1 1760 111 EARLY PREDICTORS OF ASTHMA AND ALLERGY IN CHILDREN: THE ROLE OF EPIGENETICS. PURPOSE OF REVIEW: ASTHMA AND ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NONCOMMUNICABLE DISEASES OF CHILDHOOD. ALTHOUGH EPIDEMIOLOGIC STUDIES SUGGEST THAT ASTHMA BEGINS IN THE PRESCHOOL YEARS, THE LACK OF FIRM DIAGNOSTIC CRITERIA TO DISTINGUISH CHILDREN WHO WILL WHEEZE ONLY TRANSIENTLY DURING EARLY-LIFE LOWER RESPIRATORY ILLNESSES FROM CHILDREN WHO WILL WHEEZE PERSISTENTLY AND DEVELOP ASTHMA PREVENTS PINPOINTING THE TIME AT WHICH DISEASE TRULY BEGINS. EPIGENETIC MECHANISMS LINK GENE REGULATION TO ENVIRONMENTAL CUES AND DEVELOPMENTAL TRAJECTORIES. THIS ARTICLE REVIEWS, THE SEARCH FOR EPIGENETIC PREDICTORS OF ASTHMA AND/OR ALLERGY THAT CAN BE IDENTIFIED ALREADY AT BIRTH AND/OR IN EARLY LIFE. RECENT FINDINGS: DNA METHYLATION SIGNATURES ASSOCIATED WITH ASTHMA AND/OR ALLERGY AT BIRTH, AND TIME-DEPENDENT DNA METHYLATION SIGNATURES ASSOCIATED WITH ALLERGIC DISEASE PHENOTYPES IN EARLY LIFE HAVE BEEN IDENTIFIED. SUMMARY: THE IDENTIFICATION OF EARLY EPIGENETIC PREDICTORS OF ALLERGIC DISEASES POINTS TO A POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN REGULATING THE INCEPTION OF AND THE SUSCEPTIBILITY TO THESE DISEASES. PREDICTIVE SIGNATURES TO MORE ACCURATELY ESTIMATE A CHILD'S RISK FOR ASTHMA AND ALLERGY MAY IMPROVE CHILDHOOD ASTHMA DIAGNOSIS. MOREOVER, UNDERSTANDING THE BIOLOGICAL IMPLICATIONS OF THESE SIGNATURES MAY HELP ELUCIDATE NOVEL DISEASE PATHWAYS AND ENDOTYPES. 2015 2 6808 24 [EPIGENETICS IN ALLERGIC DISEASES AND ASTHMA]. ALLERGIC DISEASES AND ASTHMA ARE THE RESULT OF COMPLEX INTERACTIONS BETWEEN GENETIC PREDISPOSITION AND ENVIRONMENTAL FACTORS. ASTHMA IS ONE OF THE MOST PREVALENT CHRONIC DISEASE AMONG CHILDREN. IN THIS ARTICLE WE REVIEW SOME ENVIRONMENTAL FACTORS LIKE: ALLERGEN EXPOSITION, TOBACCO, BACTERIA, MICROBIAL COMPONENTS, DIET, OBESITY AND STRESS, WHICH INFLUENCES DURING INTRAUTERINE AND INFANCY LIFE IN THE EPIGENETIC REGULATION OF ASTHMA AND ALLERGIC DISEASES. THE REVIEW HAS BEEN DONE IN THREE MODELS: IN-VITRO, ANIMAL AND HUMAN. 2016 3 3698 29 INFLAMMATORY MECHANISMS LINKING MATERNAL AND CHILDHOOD ASTHMA. ASTHMA IS A CHRONIC INFLAMMATORY AIRWAY DISEASE CHARACTERIZED BY AIRWAY HYPERRESPONSIVENESS, INFLAMMATION, AND REMODELING. ASTHMA OFTEN DEVELOPS DURING CHILDHOOD AND CAUSES LIFELONG DECREMENTS IN LUNG FUNCTION AND QUALITY OF LIFE. RISK FACTORS FOR CHILDHOOD ASTHMA ARE NUMEROUS AND INCLUDE GENETIC, EPIGENETIC, DEVELOPMENTAL, AND ENVIRONMENTAL FACTORS. UNCONTROLLED MATERNAL ASTHMA DURING PREGNANCY EXPOSES THE DEVELOPING FETUS TO INFLAMMATORY INSULTS, WHICH FURTHER INCREASE THE RISK OF CHILDHOOD ASTHMA INDEPENDENT OF GENETIC PREDISPOSITION. THIS REVIEW FOCUSES ON THE ROLE OF MATERNAL ASTHMA IN THE DEVELOPMENT OF ASTHMA IN OFFSPRING. WE WILL PRESENT MATERNAL ASTHMA AS A TARGETABLE AND MODIFIABLE RISK FACTOR FOR CHILDHOOD ASTHMA AND DISCUSS THE MECHANISMS BY WHICH MATERNAL INFLAMMATION INCREASES CHILDHOOD ASTHMA RISK. TOPICS INCLUDE HOW EXPOSURE TO MATERNAL ASTHMA IN UTERO SHAPES STRUCTURAL LUNG DEVELOPMENT WITH A SPECIAL EMPHASIS ON AIRWAY NERVES, HOW MATERNAL TYPE-2 CYTOKINES SUCH AS IL-5 ACTIVATE THE FETAL IMMUNE SYSTEM, AND HOW CHANGES IN LUNG AND IMMUNE CELL DEVELOPMENT INFORM RESPONSES TO AERO-ALLERGENS LATER IN LIFE. FINALLY, WE HIGHLIGHT EMERGING EVIDENCE THAT MATERNAL ASTHMA ESTABLISHES A UNIQUE "ASTHMA SIGNATURE" IN THE AIRWAYS OF CHILDREN, LEADING TO NOVEL MECHANISMS OF AIRWAY HYPERREACTIVITY AND INFLAMMATORY CELL RESPONSES. 