1 4404 154 MODULATION OF THE RESPONSE TO MYCOBACTERIUM LEPRAE AND PATHOGENESIS OF LEPROSY. THE INITIAL INFECTION BY THE OBLIGATE INTRACELLULAR BACILLUS MYCOBACTERIUM LEPRAE EVOLVES TO LEPROSY IN A SMALL SUBSET OF THE INFECTED INDIVIDUALS. TRANSMISSION IS BELIEVED TO OCCUR MAINLY BY EXPOSURE TO BACILLI PRESENT IN AEROSOLS EXPELLED BY INFECTED INDIVIDUALS WITH HIGH BACILLARY LOAD. MYCOBACTERIUM LEPRAE-SPECIFIC DNA HAS BEEN DETECTED IN THE BLOOD OF ASYMPTOMATIC HOUSEHOLD CONTACTS OF LEPROSY PATIENTS YEARS BEFORE ACTIVE DISEASE ONSET, SUGGESTING THAT, FOLLOWING INFECTION, THE BACTERIUM REACHES THE LYMPHATIC DRAINAGE AND THE BLOOD OF AT LEAST SOME INDIVIDUALS. THE LOWER TEMPERATURE AND AVAILABILITY OF PROTECTED MICROENVIRONMENTS MAY PROVIDE THE INITIAL CONDITIONS FOR THE SURVIVAL OF THE BACILLUS IN THE AIRWAYS AND SKIN. A SUBSET OF SKIN-RESIDENT MACROPHAGES AND THE SCHWANN CELLS OF PERIPHERAL NERVES, TWO M. LEPRAE PERMISSIVE CELLS, MAY PROTECT M. LEPRAE FROM EFFECTOR CELLS IN THE INITIAL PHASE OF THE INFECTION. THE INTERACTION OF M. LEPRAE WITH THESE CELLS INDUCES METABOLIC CHANGES, INCLUDING THE FORMATION OF LIPID DROPLETS, THAT ARE ASSOCIATED WITH MACROPHAGE M2 PHENOTYPE AND THE PRODUCTION OF MEDIATORS THAT FACILITATE THE DIFFERENTIATION OF SPECIFIC T CELLS FOR M. LEPRAE-EXPRESSED ANTIGENS TO A MEMORY REGULATORY PHENOTYPE. HERE, WE DISCUSS THE POSSIBLE INITIALS STEPS OF M. LEPRAE INFECTION THAT MAY LEAD TO ACTIVE DISEASE ONSET, MAINLY FOCUSING ON EVENTS PRIOR TO THE MANIFESTATION OF THE ESTABLISHED CLINICAL FORMS OF LEPROSY. WE HYPOTHESIZE THAT THE PROGRESSIVE DIFFERENTIATION OF T CELLS TO THE TREGS PHENOTYPE INHIBITS EFFECTOR FUNCTION AGAINST THE BACILLUS, ALLOWING AN INCREASE IN THE BACILLARY LOAD AND EVOLUTION OF THE INFECTION TO ACTIVE DISEASE. EPIGENETIC AND METABOLIC MECHANISMS DESCRIBED IN OTHER CHRONIC INFLAMMATORY DISEASES ARE EVALUATED FOR POTENTIAL APPLICATION TO THE UNDERSTANDING OF LEPROSY PATHOGENESIS. A POTENTIAL ROLE FOR POST-EXPOSURE PROPHYLAXIS OF LEPROSY IN REDUCING M. LEPRAE-INDUCED ANTI-INFLAMMATORY MEDIATORS AND, IN CONSEQUENCE, TREG/T EFFECTOR RATIOS IS PROPOSED. 2022 2 2563 29 EPIGENETICS IN TUBERCULOSIS: IMMUNOMODULATION OF HOST IMMUNE RESPONSE. TUBERCULOSIS IS A STERN, DIFFICULT TO TREAT CHRONIC INFECTION CAUSED BY ACID-FAST BACILLI THAT TEND TO TAKE A LONG TIME TO BE ERADICATED FROM THE HOST'S ENVIRONMENT. IT REQUIRES THE ACTION OF BOTH INNATE AND ADAPTIVE IMMUNE SYSTEMS BY THE HOST. THERE ARE VARIOUS PATTERN RECOGNITION RECEPTORS PRESENT ON IMMUNE CELLS, WHICH RECOGNIZE FOREIGN PATHOGENS OR ITS PRODUCT AND TRIGGER THE IMMUNE RESPONSE. THE EPIGENETIC MODIFICATION PLAYS A CRUCIAL ROLE IN TRIGGERING THE SUSCEPTIBILITY OF THE HOST TOWARDS THE PATHOGEN AND ACTIVATING THE HOST'S IMMUNE SYSTEM AGAINST THE INVADING PATHOGEN. IT ALTERS THE GENE EXPRESSION MODIFYING THE GENETIC MATERIAL OF THE HOST'S CELL. EPIGENETIC MODIFICATION SUCH AS HISTONE ACETYLATION, ALTERATION IN NON-CODING RNA, DNA METHYLATION AND ALTERATION IN MIRNA HAS BEEN STUDIED FOR THEIR INFLUENCE ON THE PATHOPHYSIOLOGY OF TUBERCULOSIS TO CONTROL THE SPREAD OF INFECTION. DESPITE SEVERAL STUDIES BEING CONDUCTED, MANY GAPS STILL EXIST. HEREIN, WE DISCUSS THE IMMUNOPATHOPHYSIOLOGICAL MECHANISM OF TUBERCULOSIS, THE ESSENTIALS OF EPIGENETICS AND THE RECENT ENCROACHMENT OF EPIGENETICS IN THE FIELD OF TUBERCULOSIS AND ITS INFLUENCE ON THE OUTCOME AND PATHOPHYSIOLOGY OF THE INFECTION. 