RESUMEN
Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.
Asunto(s)
Asma , Rinitis Alérgica , Rinitis , Humanos , Rinitis/diagnóstico , Rinitis/epidemiología , Rinitis/complicaciones , Asma/diagnóstico , Asma/epidemiología , Asma/etiología , Rinitis Alérgica/complicaciones , Alérgenos , MultimorbilidadRESUMEN
BACKGROUND: IL-22- and IL-17-producing T cells have important roles in allergic diseases. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and modulate numerous biological processes. Little is known about the functions of miRNAs in IL-22/IL-17-producing T cells. MATERIAL AND METHODS: IL-22- and IL-17-positive T cells were sorted from human peripheral blood mononuclear cells (PBMCs) by intracellular staining and dual-secretion assay. miRNA expression profiles were detected with TaqMan array microfluidic cards. T cells were transfected with miRNA mimics. Gene expression was analyzed using RT-qPCR and/or enzyme-linked immunosorbent assay in T-cell subsets and PBMCs from patients with asthma and atopic dermatitis. RESULTS: The increased expression of miR-323-3p and noncoding RNA nc886 and reduced expression of miR-93, miR-181a, miR-26a, and miR-874 were detected in IL-22-producing T cells. The pathway analysis of the putative targets suggested that these differentially expressed miRNAs could impact the proliferation, differentiation, and effector functions of T cells. Further analyses showed the highest expression for miR-323-3p in IL-22- and IL-17-double-positive T cells and its capacity to suppress multiple genes from the transforming growth factor-ß pathway and the production of IL-22 in T cells. An increased expression of miR-323-3p in PBMCs from patients with asthma and reverse correlation between miR-323-3p levels and IL-22 production in PBMCs cultured in T-cell growth conditions was observed. CONCLUSIONS: Our data suggest that miR-323-3p acts in a negative feedback loop to control the production of IL-22 in IL-22/IL-17-producing T cells and might thus impact the T-cell responses in asthma.
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Asma/genética , Asma/metabolismo , Regulación de la Expresión Génica , Interleucina-17/biosíntesis , Interleucinas/biosíntesis , MicroARNs/genética , Subgrupos de Linfocitos T/metabolismo , Adulto , Asma/diagnóstico , Asma/inmunología , Emparejamiento Base , Análisis por Conglomerados , Perfilación de la Expresión Génica , Humanos , MicroARNs/química , Persona de Mediana Edad , ARN Mensajero/química , ARN Mensajero/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Adulto Joven , Interleucina-22RESUMEN
BACKGROUND: Human rhinoviruses (HRVs) are one of the main causes of virus-induced asthma exacerbations. Infiltration of B lymphocytes into the subepithelial tissue of the lungs has been demonstrated during rhinovirus infection in allergic individuals. However, the mechanisms through which HRVs modulate the immune responses of monocytes and lymphocytes are not yet well described. OBJECTIVE: To study the dynamics of virus uptake by monocytes and lymphocytes, and the ability of HRVs to induce the activation of in vitro-cultured human peripheral blood mononuclear cells. METHODS: Flow cytometry was used for the enumeration and characterization of lymphocytes. Proliferation was estimated using 3 H-thymidine or CFSE labeling and ICAM-1 blocking. We used bead-based multiplex assays and quantitative PCR for cytokine quantification. HRV accumulation and replication inside the B lymphocytes was detected by a combination of in situ hybridization (ISH), immunofluorescence, and PCR for positive-strand and negative-strand viral RNA. Cell images were acquired with imaging flow cytometry. RESULTS: By means of imaging flow cytometry, we demonstrate a strong and quick binding of HRV types 16 and 1B to monocytes, and slower interaction of these HRVs with CD4+ T cells, CD8+ T cells, and CD19+ B cells. Importantly, we show that HRVs induce the proliferation of B cells, while the addition of anti-ICAM-1 antibody partially reduces this proliferation for HRV16. We prove with ISH that HRVs can enter B cells, form their viral replication centers, and the newly formed virions are able to infect HeLa cells. In addition, we demonstrate that similar to epithelial cells, HRVs induce the production of pro-inflammatory cytokines in PBMCs. CONCLUSION: Our results demonstrate for the first time that HRVs enter and form viral replication centers in B lymphocytes and induce the proliferation of B cells. Newly formed virions have the capacity to infect other cells (HeLa). These findings indicate that the regulation of human rhinovirus-induced B-cell responses could be a novel approach to develop therapeutics to treat the virus-induced exacerbation of asthma.