2020 4 5156 34 PRE-BIRTH ORIGINS OF ALLERGY AND ASTHMA. ALLERGY IS A CHRONIC DISEASE THAT CAN DEVELOP AS EARLY AS INFANCY, SUGGESTING THAT EARLY LIFE FACTORS ARE IMPORTANT IN ITS AETIOLOGY. VARIABLE ASSOCIATIONS BETWEEN SIZE AT BIRTH, A CRUDE MARKER OF THE FETAL ENVIRONMENT, AND ALLERGY HAVE BEEN REPORTED IN HUMANS AND REQUIRE COMPREHENSIVE REVIEW. ASSOCIATIONS BETWEEN BIRTH WEIGHT AND ALLERGY ARE HOWEVER CONFOUNDED IN HUMANS, AND WE AND OTHERS HAVE THEREFORE BEGUN EXPLORING THE EFFECTS OF EARLY LIFE EVENTS ON ALLERGY IN EXPERIMENTAL MODELS. IN PARTICULAR, WE ARE USING OVINE MODELS TO INVESTIGATE WHETHER AND HOW A RESTRICTED ENVIRONMENT BEFORE BIRTH PROTECTS AGAINST ALLERGY, WHETHER METHYL DONOR AVAILABILITY CONTRIBUTES TO ALLERGIC PROTECTION IN IUGR, AND WHY MATERNAL ASTHMA DURING PREGNANCY IS ASSOCIATED WITH INCREASED RISKS OF ALLERGIC DISEASE IN CHILDREN. WE FOUND THAT EXPERIMENTAL INTRAUTERINE GROWTH RESTRICTION (IUGR) IN SHEEP REDUCED CUTANEOUS RESPONSES TO ANTIGENS IN PROGENY, DESPITE NORMAL OR ELEVATED IGE RESPONSES. FURTHERMORE, MATERNAL METHYL DONOR SUPPLEMENTATION IN LATE PREGNANCY PARTIALLY REVERSED EFFECTS OF EXPERIMENTAL IUGR, CONSISTENT WITH THE PROPOSAL THAT EPIGENETIC PATHWAYS UNDERLIE SOME BUT NOT ALL EFFECTS OF IUGR ON ALLERGIC SUSCEPTIBILITY. OVINE EXPERIMENTAL ALLERGIC ASTHMA WITH EXACERBATIONS REDUCES RELATIVE FETAL SIZE IN LATE GESTATION, WITH SOME CHANGES IN IMMUNE POPULATIONS IN FETAL THYMUS SUGGESTIVE OF INCREASED ACTIVATION. MATERNAL ALLERGIC ASTHMA IN MICE ALSO PREDISPOSES PROGENY TO ALLERGY DEVELOPMENT. IN CONCLUSION, THESE FINDINGS IN EXPERIMENTAL MODELS PROVIDE DIRECT EVIDENCE THAT A PERTURBED ENVIRONMENT BEFORE BIRTH ALTERS IMMUNE SYSTEM DEVELOPMENT AND POSTNATAL FUNCTION, AND PROVIDE OPPORTUNITIES TO INVESTIGATE UNDERLYING MECHANISMS AND DEVELOP AND EVALUATE INTERVENTIONS. 2017 5 1757 29 EARLY ORIGINS OF ASTHMA (AND ALLERGY). ASTHMA IS THE MOST COMMON CHRONIC DISEASE STARTING IN CHILDHOOD AND PERSISTING INTO ADULTHOOD IN MANY CASES. DURING CHILDHOOD, DIFFERENT FORMS OF ASTHMA AND WHEEZING DISORDERS EXIST THAT CAN BE DISCRIMINATED BY THE MECHANISMS THEY ARE CAUSED BY. SPECIFIC GENETIC CONSTELLATIONS AND EXPOSURE AGAINST ENVIRONMENTAL FACTORS DURING EARLY CHILDHOOD AND IN UTERO PLAY A DECISIVE ROLE IN THE EARLY DEVELOPMENT OF THE DISEASE. EPIGENETIC MECHANISMS WHICH ARE MASTER REGULATORS OF GENE TRANSCRIPTION AND THUS GOVERN THE ACCESSIBILITY AND USE OF GENOME INFORMATION, HAVE RECENTLY BEEN IDENTIFIED AS A "THIRD POWER" DETERMINING MANY FEATURES IN THE EARLY DEVELOPMENT OF ASTHMA AND ALLERGY. 2016 6 2804 27 FETAL EPIGENETIC MECHANISMS AND INNATE IMMUNITY IN ASTHMA. ALLERGY AND ASTHMA ARE CHRONIC INFLAMMATORY DISEASES THAT RESULT FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. RECENT EVIDENCE POINTS TO THE IMPORTANCE OF PRENATAL AND POSTNATAL DEVELOPMENTAL PROCESSES IN THE MATURATION OF BALANCED IMMUNE RESPONSES. NOVEL DATA INDICATE THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE DEVELOPMENT OF T-HELPER-CELL FUNCTION. ENVIRONMENTAL FACTORS, INCLUDING DIESEL EXHAUST PARTICLES, VITAMINS, AND TOBACCO SMOKE, OPERATE THROUGH SUCH MECHANISMS. FURTHERMORE, THE ROLE OF ENVIRONMENTAL MICROBES PROVIDES ANOTHER-AND MAYBE AN EVEN MORE IMPORTANT-GROUP OF EXOGENOUS EXPOSURES THAT OPERATE IN THIS CRITICAL TIME FRAME. A BETTER UNDERSTANDING OF FETAL IMMUNO-MATURATION CONDITIONS WILL PROVIDE THE BASIS FOR THE DEVELOPMENT OF NOVEL ALLERGO-PROTECTIVE CLINICAL STRATEGIES. 