IN DETAIL THE CLINICAL SYNOPSIS AND PATHOPHYSIOLOGY OF CHRONIC NON-BACTERIAL OSTEOMYELITIS AND SAPHO SYNDROME. RECENT FINDINGS: CHRONIC NON-BACTERIAL OSTEOMYELITIS (CNO) HAS BEEN IDENTIFIED AS A DISEASE ENTITY FOR ALMOST 50 YEARS. THIS INFLAMMATORY BONE DISORDER IS CHARACTERIZED BY OSTEOLYTIC AS WELL AS HYPEROSTOTIC/OSTEOSCLEROTIC LESIONS. IT IS CHRONIC IN NATURE, BUT IT CAN PRESENT WITH EPISODIC FLAIRS AND PHASES OF REMISSION, WHICH HAVE LED TO THE DENOMINATION "CHRONIC RECURRENT OSTEOMYELITIS", WITH ITS SEVERE MULTIFOCAL FORM "CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS" (CRMO). FOR ALMOST THREE DECADES, AN INFECTIOUS AETIOLOGY HAD BEEN CONSIDERED, SINCE ESPECIALLY PROPIONIBACTERIUM ACNES HAD BEEN ISOLATED FROM BONE LESIONS OF INDIVIDUAL PATIENTS. HOWEVER, THIS CONCEPT HAS BEEN CHALLENGED SINCE LONG-TERM ANTIBIOTIC THERAPY DID NOT ALTER THE COURSE OF DISEASE AND MODERN MICROBIOLOGICAL TECHNIQUES (INCLUDING PCR) FAILED TO CONFIRM BONE INFECTION AS AN UNDERLYING CAUSE. OVER RECENT YEARS, A PROFOUND DYSREGULATION OF CYTOKINE EXPRESSION PROFILES HAS BEEN DEMONSTRATED IN INNATE IMMUNE CELLS OF CNO PATIENTS. A HALLMARK OF MONOCYTES FROM CNO PATIENTS IS THE FAILURE TO PRODUCE IMMUNE REGULATORY CYTOKINES INTERLEUKIN-10 (IL-10) AND IL-19, WHICH HAVE BEEN LINKED WITH GENETIC AND EPIGENETIC ALTERATIONS. SUBSEQUENTLY, A SIGNIFICANT UPREGULATION OF PRO-INFLAMMATORY, NLRP3 INFLAMMASOME-DEPENDENT CYTOKINES (IL-1BETA AND TNF-ALPHA), HAS BEEN DEMONSTRATED. THE CURRENT KNOWLEDGE ON CNO, THE UNDERLYING MOLECULAR PATHOPHYSIOLOGY, AND MODERN IMAGING STRATEGIES ARE SUMMARIZED; DIFFERENTIAL DIAGNOSES, TREATMENT OPTIONS, OUTCOME MEASURES, AS WELL AS QUALITY OF LIFE STUDIES ARE DISCUSSED. 2020 2 6345 43 THE ROLE OF EPIGENETICS IN AUTOIMMUNE/INFLAMMATORY DISEASE. HISTORICALLY, SYSTEMIC SELF-INFLAMMATORY CONDITIONS WERE CLASSIFIED AS EITHER AUTOINFLAMMATORY AND CAUSED BY THE INNATE IMMUNE SYSTEM OR AUTOIMMUNE AND DRIVEN BY ADAPTIVE IMMUNE RESPONSES. HOWEVER, IT BECAME CLEAR THAT REALITY IS MUCH MORE COMPLEX AND THAT AUTOIMMUNE/INFLAMMATORY CONDITIONS RANGE ALONG AN "INFLAMMATORY SPECTRUM" WITH PRIMARILY AUTOINFLAMMATORY VS. AUTOIMMUNE CONDITIONS RESEMBLING EXTREMES AT EITHER END. EPIGENETIC MODIFICATIONS INFLUENCE GENE EXPRESSION AND ALTER CELLULAR FUNCTIONS WITHOUT MODIFYING THE GENOMIC SEQUENCE. METHYLATION OF CPG DNA DINUCLEOTIDES AND/OR THEIR HYDROXYMETHYLATION, POST-TRANSLATIONAL MODIFICATIONS TO AMINO TERMINI OF HISTONE PROTEINS, AND NON-CODING RNA EXPRESSION ARE MAIN EPIGENETIC EVENTS. THE PATHOPHYSIOLOGY OF AUTOIMMUNE/INFLAMMATORY DISEASES HAS BEEN CLOSELY LINKED WITH DISEASE CAUSING GENE MUTATIONS (RARE) OR A COMBINATION OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS ARISING FROM EXPOSURE TO THE ENVIRONMENT (MORE COMMON). OVER RECENT YEARS, PROGRESS HAS BEEN MADE IN UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN SYSTEMIC INFLAMMATION AND THE CONTRIBUTION OF INNATE AND ADAPTIVE IMMUNE RESPONSES. EPIGENETIC EVENTS HAVE BEEN IDENTIFIED AS (I) CENTRAL PATHOPHYSIOLOGICAL FACTORS IN ADDITION TO GENETIC DISEASE PREDISPOSITION AND (II) AS CO-FACTORS DETERMINING CLINICAL PICTURES AND OUTCOMES IN INDIVIDUALS WITH MONOGENIC DISEASE. THUS, A COMPLETE UNDERSTANDING OF EPIGENETIC CONTRIBUTORS TO AUTOIMMUNE/INFLAMMATORY DISEASE WILL RESULT IN APPROACHES TO PREDICT INDIVIDUAL DISEASE OUTCOMES AND THE INTRODUCTION OF EFFECTIVE, TARGET-DIRECTED, AND TOLERABLE THERAPIES. HERE, WE SUMMARIZE RECENT FINDINGS THAT SIGNIFY THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN AUTOIMMUNE/INFLAMMATORY DISORDERS ALONG THE INFLAMMATORY SPECTRUM CHOOSING THREE EXAMPLES: THE AUTOINFLAMMATORY BONE CONDITION CHRONIC NONBACTERIAL OSTEOMYELITIS (CNO), THE "MIXED PATTERN" DISORDER PSORIASIS, AND THE AUTOIMMUNE DISEASE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). 