2022 3 3904 45 LEPROSY PIRNOME: EXPLORING NEW POSSIBILITIES FOR AN OLD DISEASE. LEPROSY, WHICH IS CAUSED BY THE HUMAN PATHOGEN MYCOBACTERIUM LEPRAE, CAUSES NERVE DAMAGE, DEFORMITY AND DISABILITY IN OVER 200,000 PEOPLE EVERY YEAR. BECAUSE OF THE LONG DOUBLING TIME OF M. LEPRAE (13 DAYS) AND THE DELAYED ONSET OF DETECTABLE SYMPTOMS, WHICH IS ESTIMATED TO BE APPROXIMATELY 3-7 YEARS AFTER INFECTION, THERE IS ALWAYS A LARGE PERCENTAGE OF SUBCLINICALLY INFECTED INDIVIDUALS IN THE POPULATION WHO WILL EVENTUALLY DEVELOP THE DISEASE, MAINLY IN ENDEMIC COUNTRIES. PIRNAS COMPRISE THE LARGEST GROUP OF SMALL NONCODING RNAS FOUND IN HUMANS, AND THEY ARE DISTINCT FROM MICRORNAS (MIRNAS) AND SMALL INTERFERING RNAS (SIRNAS). PIRNAS FUNCTION IN TRANSPOSON SILENCING, EPIGENETIC REGULATION, AND GERMLINE DEVELOPMENT. THE FUNCTIONAL ROLE OF PIRNAS AND THEIR ASSOCIATED PIWI PROTEINS HAVE STARTED TO EMERGE IN THE DEVELOPMENT OF HUMAN CANCERS AND VIRAL INFECTIONS, BUT THEIR RELEVANCE TO BACTERIAL DISEASES HAS NOT BEEN INVESTIGATED. THE PRESENT STUDY REPORTS THE PIRNOME OF HUMAN SKIN, REVEALING THAT ALL BUT ONE OF THE PIRNAS EXAMINED ARE DOWNREGULATED IN LEPROSY SKIN LESIONS. CONSIDERING THAT ONE OF THE BEST CHARACTERIZED FUNCTIONS OF PIRNAS IN HUMANS IS POSTTRANSCRIPTIONAL MRNA SILENCING, THEIR FUNCTIONS ARE SIMILAR TO WHAT WE HAVE DESCRIBED FOR MIRNAS, INCLUDING ACTING ON APOPTOSIS, M. LEPRAE RECOGNITION AND ENGULFMENT, SCHWANN CELL (SC) DEMYELINATION, EPITHELIAL-MESENCHYMAL TRANSITION (EMT), LOSS OF SENSATION AND NEUROPATHIC PAIN. IN ADDITION TO NEW FINDINGS ON LEPROSY PHYSIOPATHOLOGY, THE DISCOVERY OF RELEVANT PIRNAS INVOLVED IN DISEASE PROCESSES IN HUMAN SKIN MAY PROVIDE NEW CLUES FOR THERAPEUTIC TARGETS, SPECIFICALLY TO CONTROL NERVE DAMAGE, A PROMINENT FEATURE OF LEPROSY THAT HAS NO CURRENTLY AVAILABLE PHARMACEUTICAL TREATMENT. 2020 4 1349 34 DETERMINANTS OF INNATE IMMUNITY IN VISCERAL LEISHMANIASIS AND THEIR IMPLICATION IN VACCINE DEVELOPMENT. LEISHMANIASIS IS ENDEMIC TO THE TROPICAL AND SUBTROPICAL REGIONS OF THE WORLD AND IS TRANSMITTED BY THE BITE OF AN INFECTED SAND FLY. THE MULTIFACETED INTERACTIONS BETWEEN LEISHMANIA, THE HOST INNATE IMMUNE CELLS, AND THE ADAPTIVE IMMUNITY DETERMINE THE SEVERITY OF PATHOGENESIS AND DISEASE DEVELOPMENT. LEISHMANIA PARASITES ESTABLISH A CHRONIC INFECTION BY SUBVERSION AND ATTENUATION OF THE MICROBICIDAL FUNCTIONS OF PHAGOCYTIC INNATE IMMUNE CELLS SUCH AS NEUTROPHILS, MACROPHAGES AND DENDRITIC CELLS (DCS). OTHER INNATE CELLS SUCH AS INFLAMMATORY MONOCYTES, MAST CELLS AND NK CELLS, ALSO CONTRIBUTE TO RESISTANCE AND/OR SUSCEPTIBILITY TO LEISHMANIA INFECTION. IN ADDITION TO THE CYTOKINE/CHEMOKINE SIGNALS FROM THE INNATE IMMUNE CELLS, RECENT STUDIES IDENTIFIED THE SUBTLE SHIFTS IN THE METABOLIC PATHWAYS OF THE INNATE CELLS THAT ACTIVATE DISTINCT IMMUNE SIGNAL CASCADES. THE NEXUS BETWEEN METABOLIC PATHWAYS, EPIGENETIC REPROGRAMMING AND THE IMMUNE SIGNALING CASCADES THAT DRIVE THE DIVERGENT INNATE IMMUNE RESPONSES, REMAINS TO BE FULLY UNDERSTOOD IN LEISHMANIA PATHOGENESIS. FURTHER, DEVELOPMENT OF SAFE AND