2010 7 6877 31 [REASONS FOR THE DEVELOPMENT OF ALLERGIES IN CHILDREN]. ALLERGIES ARE ONE OF THE MOST COMMON CHRONIC DISEASES IN CHILDHOOD, CONTRIBUTING TO A TREMENDOUS MEDICAL AND ECONOMICAL BURDEN IN HEALTH CARE SYSTEMS OF MOST INDUSTRIALIZED COUNTRIES. THE DEVELOPMENT OF ALLERGIES IS DEPENDENT ON A COMPLEX INTERACTION OF-AMONG OTHERS-ENVIRONMENTAL FACTORS, NUTRITION, GENETIC AND EPIGENETIC MECHANISMS AS WELL AS THE MICROBIOME. THESE DIVERSE FACTORS CAN INFLUENCE EARLY LIFE IMMUNE REGULATION INCLUDING INNATE AND ADAPTIVE IMMUNE MECHANISMS IN A COMPLEX FASHION. IN CASE OF ANY CHILDHOOD ALLERGIES HAVE INCREASED SIGNIFICANTLY IN PAST DECADES. IN ADDITION TO ENVIRONMENTAL FACTORS AND NUTRITION, GENETIC AND EPIGENETIC MECHANISMS AS WELL AS THE MICROBIOME OF CHILDREN PLAY AN IMPORTANT ROLE. OF RELEVANCE IS THE WAY IN WHICH THESE DIVERSE FACTORS INFLUENCE EARLY IMMUNE DEVELOPMENT OF THE INNATE AND ADAPTIVE IMMUNE SYSTEMS OF CHILDREN. THEIR COMPLEX REGULATION IS DECISIVE FOR WHETHER OR NOT A CHILD DEVELOPS AN ALLERGY THAT MANIFESTS IN MOST CASES AS ATOPIC DERMATITIS, BRONCHIAL ASTHMA, OR ALLERGIC RHINO CONJUNCTIVITIS, OR WHETHER A CHILD DEVELOPS AN IMMUNE TOLERANCE. THESE INFLUENCES CAN BEGIN PRENATALLY, ALREADY SETTING THE COURSE FOR LATER IMMUNE SYSTEM DEVELOPMENT AND OCCURRENCE OF DISEASE. 2019 8 529 27 ASTHMA IN URBAN CHILDREN: EPIDEMIOLOGY, ENVIRONMENTAL RISK FACTORS, AND THE PUBLIC HEALTH DOMAIN. ASTHMA IS THE MOST COMMONLY REPORTED CHRONIC CONDITION OF CHILDHOOD IN DEVELOPED COUNTRIES, WITH 6.5 MILLION CHILDREN AFFECTED IN THE USA. A DISPARATE BURDEN OF CHILDHOOD ASTHMA IS SEEN AMONG SOCIOECONOMICALLY DISADVANTAGED YOUTH, OFTEN CONCENTRATED IN URBAN AREAS WITH HIGH POVERTY RATES. HOST FACTORS THAT PREDISPOSE A CHILD TO ASTHMA INCLUDE ATOPY, MALE GENDER, PARENTAL HISTORY OF ASTHMA, AND ALSO RACE, ETHNICITY, AND GENETIC AND EPIGENETIC SUSCEPTIBILITIES. ENVIRONMENTAL FACTORS, SUCH AS IMPROVED HYGIENE, AMBIENT AIR POLLUTION, AND EARLY LIFE EXPOSURES TO MICROBES AND AEROALLERGENS, ALSO INFLUENCE THE DEVELOPMENT OF ASTHMA. WITH GREATER THAN 90% OF TIME SPENT INDOORS, HOME EXPOSURES (SUCH AS COCKROACH, RODENT, AND INDOOR AIR POLLUTION) ARE HIGHLY RELEVANT FOR URBAN ASTHMA. MORBIDITY REDUCTION MAY REQUIRE FOCUSED PUBLIC HEALTH INITIATIVES FOR ENVIRONMENTAL INTERVENTION IN HIGH PRIORITY RISK GROUPS AND THE ADDITION OF IMMUNE MODULATORY AGENTS IN CHILDREN WITH POORLY CONTROLLED DISEASE. 2016 9 2861 40 FROM TRAINED IMMUNITY IN ALLERGY TO TRAINED IMMUNITY-BASED ALLERGEN VACCINES. INNATE IMMUNE CELLS EXPERIENCE LONG LASTING METABOLIC AND EPIGENETIC CHANGES AFTER AN ENCOUNTER WITH SPECIFIC STIMULI. THIS FACILITATES ENHANCED IMMUNE RESPONSES UPON SECONDARY EXPOSITION TO BOTH THE SAME AND UNRELATED PATHOGENS, A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY-BASED VACCINES (TIBV) ARE VACCINES ABLE TO INDUCE INNATE IMMUNE MEMORY, THUS CONFERRING HETEROLOGOUS PROTECTION AGAINST A BROAD RANGE OF PATHOGENS. WHILE TRAINED IMMUNITY HAS BEEN WELL DOCUMENTED IN THE CONTEXT OF INFECTIONS AND MULTIPLE IMMUNE-MEDIATED DISEASES, THE ROLE OF INNATE IMMUNE MEMORY AND ITS CONTRIBUTION TO THE INITIATION AND MAINTENANCE OF CHRONIC ALLERGIC DISEASES REMAINS POORLY UNDERSTOOD. OVER THE LAST YEARS, DIFFERENT STUDIES ATTEMPTING TO UNCOVER THE ROLE OF TRAINED IMMUNITY IN ALLERGY HAVE EMERGED. EXPOSITION TO ENVIRONMENTAL FACTORS IMPACTING ALLERGY DEVELOPMENT SUCH AS ALLERGENS OR VIRUSES INDUCES THE REPROGRAMMING OF INNATE IMMUNE CELLS TO ACQUIRE A MORE PRO-INFLAMMATORY PHENOTYPE IN THE CONTEXT OF ASTHMA OR FOOD ALLERGY. SEVERAL STUDIES HAVE CONVINCINGLY DEMONSTRATED THAT PREVENTION OF VIRAL INFECTIONS USING TIBV CONTRIBUTES TO REDUCE WHEEZING ATTACKS IN CHILDREN, WHICH REPRESENT A HIGH-RISK FACTOR FOR ASTHMA DEVELOPMENT LATER IN LIFE. INNATE IMMUNE CELLS TRAINED WITH SPECIFIC STIMULI MIGHT ALSO ACQUIRE ANTI-INFLAMMATORY FEATURES AND PROMOTE TOLERANCE, WHICH MAY HAVE IMPORTANT IMPLICATIONS FOR CHRONIC INFLAMMATORY DISEASES SUCH AS ALLERGIES. RECENT FINDINGS SHOWED THAT ALLERGOID-MANNAN CONJUGATES, WHICH ARE NEXT GENERATION VACCINES FOR ALLERGEN-SPECIFIC IMMUNOTHERAPY (AIT), ARE ABLE TO REPROGRAM MONOCYTES INTO TOLEROGENIC DENDRITIC CELLS BY MECHANISMS DEPENDING ON METABOLIC AND EPIGENETIC REWIRING. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS OF TRAINED IMMUNITY IN ALLERGY WILL PAVE THE WAY FOR THE DESIGN OF NOVEL TRAINED IMMUNITY-BASED ALLERGEN VACCINES AS POTENTIAL ALTERNATIVE STRATEGIES FOR THE PREVENTION AND TREATMENT OF ALLERGIC DISEASES. 2023 10 3580 36 IMPACT OF PERINATAL ENVIRONMENTAL TOBACCO SMOKE ON THE DEVELOPMENT OF CHILDHOOD ALLERGIC DISEASES. ALLERGIC DISEASES SUCH AS ASTHMA, ALLERGIC RHINITIS, ATOPIC DERMATITIS, AND FOOD ALLERGY, ARE MOST COMMON CHRONIC, NONCOMMUNICABLE DISEASES IN CHILDHOOD. IN THE PAST FEW DECADES, THE PREVALENCE HAS INCREASED ABRUPTLY WORLDWIDE. THERE ARE 2 POSSIBLE EXPLANATIONS FOR THE RISING PREVALENCE OF ALLERGIC DISEASES WORLDWIDE, THAT AN INCREASED DISEASE-AWARENESS OF PHYSICIAN, PATIENT, OR CAREGIVERS, AND AN ABRUPT EXPOSURE TO UNKNOWN HAZARDS. UNFORTUNATELY, THE UNDERLYING MECHANISMS REMAIN LARGELY UNKNOWN. DESPITE THE CONTINUING EFFORTS WORLDWIDE, THE ETIOLOGIES AND RISING PREVALENCE REMAIN UNCLEAR. THUS, IT IS IMPORTANT TO IDENTIFY AND CONTROL RISK FACTORS IN THE SUSCEPTIBLE INDIVIDUAL FOR THE BEST PREVENTION AND MANAGEMENT. GENETIC SUSCEPTIBILITY OR ENVIRONMENTS MAY BE A POTENTIAL BACKGROUND FOR THE DEVELOPMENT OF ALLERGIC DISEASE, HOWEVER THEY ALONE CANNOT EXPLAIN THE RISING PREVALENCE WORLDWIDE. THERE IS GROWING EVIDENCE THAT EPIGENETIC CHANGE DEPENDS ON THE GENE, ENVIRONMENT, AND THEIR INTERACTIONS, MAY INDUCE A LONG-LASTING ALTERED GENE EXPRESSION AND THE CONSEQUENT DEVELOPMENT OF ALLERGIC DISEASES. IN EPIGENETIC MECHANISMS, ENVIRONMENTAL TOBACCO SMOKE (ETS) EXPOSURE DURING CRITICAL PERIOD (I.E., DURING PREGNANCY AND EARLY LIFE) ARE CONSIDERED AS A POTENTIAL CAUSE OF THE DEVELOPMENT OF CHILDHOOD ALLERGIC DISEASES. HOWEVER, THE CAUSAL RELATIONSHIP IS STILL UNCLEAR. THIS REVIEW AIMED TO HIGHLIGHT THE IMPACT OF ETS EXPOSURE DURING THE PERINATAL PERIOD ON THE DEVELOPMENT OF CHILDHOOD ALLERGIC DISEASES AND TO PROPOSE A FUTURE RESEARCH DIRECTION. 2016 11 4094 34 MATERNAL SIGNALS FOR PROGENY PREVENTION AGAINST ALLERGY AND ASTHMA. ALLERGY AND ASTHMA ARE CHRONIC INFLAMMATORY DISEASES WHICH RESULT FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. RECENT EVIDENCE INDICATES THE IMPORTANCE OF PRENATAL AND POSTNATAL DEVELOPMENTAL PROCESSES IN TERMS OF MATURATION OF BALANCED IMMUNE RESPONSES. ACCORDING TO THE CURRENT VIEW, GENE-ENVIRONMENT INTERACTIONS DURING A RESTRICTED TIME FRAME ARE RESPONSIBLE FOR PROGRAMMING OF THE IMMUNE SYSTEM IN FAVOR OF ALLERGIC IMMUNE MECHANISMS LATER IN LIFE. THE INTERACTION BETWEEN GENES AND ENVIRONMENT IS COMPLEX AND ONLY PARTIALLY UNDERSTOOD; HOWEVER, HERITABLE EPIGENETIC MODIFICATIONS INCLUDING CHEMICAL ADDITIONS IN AND ALTERNATIVE PACKAGING OF THE DNA HAVE BEEN SHOWN TO PLAY A CRUCIAL ROLE IN THIS CONTEXT. NOVEL DATA INDICATE THAT EPIGENETIC MECHANISMS CONTRIBUTE TO THE DEVELOPMENT OF T-HELPER CELL FUNCTION. ENVIRONMENTAL FACTORS, INCLUDING DIESEL EXHAUST PARTICLES (DEP), VITAMINS AND TOBACCO SMOKE, OPERATE THROUGH SUCH MECHANISMS. FURTHERMORE, THE ROLE OF ENVIRONMENTAL MICROBES PROVIDES ANOTHER AND MAYBE EVEN MORE IMPORTANT GROUP OF EXOGENOUS EXPOSURES WHICH OPERATES IN THIS CRITICAL TIME FRAME. 