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/virología , Activación de Linfocitos/inmunología , Infecciones por Picornaviridae/inmunología , Infecciones por Picornaviridae/virología , Rhinovirus/fisiología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/virología , Infecciones por Picornaviridae/metabolismo , Rhinovirus/clasificación , Serogrupo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/virología , Acoplamiento Viral , Internalización del Virus , Replicación ViralRESUMEN
BACKGROUND: Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. METHOD: The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). RESULTS: All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. CONCLUSIONS: It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
Asunto(s)
Asma/diagnóstico , Asma/terapia , Conjuntivitis Alérgica/diagnóstico , Conjuntivitis Alérgica/terapia , Desensibilización Inmunológica , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/terapia , Alérgenos/inmunología , Asma/inmunología , Basófilos/inmunología , Basófilos/metabolismo , Biomarcadores , Conjuntivitis Alérgica/inmunología , Citocinas/metabolismo , Desensibilización Inmunológica/métodos , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Pronóstico , Rinitis Alérgica/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: Interleukin-22 is produced by certain T helper cells subsets (Th17, Th22) and at lower levels by γ-δ T cells, NKT and innate lymphoid cells. Th22 cells are unique immune cells that regulate tissue responses by IL-22 production. The exact discrimination between Th17 cells that co-produce IL-22 and single IL-22-producing Th22 cells has not been possible until the present study. Isolation of pure Th22 cells without co-expression of cytokines of other T-cell subsets is essential to better understand their function in humans. The aim of this study is the isolation and characterization of viable, human IL-22-producing CD4+ T cells that do not produce IL-17A. METHODS: Isolation of viable Th22 cells was performed with the combination of two cytokine secretion assays detecting IL-17A- and IL-22-producing cells in a single purification step. RESULTS: The newly developed cytokine secretion assay consists of anti-IL-22 and anti-IL-17A catch antibodies, which via biotin-streptavidin interaction are bound to the biotinylated surface of the target cell, and anti-IL-22 and IL-17A detection antibody labelled with a fluorescent dye, which detects cytokines bound to these catch antibodies. A unique population of human Th22 cells, which do not produce IL-17A, was sorted, and cytokine expression pattern was confirmed by quantitative PCR analysis and ELISA. The presented technique allows the detection and isolation of pure human Th22 cells. CONCLUSIONS: This technique may allow the purification of any single cytokine-producing cell subset, and the combination of several different cytokine secretion assays can be used to purify and characterize novel and unique cell subsets.
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Separación Celular , Citocinas/metabolismo , Subgrupos de Linfocitos T/metabolismo , Antígenos de Superficie/metabolismo , Separación Celular/métodos , Citocinas/genética , Expresión Génica , Humanos , Interleucina-17/biosíntesis , Interleucinas/biosíntesis , Interleucinas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Interleucina-22RESUMEN
MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.
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Hipersensibilidad/diagnóstico , Hipersensibilidad/terapia , Medicina de Precisión/métodos , Biología de Sistemas/métodos , Manejo de la Enfermedad , Unión Europea , Política de Salud , Humanos , Hipersensibilidad/etiología , Hipersensibilidad/prevención & control , Inmunización , Inmunoglobulina E/inmunología , Invenciones , Pronóstico , Organización Mundial de la SaludRESUMEN
Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.