2019 3 986 34 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) AND JUVENILE SPONDYLOARTHRITIS (JSPA): TO WHAT EXTENT ARE THEY RELATED? CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY DISEASE OCCURRING MAINLY IN THE PEDIATRIC AGE GROUP (BEFORE 16 YEARS) AND GENERALLY PRESENTS AS A SEPARATE ENTITY. SYNOVITIS, ACNE, PUSTULOSIS, HYPEROSTOSIS AND OSTEITIS (SAPHO) SYNDROME COMBINES OSTEOARTICULAR AND CUTANEOUS INVOLVEMENT, SIMILAR TO CRMO, AND FALLS INTO THE SPECTRUM OF SPONDYLOARTHRITIS (SPA). THE FACT THAT A PATIENT CAN PROGRESS FROM ONE DISEASE TO ANOTHER RAISES THE QUESTION OF WHETHER CRMO, LIKE SAPHO, COULD FALL WITHIN THE SPECTRUM OF SPA, RANGING FROM A PREDOMINANTLY OSTEOARTICULAR FORM TO AN ENTHESITIC FORM WITH MORE OR LESS MARKED SKIN INVOLVEMENT. IN THIS REVIEW, WE SET OUT TO DISCUSS THIS HYPOTHESIS BY HIGHLIGHTING THE DIFFERENCES AND SIMILARITIES BETWEEN CRMO AND JUVENILE SPA IN CLINICAL, RADIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTS. A COMMON HYPOTHESIS COULD POTENTIALLY CONSIDER INTESTINAL DYSBIOSIS AS THE ORIGIN OF THESE DIFFERENT INFLAMMATORY DISEASES. INTERINDIVIDUAL FACTORS SUCH AS GENDER, ENVIRONMENT, GENETICS AND/OR EPIGENETIC BACKGROUND COULD ACT AS COMBINED DISEASE MODIFIERS. THIS IS WHY WE SUGGEST THAT PATHOPHYSIOLOGY, RATHER THAN CLINICAL PHENOTYPE, BE USED TO RECLASSIFY THESE DISEASES. 2023 4 5905 40 TACKLING THE HETEROGENEITY OF CVID. PURPOSE OF REVIEW: COMMON VARIABLE IMMUNODEFICIENCY IS CLINICALLY THE MOST RELEVANT PRIMARY IMMUNODEFICIENCY OF THE ADULT. ITS HETEROGENEITY HAS HINDERED PROGRESS IN THE PATHOGENETIC UNDERSTANDING OF THE MAJORITY OF COMMON VARIABLE IMMUNODEFICIENCY PATIENTS. THIS ABSTRACT SUMMARIZES RECENT ASPECTS OF THE FIELD AND EMPHASIZES THE NEED FOR A COMMONLY ACCEPTED APPROACH TO CLASSIFY COMMON VARIABLE IMMUNODEFICIENCY. RECENT FINDINGS: IN THE LAST 2 YEARS, THE FIRST GENETIC DEFECTS UNDERLYING COMMON VARIABLE IMMUNODEFICIENCY, INCLUDING ICOS, TACI, BAFF-R AND CD19, HAVE BEEN IDENTIFIED. THE ANALYSIS OF DENDRITIC CELLS DEMONSTRATED ALTERATIONS IN A MAJORITY OF PATIENTS IN ADDITION TO THE DISTURBED T AND B-CELL FUNCTION. SEVERAL CHANGES OF THE ADAPTIVE IMMUNE SYSTEM MIGHT BE SECONDARY TO AN UNDERLYING CHRONIC INFLAMMATORY SETTING POSSIBLY DUE TO A HHV8 INFECTION IN A SUBGROUP OF PATIENTS WITH GRANULOMATOUS DISEASE, AUTOIMMUNE PHENOMENA AND T-CELL DYSFUNCTION. THE OCCURRENCE OF GRANULOMATOUS INFLAMMATION IS ASSOCIATED WITH A WORSE PROGNOSIS COMPARED WITH COMMON VARIABLE IMMUNODEFICIENCY PATIENTS WITHOUT GRANULOMA. SUMMARY: THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY INCLUDES DISTURBANCES OF THE ADAPTIVE AS WELL AS INNATE IMMUNE SYSTEM. IDENTIFIED MONOGENIC DEFECTS ACCOUNT FOR ABOUT 10% OF CASES, LEAVING THE MAJORITY OF DEFECTS UNDEFINED AND CERTAINLY IN PART EPIGENETIC. TO COMBINE THE KNOWN ASPECTS OF THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY TO A CONCLUSIVE PICTURE, THE CLINICAL AND IMMUNOLOGIC PHENOTYPING OF PATIENTS NEEDS TO BE STANDARDIZED. 2005 5 845 36 CHILDHOOD ATOPIC DERMATITIS: CURRENT DEVELOPMENTS, TREATMENT APPROACHES, AND FUTURE EXPECTATIONS. ATOPIC DERMATITIS (AD) IS THE MOST COMMON CHRONIC INFLAMMATORY SKIN DISORDER OF CHILDHOOD. UNDERLYING FACTORS THAT CONTRIBUTE TO AD ARE IMPAIRED EPITHELIAL BARRIER, ALTERATIONS IN THE LIPID COMPOSITION OF THE SKIN, IMMUNOLOGICAL IMBALANCE INCLUDING INCREASED TH2/TH1 RATIO, PROINFLAMMATORY CYTOKINES, DECREASED T REGULATORY CELLS, GENETIC MUTATIONS, AND EPIGENETIC ALTERATIONS. ATOPIC DERMATITIS IS A MULTIFACTORIAL DISEASE WITH A PARTICULARLY COMPLICATED PATHOPHYSIOLOGY. DISCOVERIES TO DATE MAY BE CONSIDERED THE TIP OF THE ICEBERG, AND THE INCREASING NUMBER OF STUDIES IN THIS FIELD INDICATE THAT THERE ARE MANY POINTS TO BE ELUCIDATED IN AD PATHOPHYSIOLOGY. IN THIS REVIEW, WE AIMED TO ILLUSTRATE THE CURRENT UNDERSTANDING OF THE UNDERLYING PATHOGENIC MECHANISMS IN AD, TO EVALUATE AVAILABLE TREATMENT OPTIONS WITH A FOCUS ON RECENTLY DISCOVERED THERAPEUTIC AGENTS, AND TO DETERMINE THE PERSONAL, FAMILIAL, AND ECONOMIC BURDENS OF THE DISEASE, WHICH ARE FREQUENTLY NEGLECTED ISSUES IN AD. CURRENTLY AVAILABLE THERAPIES ONLY PROVIDE TRANSIENT SOLUTIONS AND CANNOT FULLY CURE THE DISEASE. HOWEVER, ADVANCES IN THE UNDERSTANDING OF THE PATHOGENIC MECHANISMS OF THE DISEASE HAVE LED TO THE PRODUCTION OF NEW TREATMENT OPTIONS, WHILE ONGOING DRUG TRIALS ALSO HAVE HAD PROMISING RESULTS. 