2011 12 6303 43 THE PUZZLE OF IMMUNE PHENOTYPES OF CHILDHOOD ASTHMA. ASTHMA REPRESENTS THE MOST COMMON CHRONIC CHILDHOOD DISEASE WORLDWIDE. WHEREAS PRESCHOOL CHILDREN PRESENT WITH WHEEZING TRIGGERED BY DIFFERENT FACTORS (MULTITRIGGER AND VIRAL WHEEZE), CLINICAL ASTHMA MANIFESTATION IN SCHOOL CHILDREN HAS PREVIOUSLY BEEN CLASSIFIED AS ALLERGIC AND NON-ALLERGIC ASTHMA. FOR BOTH, THE UNDERLYING IMMUNOLOGICAL MECHANISMS ARE NOT YET UNDERSTOOD IN DEPTH IN CHILDREN. TREATMENT IS STILL PRESCRIBED REGARDLESS OF UNDERLYING MECHANISMS, AND CHILDREN ARE NOT ALWAYS TREATED SUCCESSFULLY. THIS REVIEW SUMMARIZES RECENT KEY FINDINGS ON THE COMPLEX MECHANISMS OF THE DEVELOPMENT AND MANIFESTATION OF CHILDHOOD ASTHMA. WHEREAS TRADITIONAL CLASSIFICATION OF CHILDHOOD ASTHMA IS PRIMARILY BASED ON CLINICAL SYMPTOMS LIKE WHEEZING AND ATOPY, NOVEL APPROACHES TO SPECIFY ASTHMA PHENOTYPES ARE UNDER WAY AND FACE CHALLENGES SUCH AS INCLUDING THE STABILITY OF PHENOTYPES OVER TIME AND TRANSITION INTO ADULTHOOD. EPIDEMIOLOGICAL STUDIES ENCLOSE MORE INFORMATION ON THE PATIENT'S DISEASE HISTORY AND ENVIRONMENTAL INFLUENCES. LATEST STUDIES DEFINE ENDOTYPES BASED ON MOLECULAR AND CELLULAR MECHANISMS, FOR EXAMPLE DEFINING RISK AND PROTECTIVE SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AND NEW IMMUNE PHENOTYPES, SHOWING PROMISING RESULTS. ALSO, REGULATORY T CELLS AND RECENTLY DISCOVERED T HELPER CELL SUBTYPES SUCH AS TH9 AND TH17 CELLS WERE SHOWN TO BE IMPORTANT FOR THE DEVELOPMENT OF ASTHMA. INNATE LYMPHOID CELLS (ILC) COULD PLAY A CRITICAL ROLE IN ASTHMA PATIENTS AS THEY PRODUCE DIFFERENT CYTOKINES ASSOCIATED WITH ASTHMA. EPIGENETIC FINDINGS SHOWED DIFFERENT ACETYLATION AND METHYLATION PATTERNS FOR CHILDREN WITH ALLERGIC AND NON-ALLERGIC ASTHMA. ON A POSTTRANSCRIPTIONAL LEVEL, MIRNAS ARE REGULATING FACTORS IDENTIFIED TO DIFFER BETWEEN ASTHMA PATIENTS AND HEALTHY CONTROLS AND ALSO INDICATE DIFFERENCES WITHIN ASTHMA PHENOTYPES. METABOLOMICS IS ANOTHER EXCITING CHAPTER IMPORTANT FOR ENDOTYPING ASTHMATIC CHILDREN. DESPITE THE DEVELOPMENT OF NEW BIOMARKERS AND THE DISCOVERY OF NEW IMMUNOLOGICAL MOLECULES, THE COMPLEX PUZZLE OF CHILDHOOD ASTHMA IS STILL FAR FROM BEING COMPLETED. ADDRESSING THE CURRENT CHALLENGES OF DISTINCT CLINICAL ASTHMA AND WHEEZE PHENOTYPES, INCLUDING THEIR STABILITY AND UNDERLYING ENDOTYPES, INVOLVES ADDRESSING THE INTERPLAY OF INNATE AND ADAPTIVE IMMUNE REGULATORY MECHANISMS IN LARGE, INTERDISCIPLINARY COHORTS. 2016 13 2160 45 EPIGENETIC MECHANISMS IN ASTHMA. ASTHMA AND ALLERGIC DISEASES ARE AMONG THE MOST PREVALENT CHRONIC NONCOMMUNICABLE DISEASES OF CHILDHOOD, BUT THE UNDERLYING PATHOGENETIC MECHANISMS ARE POORLY UNDERSTOOD. BECAUSE EPIGENETIC MECHANISMS LINK GENE REGULATION TO ENVIRONMENTAL CUES AND DEVELOPMENTAL TRAJECTORIES, THEIR CONTRIBUTION TO ASTHMA AND ALLERGY PATHOGENESIS IS UNDER ACTIVE INVESTIGATION. DNA METHYLATION SIGNATURES ASSOCIATED WITH CONCURRENT DISEASE AND WITH THE DEVELOPMENT OF ASTHMA DURING CHILDHOOD ASTHMA HAVE BEEN IDENTIFIED, BUT THEIR SIGNIFICANCE IS NOT EASILY INTERPRETABLE. ON THE OTHER HAND, THE CHARACTERIZATION OF EARLY EPIGENETIC PREDICTORS OF ASTHMA POINTS TO A POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN REGULATING THE INCEPTION OF, AND THE SUSCEPTIBILITY TO, THIS DISEASE. 