EFFICACIOUS VACCINES AGAINST LEISHMANIASIS REQUIRES A BROADER UNDERSTANDING OF THE EARLY INTERACTIONS BETWEEN THE PARASITES AND INNATE IMMUNE CELLS. IN THIS REVIEW WE FOCUS ON THE CURRENT UNDERSTANDING OF THE SPECIFIC ROLE OF INNATE IMMUNE CELLS, THE METABOLOMIC AND EPIGENETIC REPROGRAMMING AND IMMUNE REGULATION THAT OCCURS DURING VISCERAL LEISHMANIASIS, AND THE STRATEGIES USED BY THE PARASITE TO EVADE AND MODULATE HOST IMMUNITY. WE HIGHLIGHT HOW SUCH PATHWAYS COULD BE EXPLOITED IN THE DEVELOPMENT OF SAFE AND EFFICACIOUS LEISHMANIA VACCINES. 2021 5 5350 39 RATIONAL DEVELOPMENT OF ADJUNCT IMMUNE-BASED THERAPIES FOR DRUG-RESISTANT TUBERCULOSIS: HYPOTHESES AND EXPERIMENTAL DESIGNS. THE POOR TREATMENT OUTCOMES FOR EXTENSIVELY DRUG-RESISTANT AND MULTIDRUG-RESISTANT TUBERCULOSIS AND THE SLOW PROGRESS IN DEVELOPMENT AND EVALUATION OF NEW TUBERCULOSIS DRUGS GAVE RISE TO DEVELOPMENT OF SEVERAL POTENTIAL IMMUNE-BASED THERAPIES FOR ADJUNCT USE WITH DRUG TREATMENT. HOWEVER, NONE OF THESE THERAPIES HAVE BEEN SHOWN TO BE OF BENEFIT IN CONTROLLED CLINICAL TRIALS IN HUMANS. THERE IS AN URGENT NEED TO RETHINK THE IMMUNOLOGY OF MYCOBACTERIUM TUBERCULOSIS INFECTION AND TO ASCERTAIN PROTECTIVE IMMUNE MECHANISMS THAT COULD BE EXPLOITED TO DEVELOP MORE EFFECTIVE ADJUNCT IMMUNE THERAPIES. T CELLS OBTAINED FROM THE PERIPHERAL BLOOD CIRCULATION MAY NOT REFLECT THE BIOLOGICALLY RELEVANT RECOGNITION OF ANTI-M. TUBERCULOSIS T-CELL RESPONSES IN SITU. THUS, T CELLS THAT MEDIATE PROTECTIVE ANTI-M. TUBERCULOSIS IMMUNE RESPONSES RECOGNIZE AN AS-YET UNDISCOVERED SET OF M. TUBERCULOSIS ANTIGENS THAT REQUIRE DEFINITION. THE BIOLOGICALLY AND CLINICALLY RELEVANT M. TUBERCULOSIS TARGETS THAT ELICIT PROTECTIVE IMMUNE RESPONSES MAY HAVE YET TO BE DISCOVERED. THE ENTIRE M. TUBERCULOSIS PROTEOME IS NOW ACCESSIBLE FOR SCREENING BY ANTIBODY RECOGNITION AND CAN THEREFORE BE USED TO IDENTIFY SPECIFIC T-CELL M. TUBERCULOSIS TARGET ANTIGENS. INHIBITORY CYTOKINES AND LYMPHOCYTOSIS PRESENT IN CHRONIC TUBERCULOSIS INFLAMMATION MAY BE DELETERIOUS IN MOUNTING AN EFFECTIVE M. TUBERCULOSIS T-CELL RESPONSE. CONSEQUENTLY, ABERRANT AND NONEFFECTIVE IMMUNE RESPONSES COULD BE REFOCUSED WITH ANTICYTOKINE OR CELLULAR THERAPY. EPIGENETIC CHANGES DUE TO CHRONIC INFLAMMATION MAY BE RESPONSIBLE, IN PART, FOR IMPAIRED IMMUNE RESPONSES IN TUBERCULOSIS AND THESE CHANGES COULD BE REVERSED. WE PRESENT FEASIBLE EXPERIMENTAL DESIGNS TO TEST THESE HYPOTHESES; THE RESULTS OF WHICH MAY GUIDE AND REFOCUS DEVELOPMENT OF NOVEL IMMUNE-BASED THERAPIES FOR ADJUNCT TREATMENT OF DRUG-RESISTANT TUBERCULOSIS. INSIGHTS FROM CANCER IMMUNOLOGY WILL CROSS-FERTILIZE TUBERCULOSIS IMMUNOLOGY AND HELP TO DEVISE MORE EFFECTIVE ADJUNCT TREATMENT AND VACCINATION STRATEGIES. 2012 6 6495 34 TRAINED IMMUNITY AS A POTENTIAL TARGET FOR THERAPEUTIC IMMUNOMODULATION IN DUCHENNE MUSCULAR DYSTROPHY. DYSREGULATED INFLAMMATION INVOLVING INNATE IMMUNE CELLS, PARTICULARLY OF THE MONOCYTE/MACROPHAGE LINEAGE, IS A KEY CONTRIBUTOR TO THE PATHOGENESIS OF DUCHENNE MUSCULAR DYSTROPHY (DMD). TRAINED IMMUNITY IS AN EVOLUTIONARILY ANCIENT PROTECTIVE MECHANISM AGAINST INFECTION, IN WHICH EPIGENETIC AND METABOLIC ALTERATIONS CONFER NON-SPECIFIC HYPERRESPONSIVENESS OF INNATE IMMUNE CELLS TO VARIOUS STIMULI. RECENT