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Envejecimiento , Desarrollo Infantil , Enfermedad Crónica/prevención & control , Desarrollo Fetal , Adulto , Anciano , Enfermedad de Alzheimer/prevención & control , Asma/prevención & control , Depresión/prevención & control , Diabetes Mellitus/prevención & control , Conducta Alimentaria , Femenino , Humanos , Hipersensibilidad/prevención & control , Lactante , Recién Nacido , Auditoría Médica , Persona de Mediana Edad , Osteoporosis/prevención & control , Factores de RiesgoRESUMEN
BACKGROUND: B cells play a central role in IgE-mediated allergies. In damaged airway epithelium, they are exposed directly to aeroallergens. We aimed to assess whether direct exposure of B cells to pollen constituents affects allergic sensitization. METHODS: B cells from murine splenocytes and from blood samples of healthy donors were incubated for 8 days under Th2-like conditions with aqueous ragweed pollen extracts (Amb-APE) or its constituents. Secreted total IgM, IgG, and IgE was quantified by ELISA. Additionally, birch, grass, or pine-pollen extracts were tested. The number of viable cells was evaluated by ATP measurements. B-cell proliferation was measured by CFSE staining. IgE class switch was analyzed by quantitation of class switch transcripts. In an OVA/Alum i.p.-sensitization mouse model, Amb-APE was intranasally instilled for 11 consecutive days. RESULTS: Upon Th2 priming of murine B cells, ragweed pollen extract caused a dose-dependent increase in IgE production, while IgG and IgM were not affected. The low-molecular-weight fraction and phytoprostane E1 (PPE1) increased IgE production, while Amb a 1 did not. PPE1 enhanced IgE also in human memory B cells. Under Th1 conditions, Amb-APE did not influence immunoglobulin secretion. The IgE elevation was not ragweed specific. It correlated with proliferation of viable B cells, but not with IgE class switch. In vivo, Amb-APE increased total IgE and showed adjuvant activity in allergic airway inflammation. CONCLUSIONS: Aqueous pollen extracts, the protein-free fraction of Amb-APE, and the pollen-contained substance PPE1 specifically enhance IgE production in Th2-primed B cells. Thus, pollen-derived nonallergenic substances might be responsible for B-cell-dependent aggravation of IgE-mediated allergies.
Asunto(s)
Alérgenos/inmunología , Formación de Anticuerpos/inmunología , Linfocitos B/inmunología , Inmunoglobulina E/inmunología , Polen/inmunología , Células Th2/inmunología , Ambrosia/inmunología , Animales , Antígenos de Plantas/inmunología , Linfocitos B/metabolismo , Femenino , Humanos , Inmunización , Memoria Inmunológica , Activación de Linfocitos/inmunología , Ratones , Ovalbúmina/inmunología , Extractos Vegetales/inmunología , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/patología , Células Th2/metabolismoRESUMEN
Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1ß, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.
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Antialérgicos/uso terapéutico , Factores Biológicos/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Antialérgicos/farmacología , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antígenos/inmunología , Antígenos/metabolismo , Factores Biológicos/farmacología , Ensayos Clínicos como Asunto , Humanos , Hipersensibilidad/diagnóstico , Resultado del TratamientoRESUMEN
Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.
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Alérgenos/inmunología , Hipersensibilidad/etiología , Hipersensibilidad/metabolismo , Inmunoglobulina E/inmunología , Transducción de Señal , Especificidad de Anticuerpos/inmunología , Comorbilidad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hipersensibilidad/epidemiología , Inmunización , Fenotipo , Embarazo , Efectos Tardíos de la Exposición PrenatalRESUMEN
Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards.