2016 14 5254 43 PROGRAMMING OF RESPIRATORY HEALTH IN CHILDHOOD: INFLUENCE OF OUTDOOR AIR POLLUTION. PURPOSE OF REVIEW: THIS OVERVIEW HIGHLIGHTS RECENT EXPERIMENTAL AND EPIDEMIOLOGICAL EVIDENCE FOR THE PROGRAMMING EFFECTS OF OUTDOOR AIR POLLUTION EXPOSURES DURING EARLY DEVELOPMENT ON LUNG FUNCTION AND CHRONIC RESPIRATORY DISORDERS, SUCH AS ASTHMA AND RELATED ALLERGIC DISORDERS. RECENT FINDINGS: AIR POLLUTANTS MAY IMPACT ANATOMY AND/OR PHYSIOLOGICAL FUNCTIONING OF THE LUNG AND INTERRELATED SYSTEMS. PROGRAMMING EFFECTS MAY RESULT FROM POLLUTANT-INDUCED SHIFTS IN A NUMBER OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL STATES AND THEIR INTERACTING SYSTEMS. SPECIFIC KEY REGULATORY SYSTEMS SUSCEPTIBLE TO PROGRAMMING MAY INFLUENCE LUNG DEVELOPMENT AND VULNERABILITY TO RESPIRATORY DISEASES, INCLUDING BOTH CENTRAL AND PERIPHERAL COMPONENTS OF NEUROENDOCRINE PATHWAYS AND AUTONOMIC NERVOUS SYSTEM (ANS) FUNCTIONING WHICH, IN TURN, INFLUENCE THE IMMUNE SYSTEM. STARTING IN UTERO, ENVIRONMENTAL FACTORS, INCLUDING AIR POLLUTANTS, MAY PERMANENTLY ORGANIZE THESE SYSTEMS TOWARD TRAJECTORIES OF ENHANCED PEDIATRIC (E.G., ASTHMA, ALLERGY) AS WELL AS ADULT DISEASE RISK (E.G., CHRONIC OBSTRUCTIVE PULMONARY DISEASE). EVIDENCE SUPPORTS A CENTRAL ROLE OF OXIDATIVE STRESS IN THE TOXIC EFFECTS OF AIR POLLUTION. ADDITIONAL RESEARCH SUGGESTS XENOBIOTIC METABOLISM AND SUBCELLULAR COMPONENTS, SUCH AS MITOCHONDRIA ARE TARGETS OF AMBIENT AIR POLLUTION AND PLAY A ROLE IN ASTHMA AND ALLERGY PROGRAMMING. MECHANISMS OPERATING AT THE LEVEL OF THE PLACENTA ARE BEING ELUCIDATED. EPIGENETIC MECHANISMS MAY BE AT THE ROOTS OF ADAPTIVE DEVELOPMENTAL PROGRAMMING. SUMMARY: OPTIMAL COORDINATED FUNCTIONING OF MANY COMPLEX PROCESSES AND THEIR NETWORKS OF INTERACTION ARE NECESSARY FOR NORMAL LUNG DEVELOPMENT AND THE MAINTENANCE OF RESPIRATORY HEALTH. OUTDOOR AIR POLLUTION MAY PLAY AN IMPORTANT ROLE IN EARLY PROGRAMMING OF RESPIRATORY HEALTH AND IS POTENTIALLY AMENABLE TO INTERVENTION. 2013 15 602 34 BETTER UNDERSTANDING OF CHILDHOOD ASTHMA, TOWARDS PRIMARY PREVENTION - ARE WE THERE YET? CONSIDERATION OF PERTINENT LITERATURE. ASTHMA IS A CHRONIC DISEASE, CHARACTERIZED BY REVERSIBLE AIRWAY OBSTRUCTION, AIRWAY INFLAMMATION AND HYPER-REACTIVITY. THE PREVALENCE OF ASTHMA HAS RISEN DRAMATICALLY OVER THE PAST DECADE, AFFECTING AROUND 300,000,000 PEOPLE. THE ETIOLOGY IS MULTIFACTORIAL, WITH GENETIC, EPIGENETIC, DEVELOPMENTAL AND ENVIRONMENTAL FACTORS PLAYING A ROLE. A COMPLEX INTERACTION BETWEEN THE INTRAUTERINE ENVIRONMENT, THE DEVELOPING IMMUNE SYSTEM, THE INFANT'S MICROBIOME AND INFECTIOUS ORGANISMS MAY LEAD TO THE DEVELOPMENT OF ALLERGIC SENSITIZATION AND ASTHMA. THUS, A LARGE NUMBER OF STUDIES HAVE INVESTIGATED THE RISK FACTORS FOR CHILDHOOD ASTHMA, WITH A METICULOUS SEARCH OF MODIFIABLE FACTORS THAT COULD AID IN PRIMARY PREVENTION. WE PRESENT A CURRENT LITERATURE REVIEW FROM 2014-2017, AS WELL AS OLDER CLASSIC PUBLICATIONS, ON THE PATHOGENESIS AND THE POTENTIAL MODIFIABLE FACTORS FOR PRIMARY PREVENTION OF ASTHMA. NO IDEAL PREVENTIVE MEASURE HAS YET BEEN FOUND. RATHER, CREATING FAVORABLE PRENATAL AND POSTNATAL ENVIRONMENTS, MINIMAL EXPOSURE TO HOSTILE ENVIRONMENTAL FACTORS, PREVENTION OF INFECTIONS IN EARLY LIFE, ALLERGIC DESENSITIZATION AND NUTRITIONAL MODIFICATIONS COULD POSSIBLY REDUCE ASTHMA INCEPTION. IN THE ERA OF PERSONALIZED MEDICINE, IDENTIFYING INDIVIDUAL RISK FACTORS AND TAILORING SPECIFIC PREVENTIVE MEASURES IS WARRANTED. 