WORK IN AN ANIMAL MODEL OF DMD (MDX MICE) HAS SHOWN THAT MACROPHAGES EXHIBIT CARDINAL FEATURES OF TRAINED IMMUNITY, INCLUDING THE PRESENCE OF INNATE IMMUNE SYSTEM "MEMORY". THE LATTER IS REFLECTED BY EPIGENETIC CHANGES AND DURABLE TRANSMISSIBILITY OF THE TRAINED PHENOTYPE TO HEALTHY NON-DYSTROPHIC MICE BY BONE MARROW TRANSPLANTATION. MECHANISTICALLY, IT IS SUGGESTED THAT A TOLL-LIKE RECEPTOR (TLR) 4-REGULATED, MEMORY-LIKE CAPACITY OF INNATE IMMUNITY IS INDUCED AT THE LEVEL OF THE BONE MARROW BY FACTORS RELEASED FROM THE DAMAGED MUSCLES, LEADING TO EXAGGERATED UPREGULATION OF BOTH PRO- AND ANTI-INFLAMMATORY GENES. HERE WE PROPOSE A CONCEPTUAL FRAMEWORK FOR THE INVOLVEMENT OF TRAINED IMMUNITY IN DMD PATHOGENESIS AND ITS POTENTIAL TO SERVE AS A NEW THERAPEUTIC TARGET. 2023 7 5431 33 REGULATORY T CELLS: PATHOPHYSIOLOGICAL ROLES AND CLINICAL APPLICATIONS. INFLAMMATION AND IMMUNE RESPONSES AFTER TISSUE INJURY PLAY PIVOTAL ROLES IN THE RESOLUTION OF INFLAMMATION, TISSUE RECOVERY, FIBROSIS, AND REMODELING. REGULATORY T CELLS (TREGS) ARE RESPONSIBLE FOR IMMUNE TOLERANCE AND ARE USUALLY ACTIVATED IN SECONDARY LYMPHATIC TISSUES. ACTIVATED TREGS SUBSEQUENTLY REGULATE EFFECTOR T CELL AND DENDRITIC CELL ACTIVATION. FOR CLINICAL APPLICATIONS SUCH AS THE SUPPRESSION OF BOTH AUTOIMMUNE DISEASES AND THE REJECTION OF TRANSPLANTED ORGANS, METHODS TO GENERATE STABILIZED ANTIGEN-SPECIFIC TREGS ARE REQUIRED. FOR THIS PURPOSE, TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF FOXP3 EXPRESSION HAS BEEN INVESTIGATED. IN ADDITION TO CONVENTIONAL TREGS, THERE ARE SOME TREGS THAT RESIDE IN TISSUES AND ARE CALLED TISSUE TREGS. TISSUE TREGS EXHIBIT TISSUE-SPECIFIC FUNCTIONS THAT CONTRIBUTE TO THE MAINTENANCE OF TISSUE HOMEOSTASIS AND REPAIR. SUCH TISSUE TREGS COULD ALSO BE USEFUL FOR TREG-BASED CELL THERAPY. WE RECENTLY DISCOVERED BRAIN TREGS THAT ACCUMULATE IN THE BRAIN DURING THE CHRONIC PHASE OF ISCHEMIC BRAIN INJURY. BRAIN TREGS RESEMBLE OTHER TISSUE TREGS, BUT ARE UNIQUE IN EXPRESSING NEURAL CELL-SPECIFIC GENES SUCH AS THE SEROTONIN RECEPTOR (HTR7); CONSEQUENTLY, BRAIN TREGS RESPOND TO SEROTONIN. HERE, WE DESCRIBE OUR EXPERIENCES IN THE USE OF TREGS TO SUPPRESS GRAFT-VERSUS-HOST DISEASE AND TO PROMOTE NEURAL RECOVERY AFTER STROKE. 2020 8 6500 36 TRAINED IMMUNITY IN TYPE 2 IMMUNE RESPONSES. IMMUNOLOGICAL MEMORY OF INNATE IMMUNE CELLS, ALSO TERMED "TRAINED IMMUNITY", ALLOWS FOR CROSS-PROTECTION AGAINST DISTINCT PATHOGENS, BUT MAY ALSO DRIVE CHRONIC INFLAMMATION. RECENT STUDIES HAVE SHOWN THAT MEMORY RESPONSES ASSOCIATED WITH TYPE 2 IMMUNITY DO NOT SOLELY RELY ON ADAPTIVE IMMUNE CELLS, SUCH AS T- AND B CELLS, BUT ALSO INVOLVE THE INNATE IMMUNE SYSTEM AND EPITHELIAL CELLS. MEMORY RESPONSES HAVE BEEN DESCRIBED FOR MONOCYTES, MACROPHAGES AND AIRWAY EPITHELIAL CELLS OF ASTHMATIC PATIENTS AS WELL AS FOR MACROPHAGES AND GROUP 2 INNATE LYMPHOID CELLS (ILC2) FROM ALLERGEN-SENSITIZED OR HELMINTH-INFECTED MICE. THE METABOLIC AND EPIGENETIC MECHANISMS THAT MEDIATE ALLERGEN- OR HELMINTH-INDUCED REPROGRAMMING OF INNATE IMMUNE CELLS ARE ONLY BEGINNING TO BE UNCOVERED. TRAINED IMMUNITY HAS BEEN IMPLICATED IN HELMINTH-DRIVEN IMMUNE REGULATION AND ALLERGEN-SPECIFIC IMMUNOTHERAPY, SUGGESTING ITS EXPLOITATION IN FUTURE THERAPIES. HERE, WE DISCUSS RECENT ADVANCES AND KEY REMAINING QUESTIONS REGARDING THE MECHANISMS AND FUNCTIONS OF TRAINED TYPE 2 IMMUNITY IN INFECTION AND INFLAMMATION. 