2019 6 3016 33 GENETICS AND EPIGENETICS OF IBD. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC INTERMITTENT INFLAMMATORY DISORDERS OF THE GASTROINTESTINAL TRACT OF UNKNOWN ETIOLOGY BUT A CLEAR GENETIC PREDISPOSITION. PROMPTED BY THE FIRST INVESTIGATIONS ON IBD FAMILIES AND TWINS, THE GENETIC AND EPIGENETIC STUDIES HAVE PRODUCED AN UNPRECEDENTED AMOUNT OF INFORMATION IN COMPARISON WITH OTHER IMMUNE-MEDIATED OR COMPLEX DISEASES. NEW INFLAMMATORY PATHWAYS AND POSSIBLE MECHANISMS OF ACTION HAVE BEEN DISCLOSED, POTENTIALLY LEADING TO NEW-TARGETED THERAPY. HOWEVER, THE IDENTIFICATION OF GENETIC MARKERS DUE TO THE GREAT DISEASE HETEROGENEITY AND THE OVERWHELMING CONTRIBUTION OF ENVIRONMENTAL RISK FACTORS HAS NOT MODIFIED YET THE DISEASE MANAGEMENT. THE POSSIBILITY FOR THE FUTURE OF A BETTER PREDICTION OF DISEASE COURSE, RESPONSE TO THERAPY AND THERAPY-RELATED ADVERSE EVENTS MAY ALLOW A MORE EFFICIENT AND PERSONALIZED STRATEGY. THIS REVIEW WILL FOCUS ON MORE RECENT DISCOVERIES THAT MAY POTENTIALLY BE OF RELEVANCE IN DAILY CLINICAL PRACTICE. 2020 7 6791 30 [DOES THE NUMBER OF PATIENTS WITH AUTOIMMUNE DISORDERS AND THE FREQUENCY OF AUTOIMMUNE DISEASES INCREASE?]. AUTOIMMUNE DISEASES GENERALLY BELONG TO THE RARE DISEASES, HOWEVER, SOME OF THEM ARE FREQUENT IN THE POPULATION. IN THE PRESENT WORK THE AUTHORS ANALYSE WHETHER CAN ANY INCREASE BE OBSERVED IN THE NUMBER OF PATIENTS SUFFERING FROM AUTOIMMUNE DISEASES AND WHETHER DO THE FREQUENCY OF CERTAIN AUTOIMMUNE DISORDERS INCREASE. DUE MAINLY TO EPIGENETIC FACTORS THE INCIDENCE OF AUTOIMMUNE DISEASES ARE INCREASING, THEREFORE THERE ARE MORE PATIENTS RECOGNISED WITH PARTICULAR DISORDERS. ON THE OTHER HAND THE INCIDENCE IS INCREASED BY IMPROVING DIAGNOSTIC POSSIBILITIES, BY THE USE OF MORE SPECIFIC AND SENSITIVE CLASSIFICATION CRITERIA AND MORE SOPHISTICATED LABORATORY TESTS, RESULTED IN THE RECOGNITION OF MILDER AND ATYPICAL DISEASE VARIANTS AS WELL. THE PREVALENCE IS ALSO INCREASING IN CONSEQUENCE OF NOVEL IMMUNE SUPPRESSIVE THERAPEUTIC POSSIBILITIES AND THE CONSEQUENT IMPROVEMENT OF SURVIVAL IN THE MOST OF THESE DISEASES. BESIDES, MORE AND MORE DISEASES HAVE BEEN REVEALED TO HAVE AUTOIMMUNE BACKGROUND, AND LOT OF NEW AUTOIMMUNE SYNDROMES, DISEASES HAVE BEEN CHARACTERISED RECENTLY. THIS INCREASES THE NUMBER OF THE KNOWN AUTOIMMUNE RHEUMATIC DISORDERS WITH A CONSEQUENT INCREASE IN THE NUMBER OF AUTOIMMUNE PATIENTS. ASSIGNED TO THE INCREASING NUMBER OF VARIABLE CHRONIC AUTOIMMUNE DISORDERS, AND THE INCREASING NUMBER OF DISABLED PATIENTS WITH SUCH DISEASES INCREASING MEDICAL AND SOCIAL ATTENTION HAS TO BE FOCUSED ON. 2007 8 2591 38 EPIGENETICS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE, INVOLVING THE RAPID PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES AND ACTIVATION OF T CELLS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS A T CELL-DOMINANT IMMUNE DISORDER AFFECTED BY MULTIPLE FACTORS INCLUDING GENETIC SUSCEPTIBILITY, ENVIRONMENTAL FACTORS, INNATE AND ADAPTIVE IMMUNE RESPONSES, ETC. HOWEVER, THE EXACT ETIOLOGY IS LARGELY UNKNOWN. IN RECENT YEARS, EPIGENETIC INVOLVEMENTS, SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS, AND NONCODING RNA REGULATION ARE REPORTED TO BE CRITICAL FOR THE PATHOGENESIS OF PSORIASIS. HOWEVER, THE INTERPLAY BETWEEN THESE FACTORS HAS ONLY RECENTLY BEEN STARTED TO BE UNRAVELED. NOTABLY, INHIBITORS OF ENZYMES THAT WORK IN EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES, ARE BEGINNING TO APPEAR IN THE CLINICAL SETTING TO RESTORE NORMAL EPIGENETIC PATTERNS (GENERALI ET AL. IN J AUTOIMMUN 83:51-61, 2017), PROVIDING NOVEL THERAPEUTIC POTENTIAL AS NOVEL TREATMENT TARGETS FOR PSORIASIS. INDEED, MEDICATIONS PREVIOUSLY USED TO TREAT AUTOIMMUNE DISEASES HAVE LATER BEEN DISCOVERED TO EXERT THEIR ACTION VIA EPIGENETIC MECHANISMS. HEREIN, WE REVIEW THE FINDINGS ON EPIGENETICS ASSOCIATED WITH PSORIASIS, AND DISCUSS FUTURE PERSPECTIVES IN THIS FIELD. 