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Rinitis Alérgica/diagnóstico , Rinitis Alérgica/terapia , Alérgenos/inmunología , Biomarcadores , Toma de Decisiones Clínicas/métodos , Ensayos Clínicos como Asunto , Comorbilidad , Manejo de la Enfermedad , Planificación en Salud , Política de Salud , Humanos , Informática Médica/métodos , Guías de Práctica Clínica como Asunto , Reproducibilidad de los Resultados , Rinitis Alérgica/epidemiología , Rinitis Alérgica/inmunología , Rinitis Alérgica/prevención & control , Navegador WebAsunto(s)
Betacoronavirus , Infecciones por Coronavirus , Pandemias , Neumonía Viral , COVID-19 , Desensibilización Inmunológica , Humanos , SARS-CoV-2RESUMEN
The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-ß produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.
Asunto(s)
Hipersensibilidad/inmunología , Interleucina-10/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Alérgenos/inmunología , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Humanos , Tolerancia Inmunológica/inmunología , Interleucina-10/metabolismo , Modelos Inmunológicos , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: The relationships between tonsillar immune responses, and viral infection and allergy are incompletely known. OBJECTIVE: To study intratonsillar/nasopharyngeal virus detections and in vivo expressions of T-cell- and innate immune response-specific cytokines, transcription factors, and type I/II/III interferons in human tonsils. METHODS: Palatine tonsil samples were obtained from 143 elective tonsillectomy patients. Adenovirus, bocavirus-1, coronavirus, enteroviruses, influenza virus, metapneumovirus, parainfluenza virus, rhinovirus, and respiratory syncytial virus were detected using PCR. The mRNA expression levels of IFN-α, IFN-ß, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-ß, FOXP3, GATA3, RORC2, and Tbet were directly analyzed by quantitative RT-PCR. RESULTS: Fifty percentage of subjects reported allergy, 59% had ≥1 nasopharyngeal viruses, and 24% had ≥1 intratonsillar viruses. Tonsillar virus detection showed a strong negative association with age; especially rhinovirus or parainfluenza virus detection showed positive association with IFN-γ and Tbet expressions. IL-37 expression was positively associated with atopic dermatitis, whereas IFN-α, IL-13, IL-28, and Tbet expressions were negatively associated with allergic diseases. Network analyses demonstrated strongly polarized clusters of immune regulatory (IL-10, IL-17, TGF-ß, FOXP3, GATA3, RORC2, Tbet) and antiviral (IFN-α, IFN-ß, IL-28, IL-29) genes. These two clusters became more distinctive in the presence of viral infection or allergy. A negative correlation between antiviral cytokines and IL-10, IL-17, IL-37, FOXP3, and RORC2 was observed only in the presence of viruses, and interestingly, IL-13 strongly correlated with antiviral cytokines. CONCLUSIONS: Tonsillar cytokine expression is closely related to existing viral infections, age, and allergic illnesses and shows distinct clusters between antiviral and immune regulatory genes.
Asunto(s)
Tonsila Palatina/inmunología , Tonsila Palatina/virología , Virosis/inmunología , Adolescente , Adulto , Niño , Análisis por Conglomerados , Citocinas/genética , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Tonsila Palatina/metabolismo , Factores de Transcripción/genética , Transcriptoma , Virosis/genética , Adulto JovenRESUMEN
BACKGROUND: Allergen-specific immunotherapy (SIT) faces problems related to side effects and limited efficacy. Direct administration of allergen extracts into lymph nodes induces increased specific IgG production and T-cell responses using significantly lower allergen doses. METHODS: In this study, mechanisms of immune regulation by MAT vaccines in vitro and in allergen-SIT of cat-allergic rhinitis patients, who received 3 inguinal intra-lymph node injections of MAT-Fel d 1 vaccine, were investigated in PBMC and cell cultures for specific T-cell proliferation, Fel d 1-tetramer-specific responses, and multiple immune regulatory molecules. RESULTS: MAT-Fel d 1 vaccine was efficiently internalized by antigen-presenting cells. This was followed by precaspase 1 cleavage to caspase 1 and secretion of IL-1ß, indicating inflammasome activation. Mat-Fel d 1 induced specific T-cell proliferation and an IL-10- and IFN-γ-dominated T-cell responses with decreased Th2 cytokines at 100 times lower doses than Fel d 1. Induction of immune tolerance by MAT-Fel d 1-ILIT involved multiple mechanisms of immune suppression. Early Fel d 1-specific T-cell activation was followed by full T-cell unresponsiveness to allergen after 1 year in the MAT-Fel d 1 group, characterized by increased allergen-specific T regulatory cells, decreased circulating Fel d 1 tetramer-positive cells, increased IL-10 and FOXP3 expression, and change in the HR2/HR1 ratio toward HR2. CONCLUSIONS: This study demonstrates the induction of allergen tolerance after 3 intra-lymph node injections of MAT-Fel d 1 vaccine, mediated by increased cellular internalization of the allergen, activation of inflammasome, and generation of allergen-specific peripheral T-cell tolerance.