2022 9 5800 28 STEPWISE PATHOGENIC EVOLUTION OF MYCOBACTERIUM ABSCESSUS. ALTHOUGH ALMOST ALL MYCOBACTERIAL SPECIES ARE SAPROPHYTIC ENVIRONMENTAL ORGANISMS, A FEW, SUCH AS MYCOBACTERIUM TUBERCULOSIS, HAVE EVOLVED TO CAUSE TRANSMISSIBLE HUMAN INFECTION. BY ANALYZING THE RECENT EMERGENCE AND SPREAD OF THE ENVIRONMENTAL ORGANISM M. ABSCESSUS THROUGH THE GLOBAL CYSTIC FIBROSIS POPULATION, WE HAVE DEFINED KEY, GENERALIZABLE STEPS INVOLVED IN THE PATHOGENIC EVOLUTION OF MYCOBACTERIA. WE SHOW THAT EPIGENETIC MODIFIERS, ACQUIRED THROUGH HORIZONTAL GENE TRANSFER, CAUSE SALTATIONAL INCREASES IN THE PATHOGENIC POTENTIAL OF SPECIFIC ENVIRONMENTAL CLONES. ALLOPATRIC PARALLEL EVOLUTION DURING CHRONIC LUNG INFECTION THEN PROMOTES RAPID INCREASES IN VIRULENCE THROUGH MUTATIONS IN A DISCRETE GENE NETWORK; THESE MUTATIONS ENHANCE GROWTH WITHIN MACROPHAGES BUT IMPAIR FOMITE SURVIVAL. AS A CONSEQUENCE, WE OBSERVE CONSTRAINED PATHOGENIC EVOLUTION WHILE PERSON-TO-PERSON TRANSMISSION REMAINS INDIRECT, BUT POSTULATE ACCELERATED PATHOGENIC ADAPTATION ONCE DIRECT TRANSMISSION IS POSSIBLE, AS OBSERVED FOR M. TUBERCULOSIS OUR FINDINGS INDICATE HOW KEY INTERVENTIONS, SUCH AS EARLY TREATMENT AND CROSS-INFECTION CONTROL, MIGHT RESTRICT THE SPREAD OF EXISTING MYCOBACTERIAL PATHOGENS AND PREVENT NEW, EMERGENT ONES. 2021 10 3732 30 INNATE IMMUNE MEMORY AND THE HOST RESPONSE TO INFECTION. UNLIKE THE ADAPTIVE IMMUNE SYSTEM, THE INNATE IMMUNE SYSTEM HAS CLASSICALLY BEEN CHARACTERIZED AS BEING DEVOID OF MEMORY FUNCTIONS. HOWEVER, RECENT RESEARCH SHOWS THAT INNATE MYELOID AND LYMPHOID CELLS HAVE THE ABILITY TO RETAIN MEMORY OF PRIOR PATHOGEN EXPOSURE AND BECOME PRIMED TO ELICIT A ROBUST, BROAD-SPECTRUM RESPONSE TO SUBSEQUENT INFECTION. THIS PHENOMENON HAS BEEN TERMED INNATE IMMUNE MEMORY OR TRAINED IMMUNITY. INNATE IMMUNE MEMORY IS INDUCED VIA ACTIVATION OF PATTERN RECOGNITION RECEPTORS AND THE ACTIONS OF CYTOKINES ON HEMATOPOIETIC PROGENITORS AND STEM CELLS IN BONE MARROW AND INNATE LEUKOCYTES IN THE PERIPHERY. THE TRAINED PHENOTYPE IS INDUCED AND SUSTAINED VIA EPIGENETIC MODIFICATIONS THAT REPROGRAM TRANSCRIPTIONAL PATTERNS AND METABOLISM. THESE MODIFICATIONS AUGMENT ANTIMICROBIAL FUNCTIONS, SUCH AS LEUKOCYTE EXPANSION, CHEMOTAXIS, PHAGOCYTOSIS, AND MICROBIAL KILLING, TO FACILITATE AN AUGMENTED HOST RESPONSE TO INFECTION. ALTERNATIVELY, INNATE IMMUNE MEMORY MAY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS AND ALZHEIMER'S DISEASE. 2022 11 1310 26 DEFINING TRAINED IMMUNITY AND ITS ROLE IN HEALTH AND DISEASE. IMMUNE MEMORY IS A DEFINING FEATURE OF THE ACQUIRED IMMUNE SYSTEM, BUT ACTIVATION OF THE INNATE IMMUNE SYSTEM CAN ALSO RESULT IN ENHANCED RESPONSIVENESS TO SUBSEQUENT TRIGGERS. THIS PROCESS HAS BEEN TERMED 'TRAINED IMMUNITY', A DE FACTO INNATE IMMUNE MEMORY. RESEARCH IN THE PAST DECADE HAS POINTED TO THE BROAD BENEFITS OF TRAINED IMMUNITY FOR HOST DEFENCE BUT HAS ALSO SUGGESTED POTENTIALLY DETRIMENTAL OUTCOMES IN IMMUNE-MEDIATED AND CHRONIC INFLAMMATORY DISEASES. HERE WE DEFINE 'TRAINED IMMUNITY' AS A BIOLOGICAL PROCESS AND DISCUSS THE INNATE STIMULI AND THE EPIGENETIC AND METABOLIC REPROGRAMMING EVENTS THAT SHAPE THE INDUCTION OF TRAINED IMMUNITY. 