2020 9 6136 38 THE EPIGENETICS OF MULTIPLE SCLEROSIS AND OTHER RELATED DISORDERS. MULTIPLE SCLEROSIS (MS) IS A DEMYELINATING DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE CENTRAL NERVOUS SYSTEM (CNS) GRAY AND WHITE MATTER. ALTHOUGH THE CAUSE OF MS IS UNKNOWN, IT IS WIDELY APPRECIATED THAT INNATE AND ADAPTIVE IMMUNE PROCESSES CONTRIBUTE TO ITS PATHOGENESIS. THESE INCLUDE MICROGLIA/MACROPHAGE ACTIVATION, PRO-INFLAMMATORY T-CELL (TH1) RESPONSES AND HUMORAL RESPONSES. ADDITIONALLY, THERE IS EVIDENCE INDICATING THAT MS HAS A NEURODEGENERATIVE COMPONENT SINCE NEURONAL AND AXONAL LOSS OCCURS EVEN IN THE ABSENCE OF OVERT INFLAMMATION. THESE ASPECTS ALSO FORM THE RATIONALE FOR CLINICAL MANAGEMENT OF THE DISEASE. HOWEVER, THE CURRENTLY AVAILABLE THERAPIES TO CONTROL THE DISEASE ARE ONLY PARTIALLY EFFECTIVE AT BEST INDICATING THAT MORE EFFECTIVE THERAPEUTIC SOLUTIONS ARE URGENTLY NEEDED. IT IS APPRECIATED THAT IN THE IMMUNE-DRIVEN AND NEURODEGENERATIVE PROCESSES MS-SPECIFIC DEREGULATION OF GENE EXPRESSIONS AND RESULTING PROTEIN DYSFUNCTION ARE THOUGHT TO PLAY A CENTRAL ROLE. THESE DEVIATIONS IN GENE EXPRESSION PATTERNS CONTRIBUTE TO THE INFLAMMATORY RESPONSE IN THE CNS, AND TO NEURONAL OR AXONAL LOSS. EPIGENETIC MECHANISMS CONTROL TRANSCRIPTION OF MOST, IF NOT ALL GENES, IN NUCLEATED CELLS INCLUDING CELLS OF THE CNS AND IN HAEMATOPOIETIC CELLS. MS-SPECIFIC ALTERATIONS IN EPIGENETIC REGULATION OF GENE EXPRESSION MAY THEREFORE LIE AT THE HEART OF THE DEREGULATION OF GENE EXPRESSION IN MS. AS SUCH, EPIGENETIC MECHANISMS MOST LIKELY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. IN THIS REVIEW WE DISCUSS A ROLE FOR MS-SPECIFIC DEREGULATION OF EPIGENETIC FEATURES THAT CONTROL GENE EXPRESSION IN THE CNS AND IN THE PERIPHERY. FURTHERMORE, WE DISCUSS THE APPLICATION OF SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY TO AMELIORATE DISEASE IN EXPERIMENTAL ANIMAL MODELS, INDICATING THAT SUCH APPROACHES MAY BE APPLICABLE TO MS PATIENTS. 2014 10 3549 34 IMMUNOSENESCENCE AND MULTIPLE SCLEROSIS. CHANGES IN THE IMMUNE SYSTEM ASSOCIATED WITH AGEING ARE KNOWN AS IMMUNOSENESCENCE. THIS IS CHARACTERISED BY A DECLINE IN IMMUNE RESPONSE, CHRONIC INFLAMMATION AND AN INCREASED RISK OF AUTOIMMUNE DISEASES. A CHRONIC INFLAMMATORY PROCESS WITH PERSISTENT PRODUCTION OF PROINFLAMMATORY MEDIATORS INCREASES THE RISK FOR MORBIDITY AND MORTALITY RELATED TO AGE, AND HAS BEEN DUBBED 'INFLAMM-AGEING'. IMMUNOSENESCENCE IS ASSOCIATED WITH A DECREASE IN THE NUMBER OF NAIVE T AND B CELLS, NK CELLS AND DISRUPTION OF THE PRO- AND ANTI-INFLAMMATORY BALANCE BY CHANGES IN THE PRODUCTION OF CYTOKINES. IN FACT, AGEING OF THE IMMUNE SYSTEM HAS A COMPLEX NETWORK OF UNDERLYING CAUSES WHICH INCLUDE NOT ONLY NATURAL MECHANISMS OF SENESCENCE BUT ALSO CHRONIC DISORDERS, LIFESTYLE, ENVIRONMENTAL AND EPIGENETIC FACTORS, AND INFECTIONS. MOREOVER, IMMUNOSENESCENCE HAS AN INFLUENCE ON THE COURSE OF CHRONIC DISEASES WHICH HAVE AN ONSET IN YOUNG ADULTS, SUCH AS MULTIPLE SCLEROSIS (MS). CURRENT DISEASE MODIFYING THERAPIES (DMTS) IN MS AIM TO REDUCE THE FREQUENCY OF RELAPSES AND TO SLOW DISEASE PROGRESSION, BUT THEY DO NOT NECESSARILY STOP THE ACCUMULATION OF DISABILITY RELATED TO DISEASE PROGRESSION. SOME FEATURES OF IMMUNOSENESCENCE FOUND IN AGED HEALTHY CONTROLS ARE ALREADY OBSERVED IN MS PATIENTS AT A YOUNGER AGE. THE OLDER POPULATION IS CHARACTERISED BY AN INCREASED SUSCEPTIBILITY TO INFECTIONS, A POOR RESPONSE TO VACCINATIONS, AND A HIGHER RISK OF DEVELOPING CANCER, VASCULAR DISEASES AND NEURODEGENERATION. IMMUNOSENESCENCE IS AN IMPORTANT FACTOR INFLUENCING THE COURSE OF MS, AND THE SAFETY AND EFFECTIVENESS OF DMTS. THE RELATIONSHIP BETWEEN THE PATHOGENIC PROCESS UNDERLYING THE DEVELOPMENT OF MS AND IMMUNOSENESCENCE REQUIRES FURTHER INVESTIGATION. 