Asunto(s)
Desensibilización Inmunológica/métodos , Glicoproteínas/administración & dosificación , Linfocitos T/inmunología , Vacunas/administración & dosificación , Western Blotting , Citometría de Flujo , Glicoproteínas/inmunología , Humanos , Microscopía Confocal , Reacción en Cadena en Tiempo Real de la Polimerasa , Vacunas/inmunologíaRESUMEN
The immune system is regulated to protect the host from exaggerated stimulatory signals establishing a state of tolerance in healthy individuals. The disequilibrium in immune regulatory vs effector mechanisms results in allergic or autoimmune disorders in genetically predisposed subjects under certain environmental conditions. As demonstrated in allergen-specific immunotherapy and in the healthy immune response to high-dose allergen exposure models in humans, T regulatory cells are essential in the suppression of Th2-mediated inflammation, maintenance of immune tolerance, induction of the two suppressive cytokines interleukin-10 and transforming growth factor-ß, inhibition of allergen-specific IgE, and enhancement of IgG4 and IgA. Also, suppression of dendritic cells, mast cells, and eosinophils contributes to the construction of peripheral tolerance to allergens. This review focuses on mechanisms of peripheral tolerance to allergens with special emphasis on recent developments in the area of immune regulation.
Asunto(s)
Alérgenos/inmunología , Formación de Anticuerpos/inmunología , Tolerancia Inmunológica/inmunología , Tolerancia Periférica/inmunología , Alérgenos/efectos adversos , Linfocitos B Reguladores/citología , Linfocitos B Reguladores/inmunología , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/citología , Células Dendríticas/inmunología , Desensibilización Inmunológica/métodos , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/fisiopatología , Hipersensibilidad/terapia , Tolerancia Inmunológica/fisiología , Inmunoglobulina G/inmunología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Tolerancia Periférica/fisiología , Sensibilidad y Especificidad , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Células Th17/citología , Células Th17/inmunologíaRESUMEN
BACKGROUND: The fine balance of immunoglobulins (Ig) E, IgG1, IgG4 and IgA in healthy production is maintained by the interaction of B cells with adaptive and innate immune response. The regulation of toll-like receptors (TLRs)-driven innate and adaptive immune effector B-cell response and the role of mammalian telomeric TTAGGG repeat elements represent an important research area. METHODS: Human PBMC and purified naive and memory B cells were stimulated with specific ligands for TLR2, TLR3, TLR4, TLR5, TLR7, TLR8 and TLR9 in the presence or absence of telomeric oligonucleotides. B-cell proliferation, differentiation and antibody production were determined. RESULTS: TLR9 ligand directly activates naive and memory B cells, whereas TLR7 can stimulate them in the presence of plasmacytoid dendritic cells. Human B cells proliferate and turn into antibody-secreting cells in response to TLR3, TLR7 and TLR9, but not to TLR2, TLR4, TLR5 and TLR8 ligands. Stimulation of B cells with intracellular TLR3, TLR7 and TLR9 induced an activation cascade leading to memory B-cell generation and particularly IgG1, but also IgA, IgG4 and very low levels of IgE production. Mammalian telomeric oligodeoxynucleotide (ODN) significantly inhibited all features of TLR ligand-induced events in B cells including B-cell proliferation, IgE, IgG1, IgG4, IgA production, class switch recombination, plasma cell differentiation induced by TLR3, TLR7 and TLR9 ligands. CONCLUSION: B cells require specific TLR stimulation, T-cell and plasmacytoid dendritic cell help for distinct activation and Ig production profiles. Host-derived telomeric ODN suppress B-cell activation and antibody production demonstrating a natural mechanism for the control of overexuberant B-cell activation, antibody production and generation of memory.