2020 12 2861 41 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 13 233 24 ADAPTIVE T CELL TUNING IN IMMUNE REGULATION AND IMMUNOTHERAPY OF AUTOIMMUNE DISEASES(?). LYMPHOCYTE RECEPTORS CONFER ANTIGEN SPECIFICITY ON THE ADAPTIVE IMMUNE RESPONSE. INCREASING EVIDENCE POINTS TO THE ROLE OF ADAPTIVE TUNING PARTICULARLY AMONGST CD4(+) T CELL RESPONSES. THIS REVIEW SUMMARISES HOW T CELL TUNING IMPACTS ON CRITICALLY IMPORTANT ASPECTS OF IMMUNE REGULATION INCLUDING THYMIC SELECTION, THE IMMUNE RESPONSE TO CHRONIC ANTIGEN EXPOSURE AND ANTIGEN-SPECIFIC IMMUNOTHERAPY OF AUTOIMMUNE CONDITIONS. RECENT WORK HAS REVEALED A NOVEL MECHANISM FOR T CELL ANERGY AND REGULATORY TYPE 1 T CELL DIFFERENTIATION THROUGH A LIMITATION OF T CELL RECEPTOR MEDIATED SIGNALLING COMBINED WITH EPIGENETIC PRIMING OF TOLERANCE ASSOCIATED GENES. 2022 14 6503 28 TRAINED IMMUNITY: REPROGRAMMING INNATE IMMUNITY IN HEALTH AND DISEASE. TRADITIONALLY, THE INNATE AND ADAPTIVE IMMUNE SYSTEMS ARE DIFFERENTIATED BY THEIR SPECIFICITY AND MEMORY CAPACITY. IN RECENT YEARS, HOWEVER, THIS PARADIGM HAS SHIFTED: CELLS OF THE INNATE IMMUNE SYSTEM APPEAR TO BE ABLE TO GAIN MEMORY CHARACTERISTICS AFTER TRANSIENT STIMULATION, RESULTING IN AN ENHANCED RESPONSE UPON SECONDARY CHALLENGE. THIS PHENOMENON HAS BEEN CALLED TRAINED IMMUNITY. TRAINED IMMUNITY IS CHARACTERIZED BY NONSPECIFIC INCREASED RESPONSIVENESS, MEDIATED VIA EXTENSIVE METABOLIC AND EPIGENETIC REPROGRAMMING. TRAINED IMMUNITY EXPLAINS THE HETEROLOGOUS EFFECTS OF VACCINES, WHICH RESULT IN INCREASED PROTECTION AGAINST SECONDARY INFECTIONS. HOWEVER, IN CHRONIC INFLAMMATORY CONDITIONS, TRAINED IMMUNITY CAN INDUCE MALADAPTIVE EFFECTS AND CONTRIBUTE TO HYPERINFLAMMATION AND PROGRESSION OF CARDIOVASCULAR DISEASE, AUTOINFLAMMATORY SYNDROMES, AND NEUROINFLAMMATION. IN THIS REVIEW WE SUMMARIZE THE CURRENT STATE OF THE FIELD OF TRAINED IMMUNITY, ITS MECHANISMS, AND ITS ROLES IN BOTH HEALTH AND DISEASE. 2021 15 6502 30 TRAINED IMMUNITY: LONG-TERM ADAPTATION IN INNATE IMMUNE RESPONSES. ADAPTIVE IMMUNE RESPONSES ARE CHARACTERIZED BY ANTIGEN SPECIFICITY AND INDUCTION OF LIFELONG IMMUNOLOGIC MEMORY. RECENTLY, IT HAS BEEN REPORTED THAT INNATE IMMUNE CELLS CAN ALSO BUILD IMMUNE MEMORY CHARACTERISTICS-A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY DESCRIBES THE PERSISTENT HYPERRESPONSIVE PHENOTYPE THAT INNATE IMMUNE CELLS CAN DEVELOP AFTER BRIEF STIMULATION. PATHOGENIC STIMULI SUCH AS MICROORGANISMS, AND ALSO ENDOGENOUS MOLECULES INCLUDING URIC ACID, OXIDIZED LDL (LOW-DENSITY LIPOPROTEIN), AND CATECHOLAMINES, ARE CAPABLE OF INDUCING MEMORY IN MONOCYTES AND MACROPHAGES. WHILE TRAINED IMMUNITY PROVIDES FAVORABLE CROSS-PROTECTION IN THE CONTEXT OF INFECTIOUS DISEASES, THE HEIGHTENED IMMUNE RESPONSE CAN BE MALADAPTIVE IN DISEASES DRIVEN BY CHRONIC SYSTEMIC INFLAMMATION, SUCH AS ATHEROSCLEROSIS. TRAINED IMMUNITY IS MAINTAINED BY DISTINCT EPIGENETIC AND METABOLIC MECHANISMS AND PERSISTS FOR AT LEAST SEVERAL MONTHS IN VIVO DUE TO REPROGRAMMING OF MYELOID PROGENITOR CELLS. ADDITIONALLY, CERTAIN NONIMMUNE CELLS ARE ALSO FOUND TO EXHIBIT TRAINED IMMUNITY CHARACTERISTICS. THUS, TRAINED IMMUNITY PRESENTS AN EXCITING FRAMEWORK TO DEVELOP NEW APPROACHES TO VACCINATION AND ALSO NOVEL PHARMACOLOGICAL TARGETS IN THE TREATMENT OF INFLAMMATORY DISEASES. 