2022 11 1935 39 ENVIRONMENTAL RISK FACTORS AND EPIGENETIC ALTERNATIONS IN PSORIASIS. INTRODUCTION AND OBJECTIVE: PSORIASIS ISA QUITE COMMON, CHRONIC AND IMMUNE-MEDIATED SKIN DISORDER. THE PREVALENCE OF PSORIASIS DIFFERS IN VARIOUS COUNTRIES, BUT IT IS SAID TO AFFECT 2% OF THE WORLD'S POPULATION IN GENERAL. PSORIASIS HAS MANY DIFFERENT CLINICAL FEATURES BUT ALL LESIONS HAVE THE SAME CHARACTERISTIC: ERYTHEMA, THICKENING AND SCALE, ALTHOUGH OTHER CLINICAL FEATURES ARE ALSO CONNECTED, SUCH AS PSORIATIC ARTHRITIS, OBESITY AND METABOLIC SYNDROME. ALL OF THESE MAY LEAD TO CONDITIONS IMPAIRING THE QUALITY OF LIFE. THIS REVIEW IS AN ATTEMPT TO SUMMARIZE RECENT DATA REGARDING ENVIRONMENTAL FACTORS, TOGETHER WITH EPIGENETIC MARKERS AND PROCESSES PLAYING AN IMPORTANT ROLE IN PSORIASIS. STATE OF KNOWLEDGE: MANY DIFFERENT ENVIRONMENTAL FACTORS PLAY A ROLE IN GENETICALLY PREDISPOSED PATIENTS. THIS IS CAUSES EPIGENETIC ALTERNATIONS WHICH MAY BE A LINKING PART IN THE WHOLE PROCESS. MANY STUDIES HAVE INDICATED A CONNECTION BETWEEN PSORIASIS AND VARIOUS GENES AND ANTIGENS. THE PRESENCE OF HLA-CW6 IS COMMON AS WELL A STRONG LINK BETWEEN ITS PRESENCE AND THE ONSET OF PSORIASIS BEING OBSERVED. THE MAIN ALTERNATIONS ARE DNA METHYLATION, HISTONE'S MODIFICATIONS AND THE ROLE OF MICRORNA. EXCESSIVE REACTION IS USUALLY NOT PRESENT WITHOUT A TRIGGERING FACTOR. ENVIRONMENTAL FACTORS ARE MOSTLY RATED, SUCH AS DRUGS, LIFE STYLE AND HABITS (SMOKING, ALCOHOL), DIET, PHYSICAL TRAUMA (SKIN INJURY PROVOKING KOEBNER PHENOMENON), STRESS, MICROORGANISM AND INFECTIONS. CONCLUSIONS: THE CORRELATION BETWEEN PATHOGENESIS OF PSORIASIS AND ENVIRONMENTAL RISK FACTORS, TOGETHER WITH EPIGENETIC ALTERNATIONS STILL REQUIRE MORE INVESTIGATION. EDUCATION ABOUT DIET HABITS, NUTRITION, WEIGHT LOSS AND HEALTHY LIFESTYLE SEEMS TO BE IMPORTANT DURING THE TREATMENT OF PSORIASIS. 2020 12 2027 36 EPIGENETIC CHANGES IN CHRONIC INFLAMMATORY DISEASES. THE NUMBER OF PEOPLE DIAGNOSED WITH CHRONIC INFLAMMATORY DISEASES HAS INCREASED NOTEWORTHY IN THE LAST 40 YEARS. SPONDYLOARTHRITIS (SPA), INFLAMMATORY BOWEL DISEASES (IBD), AND PSORIASIS ARE THE MOST FREQUENT CHRONIC INFLAMMATORY DISEASES, RESULTING FROM A COMBINATION OF GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL AND LONG NONCODING RNAS. THEY ARE INFLUENCED BY ENVIRONMENTAL EXPOSURE, LIFE-STYLE, AND AGING AND HAVE RECENTLY BEEN SHOWN TO BE ALTERED IN MANY COMPLEX DISEASES INCLUDING INFLAMMATORY DISEASES. WHILE EPIGENETIC MODIFICATIONS HAVE BEEN WELL CHARACTERIZED IN OTHER DISEASES SUCH AS CANCER AND AUTOIMMUNE DISEASES, KNOWLEDGE ON CHANGES IN INFLAMMATORY DISEASES IS LAGGING BEHIND WITH SOME DISEASE-SPECIFIC DIFFERENCES. WHILE THE DNA METHYLATION PROFILE OF DIFFERENT CELL TYPES IN PATIENTS WITH IBD HAS BEEN RELATIVELY WELL DESCRIBED, LESS IS KNOWN ON CHANGES IMPLICATED IN PSORIASIS, AND NO SYSTEMATIC GENOME-WIDE STUDIES HAVE SO FAR BEEN PERFORMED IN SPA. IN THIS CHAPTER, WE REVIEW IN DETAIL THE REPORTED CHANGES IN PATTERNS OF DNA METHYLATION AND POSTTRANSLATIONAL HISTONE MODIFICATIONS IN CHRONIC INFLAMMATORY DISEASES HIGHLIGHTING POTENTIAL CONNECTIONS BETWEEN DISEASE-ASSOCIATED PATHOPHYSIOLOGICAL CHANGES SUCH AS THE DYSBIOSIS OF THE MICROBIOME OR GENETIC VARIATIONS ASSOCIATED WITH DISEASE SUSCEPTIBILITY AND THE EPIGENOME. WE ALSO DISCUSS IMPORTANT PARAMETERS OF MEANINGFUL EPIGENETIC STUDIES SUCH AS THE USE OF WELL DEFINED, DISEASE-RELEVANT CELL POPULATIONS, AND ELUDE ON THE POTENTIAL FUTURE OF ENGINEERING OF THE EPIGENOME IN INFLAMMATORY DISEASES. 2017 13 5031 35 PERSPECTIVES ON THE ETIOLOGY OF CHRONIC RHINOSINUSITIS: AN IMMUNE BARRIER HYPOTHESIS. BACKGROUND: CHRONIC RHINOSINUSITIS (CRS) HAS BEEN DEFINED AS PERSISTENT SYMPTOMATIC INFLAMMATION OF THE NASAL AND SINUS MUCOSA RESULTING FROM THE INTERACTION OF MULTIPLE HOST AND ENVIRONMENTAL FACTORS. RECENT STUDIES HAVE IMPLICATED ALTERNARIA FUNGI OR TOXIGENIC STAPHYLOCOCCUS AUREUS AS CRITICAL AGENTS IN CRS PATHOGENESIS. THE EMPHASIS ON ENVIRONMENTAL AGENTS IN CRS ETIOLOGY HAS FOCUSED INTEREST TOWARD ELIMINATION OF THOSE AGENTS AS THE PRIME MECHANISM OF THERAPY. THIS VIEWPOINT IS IN MARKED CONTRAST TO THE CURRENT PERSPECTIVE ON SOME OTHER CHRONIC INFLAMMATORY EPITHELIAL DISORDERS THAT AFFLICT THE SKIN, LUNGS, AND GUT, WHEREIN HOST FACTORS ARE BELIEVED TO PREDISPOSE TO DISEASE EXPRESSION IN THE PRESENCE OF UBIQUITOUS ENVIRONMENTAL AGENTS. METHODS: THE CURRENT REVIEW EVALUATES CRS ETIOLOGY FROM THIS PERSPECTIVE AND CONSIDERS THAT CRS DEVELOPS, IN PART, AS AN OUTCOME OF A DYSFUNCTIONAL HOST RESPONSE. SPECIFICALLY, EVIDENCE FROM OUR LABORATORY AND OTHERS WILL BE REVIEWED INDICATING THAT CRS IS ASSOCIATED WITH A FAILURE OF THE MECHANICAL AND IMMUNOLOGIC BARRIERS ACROSS THE NASAL MUCOSA. THE HYPOTHESIS WOULD FURTHER PROPOSE THAT GENETIC AND EPIGENETIC VARIATION PREDISPOSES SUSCEPTIBLE INDIVIDUALS TO BARRIER FAILURE IN THE PRESENCE OF ENVIRONMENTAL STRESS LEADING TO CRS. RESULTS: FROM THIS UNIFYING PERSPECTIVE, BACTERIA AND FUNGI ARE SEEN AS DISEASE MODIFIERS RATHER THAN PRIMARY ETIOLOGIC AGENTS. CONCLUSION: THE GOAL IS TO PLACE CONCEPTS OF CRS PATHOPHYSIOLOGY IN A FRAMEWORK CONSISTENT WITH A CURRENT UNDERSTANDING OF CHRONIC INFLAMMATION IN GENERAL AND EPITHELIAL DISEASE IN PARTICULAR. 