2017 16 6191 41 THE IMPACT OF MILK AND ITS COMPONENTS ON EPIGENETIC PROGRAMMING OF IMMUNE FUNCTION IN EARLY LIFE AND BEYOND: IMPLICATIONS FOR ALLERGY AND ASTHMA. SPECIFIC AND ADEQUATE NUTRITION DURING PREGNANCY AND EARLY LIFE IS AN IMPORTANT FACTOR IN AVOIDING NON-COMMUNICABLE DISEASES SUCH AS OBESITY, TYPE 2 DIABETES, CARDIOVASCULAR DISEASE, CANCERS, AND CHRONIC ALLERGIC DISEASES. ALTHOUGH EPIDEMIOLOGIC AND EXPERIMENTAL STUDIES HAVE SHOWN THAT NUTRITION IS IMPORTANT AT ALL STAGES OF LIFE, IT IS ESPECIALLY IMPORTANT IN PRENATAL AND THE FIRST FEW YEARS OF LIFE. DURING THE LAST DECADE, THERE HAS BEEN A GROWING INTEREST IN THE POTENTIAL ROLE OF EPIGENETIC MECHANISMS IN THE INCREASING HEALTH PROBLEMS ASSOCIATED WITH ALLERGIC DISEASE. EPIGENETICS INVOLVES SEVERAL MECHANISMS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS WHICH CAN MODIFY THE EXPRESSION OF GENES. IN THIS STUDY, WE FOCUS ON THE EFFECTS OF MATERNAL NUTRITION DURING PREGNANCY, THE EFFECTS OF THE BIOACTIVE COMPONENTS IN HUMAN AND BOVINE MILK, AND THE ENVIRONMENTAL FACTORS THAT CAN AFFECT EARLY LIFE (I.E., FARMING, MILK PROCESSING, AND BACTERIAL EXPOSURE), AND WHICH CONTRIBUTE TO THE EPIGENETIC MECHANISMS UNDERLYING THE PERSISTENT PROGRAMMING OF IMMUNE FUNCTIONS AND ALLERGIC DISEASES. THIS KNOWLEDGE WILL HELP TO IMPROVE APPROACHES TO NUTRITION IN EARLY LIFE AND HELP PREVENT ALLERGIES IN THE FUTURE. 2020 17 5163 35 PRECISION/PERSONALIZED MEDICINE IN ALLERGIC DISEASES AND ASTHMA. LIKE MANY OTHER CHRONIC DISEASES, EVERY ALLERGIC PATIENT HAS DIFFERENT CHARACTERISTICS BASED ON CLINICAL COURSE, TREATMENT RESPONSIVENESS AND DISEASE OUTCOMES, WHICH ARE ASSOCIATED WITH THE GENETIC AND EPIGENETIC CONTROL OF MOLECULAR MECHANISMS AND ENVIRONMENT. THIS VARIABILITY NECESSITATES THE ESTABLISHMENT OF PATIENT-TAILORED AND PRECISION APPROACHES IN HANDLING ALLERGIC DISORDERS. BETTER UNDERSTANDING OF THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS FOR THE DEVELOPMENT OF ALLERGIC DISORDERS WILL PROVIDE MORE RATIONALE STRATEGIES BASED ON INDIVIDUAL CASES IN CONTROLLING AND TREATING THESE DISORDERS. ENDOTYPING, PHENOTYPING, GENOTYPING AND THERATYPING, AND BIOMARKERS ARE KEYWORDS IN THIS AREA AND HAVE BEEN GAINING LOTS OF ATTENTION IN THE FIELD OF PRECISION MEDICINE, WHICH AIMS TO REVOLUTIONIZE PATIENT CARE AND DEVELOP BETTER PREVENTION AND TREATMENT STRATEGIES. IN ADDITION, PRECISION HEALTH IS A NEW CONCEPT THAT BRINGS PRECISE APPROACHES TO THE SCENE FOR BEING HEALTHY AND PREVENTION OF ALLERGIC DISEASE AND ASTHMA. THE SPECIALTY OF ALLERGY HAS A LEADING ROLE IN THE FIELD, BECAUSE ALLERGEN-SPECIFIC IMMUNOTHERAPY STARTED 105 YEARS AGO, AND IS HISTORICALLY A LEADING PERSONALIZED/PRECISION MEDICINE APPROACH IN ALL MEDICINE DISCIPLINES PROVIDING THE POSSIBILITY OF CURE IN AN INDIVIDUALIZED MANNER INSTEAD OF CONVENTIONAL SYMPTOMATIC TREATMENTS. 2018 18 4063 33 MATERNAL AND CHILDHOOD ASTHMA: RISK FACTORS, INTERACTIONS, AND RAMIFICATIONS. ASTHMA IS EMERGING AS A PREMIER EXAMPLE OF A HEALTH RISK THAT CAN LARGELY BE MOLDED BY THE STATUS OF THE MOTHER AND THE ENVIRONMENTAL CONDITIONS ENCOUNTERED DURING SENSITIVE WINDOWS OF PRENATAL AND EARLY CHILDHOOD DEVELOPMENT. WHILE GENETIC BACKGROUND, ALLERGIC STATUS OF PARENTS, AND PREDISPOSITION FOR ATOPY AND INFLAMMATION PLAY A ROLE, EARLY-LIFE ENVIRONMENTAL CONDITIONS CAN COMPLETELY ALTER THE COURSE OF IMMUNE AND RESPIRATORY SYSTEM DEVELOPMENT. ENVIRONMENTALLY INDUCED ALTERATIONS THAT (1) MAINTAIN THE TH2 BIAS SEEN DURING GESTATION, (2) BLOCK THE MATURATION OF INNATE IMMUNE CELLS AND (3) CREATE INFLAMMATORY DYSFUNCTION IN THE INFANT PROVIDE THE FOUNDATION FOR CHILDHOOD ASTHMA. NO SINGLE RISK FACTOR CAN FULLY EXPLAIN THE INCREASED PREVALENCE OF ASTHMA IN RECENT DECADES BUT IT IS ASSUMED THAT THE RAPID INCREASE IS DUE TO ENVIRONMENTAL AND/OR EPIGENETIC CHANGES. WELL-ESTABLISHED AND SUSPECTED ENVIRONMENTAL RISK FACTORS COVER ALL CATEGORIES OF EARLY LIFE INTERACTIONS FROM DIET, EXPOSURE TO ENVIRONMENTAL CONTAMINANTS AND DRUGS, MATERNAL AND NEONATAL INFECTIONS, HYGIENE, TIMING OF VACCINATIONS AND EVEN THE MODE OF BIRTH DELIVERY. BECAUSE ASTHMA IS CONNECTED TO THE RISK OF SEVERAL COMORBID CHRONIC CONDITIONS, THE BENEFIT OF ASTHMA RISK REDUCTION AND PREVENTION IS GREATER THAN INITIALLY MAY BE APPARENT. THIS REVIEW DISCUSSES STRATEGIES TO OPTIMIZE PREVENTATIVE AND THERAPEUTIC OPTIONS ACROSS LIFE STAGES. 