2021 16 2369 34 EPIGENETIC REGULATION OF T-HELPER CELL DIFFERENTIATION, MEMORY, AND PLASTICITY IN ALLERGIC ASTHMA. AN ESTIMATED 300 MILLION PEOPLE CURRENTLY SUFFER FROM ASTHMA, WHICH CAUSES APPROXIMATELY 250 000 DEATHS A YEAR. ALLERGEN-SPECIFIC T-HELPER (TH) CELLS PRODUCE CYTOKINES THAT INDUCE MANY OF THE HALLMARK FEATURES OF ASTHMA INCLUDING AIRWAYS HYPERREACTIVITY, EOSINOPHILIC AND NEUTROPHILIC INFLAMMATION, MUCUS HYPERSECRETION, AND AIRWAY REMODELING. CYTOKINE-PRODUCING TH SUBSETS INCLUDING TH1 (IFN-GAMMA), TH2 (IL-4, IL-5, IL-13), TH9 (IL-9), TH17 (IL-17), TH22 (IL-22), AND T REGULATORY (IL-10) CELLS HAVE ALL BEEN SUGGESTED TO PLAY A ROLE IN THE DEVELOPMENT OF ASTHMA. TH DIFFERENTIATION INVOLVES GENETIC REGULATION OF GENE EXPRESSION THROUGH THE CONCERTED ACTION OF CYTOKINES, TRANSCRIPTION FACTORS, AND EPIGENETIC REGULATORS. WE DESCRIBE HOW TH DIFFERENTIATION AND PLASTICITY IS REGULATED BY EPIGENETIC HISTONE AND DNA MODIFICATIONS, WITH A FOCUS ON THE REGULATION OF HISTONE METHYLATION BY MEMBERS OF THE POLYCOMB AND TRITHORAX COMPLEXES. IN ADDITION, WE OUTLINE ENVIRONMENTAL INFLUENCES THAT COULD INFLUENCE EPIGENETIC REGULATION OF TH CELLS AND DISCUSS THE POTENTIAL TO REGULATE TH PLASTICITY AND FUNCTION THROUGH DRUGS TARGETING THE EPIGENETIC MACHINERY. IT IS ALSO BECOMING APPARENT THAT EPIGENETIC REGULATION OF ALLERGEN-SPECIFIC MEMORY TH CELLS MAY BE IMPORTANT IN THE DEVELOPMENT AND PERSISTENCE OF CHRONIC ALLERGIES. FINALLY, WE DESCRIBE HOW EPIGENETIC MODIFIERS REGULATE CYTOKINE MEMORY IN TH CELLS AND DESCRIBE RECENTLY IDENTIFIED HYBRID, PLASTIC, AND PATHOGENIC MEMORY TH SUBSETS THE CONTEXT OF ALLERGIC ASTHMA. 2017 17 6376 32 THE ROLE OF NEUTROPHILS IN TRAINED IMMUNITY. THE PRINCIPLE OF TRAINED IMMUNITY REPRESENTS INNATE IMMUNE MEMORY DUE TO SUSTAINED, MAINLY EPIGENETIC, CHANGES TRIGGERED BY ENDOGENOUS OR EXOGENOUS STIMULI IN BONE MARROW (BM) PROGENITORS (CENTRAL TRAINED IMMUNITY) AND THEIR INNATE IMMUNE CELL PROGENY, THEREBY TRIGGERING ELEVATED RESPONSIVENESS AGAINST SECONDARY STIMULI. BM PROGENITORS CAN RESPOND TO MICROBIAL AND STERILE SIGNALS, THEREBY POSSIBLY ACQUIRING TRAINED IMMUNITY-MEDIATED LONG-LASTING ALTERATIONS THAT MAY SHAPE THE FATE AND FUNCTION OF THEIR PROGENY, FOR EXAMPLE, NEUTROPHILS. NEUTROPHILS, THE MOST ABUNDANT INNATE IMMUNE CELL POPULATION, ARE PRODUCED IN THE BM FROM COMMITTED PROGENITOR CELLS IN A PROCESS DESIGNATED GRANULOPOIESIS. NEUTROPHILS ARE THE FIRST RESPONDERS AGAINST INFECTIOUS OR INFLAMMATORY CHALLENGES AND HAVE VERSATILE FUNCTIONS IN IMMUNITY. TOGETHER WITH OTHER INNATE IMMUNE CELLS, NEUTROPHILS ARE EFFECTORS OF PERIPHERAL TRAINED IMMUNITY. HOWEVER, GIVEN THE SHORT LIFETIME OF NEUTROPHILS, THEIR ABILITY TO ACQUIRE IMMUNOLOGICAL MEMORY MAY LIE IN THE CENTRAL TRAINING OF THEIR BM PROGENITORS RESULTING IN GENERATION OF REPROGRAMMED, THAT IS, "TRAINED", NEUTROPHILS. ALTHOUGH TRAINED IMMUNITY MAY HAVE BENEFICIAL EFFECTS IN INFECTION OR CANCER, IT MAY ALSO MEDIATE DETRIMENTAL OUTCOMES IN CHRONIC INFLAMMATION. HERE, WE REVIEW THE EMERGING RESEARCH AREA OF TRAINED IMMUNITY WITH A PARTICULAR EMPHASIS ON THE ROLE OF NEUTROPHILS AND GRANULOPOIESIS. 