2008 14 943 32 CHRONIC LYMPHOCYTIC LEUKEMIA. PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA CAN BE DIVIDED INTO THREE CATEGORIES: THOSE WHO ARE MINIMALLY AFFECTED BY THE PROBLEM, OFTEN NEVER REQUIRING THERAPY; THOSE THAT INITIALLY FOLLOW AN INDOLENT COURSE BUT SUBSEQUENTLY PROGRESS AND REQUIRE THERAPY; AND THOSE THAT FROM THE POINT OF DIAGNOSIS EXHIBIT AN AGGRESSIVE DISEASE NECESSITATING TREATMENT. LIKEWISE, SUCH PATIENTS PASS THROUGH THREE PHASES: DEVELOPMENT OF THE DISEASE, DIAGNOSIS, AND NEED FOR THERAPY. FINALLY, THE LEUKEMIC CLONES OF ALL PATIENTS APPEAR TO REQUIRE CONTINUOUS INPUT FROM THE EXTERIOR, MOST OFTEN THROUGH MEMBRANE RECEPTORS, TO ALLOW THEM TO SURVIVE AND GROW. THIS REVIEW IS PRESENTED ACCORDING TO THE TEMPORAL COURSE THAT THE DISEASE FOLLOWS, FOCUSING ON THOSE EXTERNAL INFLUENCES FROM THE TISSUE MICROENVIRONMENT (TME) THAT SUPPORT THE TIME LINES AS WELL AS THOSE INTERNAL INFLUENCES THAT ARE INHERITED OR DEVELOP AS GENETIC AND EPIGENETIC CHANGES OCCURRING OVER THE TIME LINE. REGARDING THE FORMER, SPECIAL EMPHASIS IS PLACED ON THE INPUT PROVIDED VIA THE B-CELL RECEPTOR FOR ANTIGEN AND THE C-X-C-MOTIF CHEMOKINE RECEPTOR-4 AND THE THERAPEUTIC AGENTS THAT BLOCK THESE INPUTS. REGARDING THE LATTER, PROMINENCE IS LAID UPON INHERITED SUSCEPTIBILITY GENES AND THE GENETIC AND EPIGENETIC ABNORMALITIES THAT LEAD TO THE DEVELOPMENTAL AND PROGRESSION OF THE DISEASE. 2021 15 3108 30 GENOMICS OF PAIN IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) ACCOUNTS FOR THE MAJORITY OF THE DISEASE BURDEN FOR MUSCULOSKELETAL DISORDERS AND IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. THIS DISABILITY IS THE RESULT NOT OF THE CARTILAGE LOSS THAT DEFINES OA RADIOGRAPHICALLY, BUT OF THE CHRONIC PAIN WHOSE PRESENCE DEFINES SYMPTOMATIC OA. IT IS BECOMING CLEAR THAT MANY GENES, EACH WITH A SMALL EFFECT SIZE, CONTRIBUTE TO THE RISK OF DEVELOPING OA. HOWEVER, THE GENETICS OF OA PAIN ARE ONLY JUST STARTING TO BE EXPLORED. THIS REVIEW WILL DESCRIBE THE FIRST GENES TO HAVE BEEN IDENTIFIED IN GENOMIC STUDIES OF OA PAIN, AS WELL AS THE POSSIBLE DUAL ROLES OF GENES PREVIOUSLY IDENTIFIED IN GENOMIC STUDIES OF OA IN THE CONTEXT OF PAIN. DIFFICULTIES ASSOCIATED WITH ATTEMPTING TO CHARACTERISE THE GENETICS OF OA PAIN WILL BE DISCUSSED AND PROMISING FUTURE AVENUES OF RESEARCH INTO GENETIC AND EPIGENETIC FACTORS AFFECTING OA PAIN DESCRIBED. 2013 16 6821 34 [GASTROINTESTINAL MANIFESTATIONS IN IMMUNODEFICIENCIES WITH MONOGENIC ORIGIN]. ALTHOUGH VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE THAT DEVELOPS IN EARLY CHILDHOOD (BEFORE THE AGE OF 6 YEARS) HAS A DIFFERENT ETIOLOGY FROM CROHN'S DISEASE AND ULCERATIVE COLITIS, IT IS ALSO CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT. BASICALLY, VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE SHOULD BE CONSIDERED AS AN IMMUNODEFICIENCY WITH MONOGENIC ORIGIN WHERE BOTH GASTROINTESTINAL MANIFESTATIONS AND SYMPTOMS OF IMMUNODEFICIENCIES MAY DEVELOP IN VARIABLE COMBINATIONS. HOWEVER, IN THE FUTURE, THE EVALUATION OF GENETIC ALTERATIONS IN THE BACKGROUND OF THE DISEASE WILL PROBABLY BE PERFORMED BY NEXT-GENERATION SEQUENCING TECHNOLOGY; ONE SHOULD ALSO CONSIDER THAT THE SEQUENCE OF THE DNA STANDS IN CONTINUOUS INTERACTION WITH A WIDE VARIETY OF ENVIRONMENTAL EFFECTS, AMONG WHICH NUTRITION SHOULD BE EMPHASIZED BY ALL MEANS. EPIGENETIC ALTERATIONS THAT ARE INDUCED BY ENVIRONMENTAL FACTORS, COULD CONTRIBUTE TO THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES THAT DEVELOP DURING CHILDHOOD, THEREFORE, THEY SHOULD ALSO BE IDENTIFIED DURING FURTHER RESEARCH. IT HAS A KEY SIGNIFICANCE TO ESTABLISH THE DIAGNOSIS OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE AS EARLY AS POSSIBLE, BECAUSE THIS COULD GIVE THE OPPORTUNITY TO START THE ADEQUATE TREATMENT WHICH IS BONE MARROW TRANSPLANTATION IN THE CASE OF MONOGENIC IMMUNODEFICIENCIES. ORV HETIL. 