2011 19 530 33 ASTHMA. ASTHMA IS THE MOST COMMON INFLAMMATORY DISEASE OF THE LUNGS. THE PREVALENCE OF ASTHMA IS INCREASING IN MANY PARTS OF THE WORLD THAT HAVE ADOPTED ASPECTS OF THE WESTERN LIFESTYLE, AND THE DISEASE POSES A SUBSTANTIAL GLOBAL HEALTH AND ECONOMIC BURDEN. ASTHMA INVOLVES BOTH THE LARGE-CONDUCTING AND THE SMALL-CONDUCTING AIRWAYS, AND IS CHARACTERIZED BY A COMBINATION OF INFLAMMATION AND STRUCTURAL REMODELLING THAT MIGHT BEGIN IN UTERO. DISEASE PROGRESSION OCCURS IN THE CONTEXT OF A DEVELOPMENTAL BACKGROUND IN WHICH THE POSTNATAL ACQUISITION OF ASTHMA IS STRONGLY LINKED WITH ALLERGIC SENSITIZATION. MOST ASTHMA CASES FOLLOW A VARIABLE COURSE, INVOLVING VIRAL-INDUCED WHEEZING AND ALLERGEN SENSITIZATION, THAT IS ASSOCIATED WITH VARIOUS UNDERLYING MECHANISMS (OR ENDOTYPES) THAT CAN DIFFER BETWEEN INDIVIDUALS. EACH SET OF ENDOTYPES, IN TURN, PRODUCES SPECIFIC ASTHMA CHARACTERISTICS THAT EVOLVE ACROSS THE LIFECOURSE OF THE PATIENT. STRONG GENETIC AND ENVIRONMENTAL DRIVERS OF ASTHMA INTERCONNECT THROUGH NOVEL EPIGENETIC MECHANISMS THAT OPERATE PRENATALLY AND THROUGHOUT CHILDHOOD. ASTHMA CAN SPONTANEOUSLY REMIT OR BEGIN DE NOVO IN ADULTHOOD, AND THE FACTORS THAT LEAD TO THE EMERGENCE AND REGRESSION OF ASTHMA, IRRESPECTIVE OF AGE, ARE POORLY UNDERSTOOD. NONETHELESS, THERE IS MOUNTING EVIDENCE THAT SUPPORTS A PRIMARY ROLE FOR STRUCTURAL CHANGES IN THE AIRWAYS WITH ASTHMA ACQUISITION, ON WHICH ALTERED INNATE IMMUNE MECHANISMS AND MICROBIOTA INTERACTIONS ARE SUPERIMPOSED. ON THE BASIS OF THE IDENTIFICATION OF NEW CAUSATIVE PATHWAYS, THE SUBPHENOTYPING OF ASTHMA ACROSS THE LIFECOURSE OF PATIENTS IS PAVING THE WAY FOR MORE-PERSONALIZED AND PRECISE PATHWAY-SPECIFIC APPROACHES FOR THE PREVENTION AND TREATMENT OF ASTHMA, CREATING THE REAL POSSIBILITY OF TOTAL PREVENTION AND CURE FOR THIS CHRONIC INFLAMMATORY DISEASE. 2015 20 5552 36 ROLE OF EPIGENETICS IN THE PATHOGENESIS OF ASTHMA. ASTHMA IS A COMPLEX, HETEROGENEOUS AND CHRONIC AIRWAY INFLAMMATORY DISEASE WITH DIFFERENT CLINICAL PHENOTYPES CAUSED BY DIVERSE TRIGGERS AND PATHOPHYSIOLOGICAL MECHANISMS. ASTHMA HERITABILITY HAS BEEN ESTABLISHED IN MANY GENETIC STUDIES BUT IT IS EVIDENT THAT ONLY GENETIC ELEMENTS ARE NOT RESPONSIBLE FOR THE DEVELOPMENT OF ASTHMA. INCREASING RATE OF ASTHMA INCIDENCE DURING PAST DECADES HAS IMPLICATED THE ROLE OF EPIGENETICS IN DEVELOPMENT OF ASTHMA. ENVIRONMENTAL FACTORS PERFORM AS INITIATOR SIGNALS THROUGH EPIGENETIC MECHANISMS. THREE EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND SMALL NONCODING RNAS. THESE MECHANISMS REGULATE THE IMMUNE RESPONSES AND INFLAMMATORY GENES EXPRESSION IN ASTHMA AND ALLERGY. THIS REVIEW EXPLAINS THE ROLE OF EPIGENETIC MODIFICATIONS IN CONTROLLING TH2 RESPONSE AND IGE PRODUCTION IN ASTHMA AND ALSO BRIEFLY OVERVIEWS THE ROLE OF ENVIRONMENTAL FACTORS SUCH AS POLLUTIONS, ALLERGENS, PRENATAL EXPOSURES AND DIET IN DEVELOPING ASTHMA. RECOGNIZING ENVIRONMENTAL RISK FACTORS AND THEIR EFFECTS ON EPIGENETIC MECHANISMS WOULD BE OF GREAT INTEREST FOR PROGNOSTIC AND PREVENTIVE ASPECT IN TREATMENT OF ASTHMA. 2017