2023 18 2342 31 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION AND FUNCTION. MACROPHAGE POLARIZATION REFERS TO DEVELOPMENT OF A SPECIFIC PHENOTYPE IMPORTANT FOR TISSUE HOMEOSTASIS OR HOST DEFENSE IN RESPONSE TO ENVIRONMENTAL CUES. ENVIRONMENTAL FACTORS THAT INDUCE MACROPHAGE POLARIZATION INCLUDE CYTOKINES AND MICROBIAL FACTORS PRODUCED BY PATHOGENS OR COMMENSAL MICROBIOTA. SIGNALING PATHWAYS UTILIZED BY THESE POLARIZING FACTORS HAVE BEEN WELL CHARACTERIZED, BUT IT IS LESS CLEAR HOW SIGNALS ARE CONVERTED INTO COMPLEX AND SUSTAINED PATTERNS OF GENE EXPRESSION, AND HOW MACROPHAGES ARE REPROGRAMMED DURING POLARIZATION TO ALTER THEIR RESPONSES TO SUBSEQUENT ENVIRONMENTAL CHALLENGES. EMERGING EVIDENCE, REVIEWED HERE, SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING AND TRANSMITTING SIGNALS DURING MACROPHAGE POLARIZATION AND REPROGRAMMING. DEEPER UNDERSTANDING OF EPIGENETIC REGULATION OF MACROPHAGE PHENOTYPE WILL ENABLE DEVELOPMENT OF GENE-SPECIFIC THERAPEUTIC APPROACHES TO ENHANCE HOST DEFENSE WHILE PRESERVING TISSUE INTEGRITY AND PREVENTING CHRONIC INFLAMMATORY DISEASES. 2013 19 2344 30 EPIGENETIC REGULATION OF MACROPHAGES: FROM HOMEOSTASIS MAINTENANCE TO HOST DEFENSE. MACROPHAGES ARE CRUCIAL MEMBERS OF THE INNATE IMMUNE RESPONSE AND IMPORTANT REGULATORS. THE DIFFERENTIATION AND ACTIVATION OF MACROPHAGES REQUIRE THE TIMELY REGULATION OF GENE EXPRESSION, WHICH DEPENDS ON THE INTERACTION OF A VARIETY OF FACTORS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC MODIFICATIONS. EPIGENETIC CHANGES ALSO GIVE MACROPHAGES THE ABILITY TO SWITCH RAPIDLY BETWEEN CELLULAR PROGRAMS, INDICATING THE ABILITY OF EPIGENETIC MECHANISMS TO AFFECT PHENOTYPE PLASTICITY. IN THIS REVIEW, WE FOCUS ON KEY EPIGENETIC EVENTS ASSOCIATED WITH MACROPHAGE FATE, HIGHLIGHTING EVENTS RELATED TO THE MAINTENANCE OF TISSUE HOMEOSTASIS, RESPONSES TO DIFFERENT STIMULI AND THE FORMATION OF INNATE IMMUNE MEMORY. FURTHER UNDERSTANDING OF THE EPIGENETIC REGULATION OF MACROPHAGES WILL BE HELPFUL FOR MAINTAINING TISSUE INTEGRITY, PREVENTING CHRONIC INFLAMMATORY DISEASES AND DEVELOPING THERAPIES TO ENHANCE HOST DEFENSE. 2020 20 232 27 ADAPTIVE PLASTICITY IN THE RETINA: PROTECTION AGAINST ACUTE INJURY AND NEURODEGENERATIVE DISEASE BY CONDITIONING STIMULI. ALTHOUGH BOTH PRECLINICAL AND CLINICAL CONDITIONING STUDIES IN HEART AND BRAIN LEAD THE FIELD OF CONDITIONING MEDICINE, INVESTIGATIONS OF RETINAL CONDITIONING STILL NUMBER MORE THAN 100. IN THIS BRIEF REVIEW, WE HIGHLIGHT FINDINGS TO DATE FROM ANIMAL AND CELL CULTURE MODELS OF CONDITIONING THAT PROVIDE DEMONSTRATED PROTECTION IN ACUTE AND CHRONIC RETINAL INJURY AND DISEASE MODELS. THE MULTITUDE OF STIMULI USED TO CONDITION THE RETINA, THE SIGNALING MEDIATORS AND PATHWAYS IDENTIFIED, AND THE INJURY- AND DISEASE-RESILIENT PHENOTYPES DOCUMENTED ARE DISCUSSED HEREIN, ALONG WITH OUR RECOMMENDATIONS FOR THE KINDS OF STUDIES NEEDED TO CONTINUE TO ADVANCE THIS PROMISING FIELD. IN OUR VIEW, THE ROBUST PROTECTION AFFORDED BY THESE ADAPTIVE EPIGENETIC RESPONSES TO CONDITIONING STRESS PROVIDES SIGNIFICANT INCENTIVES FOR BOTH FURTHERING OUR INVESTMENT IN BENCH RESEARCH AND UNDERWRITING CLINICAL TRIALS, SO THAT THE FULL POTENTIAL OF THIS THERAPY CAN BE REALIZED. 2018