2018; 159(49): 2050-2056. 2018 17 3020 29 GENETICS AND EPIGENETICS OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGE-RELATED DISEASE THAT AFFECTS THE TISSUES OF THE SYNOVIAL JOINT, LEADING TO LOSS OF FUNCTION AND PAIN. IT IMPACTS ON BOTH PATIENT MORBIDITY AND MORTALITY. IT IS A COMPLEX, POLYGENIC DISEASE THAT LACKS ANY LARGE-EFFECT SUSCEPTIBILITY LOCI. INSTEAD, OA SUSCEPTIBILITY ALLELES INDIVIDUALLY CONTRIBUTE ONLY MODESTLY TO THE OVERALL DISEASE RISK, MAKING THEIR IDENTIFICATION CHALLENGING. DESPITE THIS, BREAKTHROUGHS HAVE OCCURRED WITH COMPELLING ASSOCIATIONS SO FAR REPORTED TO POLYMORPHISMS WITHIN THE GENES GDF5 AND MCF2L AND TO THE GENOMIC REGION 7Q22. THE LATTER TWO HAVE EMERGED FROM GENOME-WIDE ASSOCIATION SCANS, WHICH ARE LIKELY TO YIELD MORE HITS IN THE NEAR FUTURE. AS FOR MANY COMPLEX DISEASES, IT IS NOW APPARENT THAT EPIGENETIC EFFECTS ARE ALSO IMPORTANT MEDIATORS OF DISEASE BIOLOGY, WITH DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS ALL HAVING A ROLE. AT PRESENT, MUCH OF THE EPIGENETIC FOCUS HAS BEEN ON CARTILAGE, THE TISSUE AT THE CENTER OF THE OA DISEASE PROCESS. IF WE ARE TO GET CLOSE TO A QUALITATIVE AND QUANTITATIVE UNDERSTANDING OF THE IMPACT OF EPIGENETICS ON OA, THEN IN FUTURE THE OTHER TISSUES OF THE JOINT WILL ALSO NEED TO BE INVESTIGATED. ONE OF THE MORE EXCITING INSIGHTS TO HAVE EMERGED RECENTLY IS THE FACT THAT EPIGENETIC EFFECTS CAN IMPACT ON OA GENETIC EFFECTS AND THIS MAY BE A PARTICULARLY FRUITFUL AVENUE FOR INTEGRATING BOTH AS WE MOVE TOWARD A CLEARER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF THIS INTRIGUING DISEASE. 2012 18 551 38 AUTOIMMUNITY AS AN ETIOLOGICAL FACTOR OF CANCER: THE TRANSFORMATIVE POTENTIAL OF CHRONIC TYPE 2 INFLAMMATION. RECENT EPIDEMIOLOGICAL STUDIES HAVE FOUND AN ALARMING TREND OF INCREASED CANCER INCIDENCE IN ADULTS YOUNGER THAN 50 YEARS OF AGE AND PROJECTED A SUBSTANTIAL RISE IN CANCER INCIDENCE OVER THE NEXT 10 YEARS IN THIS AGE GROUP. THIS TREND WAS EXEMPLIFIED IN THE INCIDENCE OF NON-CARDIA GASTRIC CANCER AND ITS DISPROPORTIONATE IMPACT ON NON-HISPANIC WHITE FEMALES UNDER THE AGE OF 50. THE TREND IS CONCURRENT WITH THE INCREASING INCIDENCE OF AUTOIMMUNE DISEASES IN INDUSTRIALIZED COUNTRIES, SUGGESTING A CAUSAL LINK BETWEEN THE TWO. WHILE AUTOIMMUNITY HAS BEEN SUSPECTED TO BE A RISK FACTOR FOR SOME CANCERS, THE EXACT MECHANISMS UNDERLYING THE CONNECTION BETWEEN AUTOIMMUNITY AND CANCER REMAIN UNCLEAR AND ARE OFTEN CONTROVERSIAL. THE LINK HAS BEEN ATTRIBUTED TO SEVERAL MEDIATORS SUCH AS IMMUNE SUPPRESSION, INFECTION, DIET, ENVIRONMENT, OR, PERHAPS MOST PLAUSIBLY, CHRONIC INFLAMMATION BECAUSE OF ITS WELL-RECOGNIZED ROLE IN TUMORIGENESIS. IN THAT REGARD, AUTOIMMUNE CONDITIONS ARE COMMON CAUSES OF CHRONIC INFLAMMATION AND MAY TRIGGER REPETITIVE CYCLES OF ANTIGEN-SPECIFIC CELL DAMAGE, TISSUE REGENERATION, AND WOUND HEALING. ILLUSTRATING THE CONNECTION BETWEEN AUTOIMMUNE DISEASES AND CANCER ARE PATIENTS WHO HAVE AN INCREASED RISK OF CANCER DEVELOPMENT ASSOCIATED WITH GENETICALLY PREDISPOSED INSUFFICIENCY OF CYTOTOXIC T LYMPHOCYTE-ASSOCIATED PROTEIN 4 (CTLA4), A PROTOTYPICAL IMMUNE CHECKPOINT AGAINST AUTOIMMUNITY AND ONE OF THE MAIN TARGETS OF CANCER IMMUNE THERAPY. THE TUMORIGENIC PROCESS TRIGGERED BY CTLA4 INSUFFICIENCY HAS BEEN SHOWN IN A MOUSE MODEL TO BE DEPENDENT ON THE TYPE 2 CYTOKINES INTERLEUKIN-4 (IL4) AND INTERLEUKIN-13 (IL13). IN THIS TYPE 2 INFLAMMATORY MILIEU, CROSSTALK WITH TYPE 2 IMMUNE CELLS MAY INITIATE EPIGENETIC REPROGRAMMING OF EPITHELIAL CELLS, LEADING TO A METAPLASTIC DIFFERENTIATION AND EVENTUALLY MALIGNANT TRANSFORMATION EVEN IN THE ABSENCE OF CLASSICAL ONCOGENIC MUTATIONS. THOSE FINDINGS COMPLEMENT A LARGE BODY OF EVIDENCE FOR TYPE 1, TYPE 3, OR OTHER INFLAMMATORY MEDIATORS IN INFLAMMATORY TUMORIGENESIS. THIS REVIEW ADDRESSES THE POTENTIAL OF AUTOIMMUNITY AS A CAUSAL FACTOR FOR TUMORIGENESIS, THE UNDERLYING INFLAMMATORY MECHANISMS THAT MAY VARY DEPENDING ON HOST-ENVIRONMENT VARIATIONS, AND IMPLICATIONS TO CANCER PREVENTION AND IMMUNOTHERAPY. 2021 19 6142 39 THE EVALUATION OF CYTOKINES TO HELP ESTABLISH DIAGNOSIS AND GUIDE TREATMENT OF AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES. OUR KNOWLEDGE OF THE ROLE OF CYTOKINES IN PATHOLOGIC CONDITIONS HAS INCREASED CONSIDERABLY WITH THE EMERGENCE OF MOLECULAR AND GENETIC STUDIES, PARTICULARLY IN THE CASE OF AUTOINFLAMMATORY MONOGENIC DISEASES. MANY RARE DISORDERS, CONSIDERED ORPHAN UNTIL RECENTLY, ARE DIRECTLY RELATED TO ABNORMAL GENE REGULATION, AND THE TREATMENT WITH BIOLOGIC AGENTS (BIOLOGICS) TARGETING CYTOKINE RECEPTORS, INTRACELLULAR SIGNALING OR SPECIFIC CYTOKINES IMPROVE THE SYMPTOMS OF AN INCREASING NUMBER OF CHRONIC INFLAMMATORY DISEASES. AS IT IS CURRENTLY IMPOSSIBLE TO SYSTEMATICALLY CONDUCT GENETIC STUDIES FOR ALL PATIENTS WITH AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, THE EVALUATION OF CYTOKINES CAN BE SEEN AS A SIMPLE, LESS TIME CONSUMING, AND LESS EXPENSIVE ALTERNATIVE. THIS APPROACH COULD BE ESPECIALLY USEFUL WHEN THE DIAGNOSIS OF SYNDROMES OF DISEASES OF UNKNOWN ETIOLOGY REMAINS PROBLEMATIC. THE EVALUATION OF CYTOKINES COULD ALSO HELP AVOID THE CURRENT TRIAL-AND-ERROR APPROACH, WHICH HAS THE DISADVANTAGES OF EXPOSING PATIENTS TO INEFFECTIVE DRUGS WITH POSSIBLE UNNECESSARY SIDE EFFECTS AND PERMANENT ORGAN DAMAGES. IN THIS REVIEW, WE DISCUSS THE VARIOUS POSSIBILITIES, AS WELL AS THE LIMITATIONS OF EVALUATING THE CYTOKINE PROFILES OF PATIENTS SUFFERING FROM AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, WITH METHODS SUCH AS DIRECT DETECTION OF CYTOKINES IN THE PLASMA/SERUM OR FOLLOWING EX VIVO STIMULATION OF PBMCS LEADING TO THE PRODUCTION OF THEIR CYTOKINE SECRETOME. THE PATIENTS' SECRETOME, COMBINED WITH BIOMARKERS RANGING FROM GENETIC AND EPIGENETIC ANALYSES TO IMMUNOLOGIC BIOMARKERS, MAY HELP NOT ONLY THE DIAGNOSIS BUT ALSO GUIDE THE CHOICE OF BIOLOGICS FOR MORE EFFICIENT AND RAPID TREATMENTS. 2020 20 269 41 AGE AND PERIODONTAL HEALTH - IMMUNOLOGICAL VIEW. PURPOSE OF THE REVIEW: AGING CLEARLY IMPACTS A WIDE ARRAY OF SYSTEMS, IN PARTICULAR THE BREADTH OF THE IMMUNE SYSTEM LEADING TO IMMUNOSENESCENCE, ALTERED IMMUNOACTIVATION, AND COINCIDENT INFLAMMAGING PROCESSES. THE NET RESULT OF THESE CHANGES LEADS TO INCREASED SUSCEPTIBILITY TO INFECTIONS, INCREASED NEOPLASTIC OCCURRENCES, AND ELEVATED FREQUENCY OF AUTOIMMUNE DISEASES WITH AGING. HOWEVER, AS THE BACTERIA IN THE ORAL MICROBIOME THAT CONTRIBUTE TO THE CHRONIC INFECTION OF PERIODONTITIS IS ACQUIRED EARLIER IN LIFE, THE CHARACTERISTICS OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS TO REGULATE THESE MEMBERS OF THE AUTOCHTHONOUS MICROBIOTA ACROSS THE LIFESPAN REMAINS ILL DEFINED. RECENT FINDINGS: CLEAR DATA DEMONSTRATE THAT BOTH CELLS AND MOLECULES OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE ARE ADVERSELY IMPACTED BY AGING, INCLUDING IN THE ORAL CAVITY, YIELDING A REASONABLE TENET THAT THE INCREASED PERIODONTITIS NOTED IN AGING POPULATIONS IS REFLECTIVE OF THE AGE-ASSOCIATED IMMUNE DYSREGULATION. ADDITIONALLY, THIS FACET OF HOST-MICROBE INTERACTIONS AND DISEASE NEEDS TO ACCOMMODATE THE POPULATION VARIATION IN DISEASE ONSET AND PROGRESSION, WHICH MAY ALSO REFLECT AN ACCUMULATION OF ENVIRONMENTAL STRESSORS AND/OR DECREASED PROTECTIVE NUTRIENTS THAT COULD FUNCTION AT THE GENE LEVEL (IE. EPIGENETIC) OR TRANSLATIONAL LEVEL FOR PRODUCTION AND SECRETION OF IMMUNE SYSTEM MOLECULES. SUMMARY: FINALLY, THE MAJORITY OF STUDIES OF AGING AND PERIODONTITIS HAVE EMPHASIZED THE INCREASED PREVALENCE/SEVERITY OF DISEASE WITH AGING, ALL BASED UPON CHRONOLOGICAL AGE. HOWEVER, EVOLVING AREAS OF STUDY FOCUSING ON "BIOLOGICAL AGING" TO HELP ACCOUNT FOR POPULATION VARIATION IN DISEASE EXPRESSION, MAY SUGGEST THAT CHRONIC PERIODONTITIS REPRESENTS A CO-MORBIDITY THAT CONTRIBUTES TO "GEROVULNERABILITY" WITHIN THE POPULATION. 2018