Asunto(s)
Linfocitos B/inmunología , Inmunoglobulina A/biosíntesis , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/biosíntesis , Activación de Linfocitos/efectos de los fármacos , Oligonucleótidos/farmacología , Telómero/química , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Humanos , Cambio de Clase de Inmunoglobulina/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Ligandos , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 3/inmunología , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 9/inmunología , Recombinación V(D)J/efectos de los fármacosRESUMEN
Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.
Asunto(s)
Asma/fisiopatología , Hipersensibilidad/complicaciones , Guías de Práctica Clínica como Asunto/normas , Índice de Severidad de la Enfermedad , Asma/terapia , Enfermedad Crónica , Comorbilidad , Dermatitis Atópica/complicaciones , Humanos , Hipersensibilidad/epidemiología , Rinitis/complicaciones , Rinitis/epidemiología , Sinusitis/complicaciones , Sinusitis/epidemiología , Urticaria/complicaciones , Urticaria/epidemiologíaRESUMEN
Hymenoptera venoms are important allergens that can elicit both local and systemic allergic reactions, including life-threatening anaphylaxis. Venom immunotherapy (VIT) remains the most effective treatment, reducing the risk of systemic reactions in individuals with Hymenoptera venom allergy. VIT can restore normal immunity against venom allergens and provide patients with a lifetime of tolerance to venoms. During VIT, peripheral tolerance is induced by the generation of allergen-specific regulatory T (Treg) cells, which suppress proliferative and cytokine responses against the venom allergens. Treg cells are characterized by IL-10 secretion that directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. Treg cells also have influence on B cells, suppressing IgE production and inducing the production of blocking type IgG4 antibodies against venom allergens. An accumulating body of evidence suggests that Treg cells may affect allergen sensitization and methods for enhancing this cell population may eventually improve the efficacy of VIT. In this article, immune mechanisms enrolled in bee and wasp VIT are reviewed.
Asunto(s)
Venenos de Abeja/inmunología , Inmunoterapia , Venenos de Avispas/inmunología , Alérgenos/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Epítopos/inmunología , Histamina/uso terapéutico , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Secreted phospholipases A2 (sPLA2) represent antigens to which humans may be rarely or frequently exposed. Thus, the investigation of humoral and cellular immune responses to sPLA2s from different species can provide a suitable model in the study of antibody and T-cell cross-reactivity. METHODS: Specific IgE, IgG1, IgG4, and IgA antibodies were analyzed by ELISA against sPLA2s from pancreas of Bos taurus (BT), Apis mellifera (AM) bee venom, Daboia russellii (DR) and Naja mossambica (NM) snake venoms, and human group III (hGIII) sPLA2 using sera of nonallergic beekeepers, AM-allergic patients, and healthy controls. T-cell cross-reactivity was investigated in PBMC, and T-cell clones (TCC) are generated against AM sPLA2. RESULTS: Hyperimmune and allergic individuals showed high levels of sPLA2-specific IgG4 and significant IgG4 cross-reactivity between BT, DR, and NM sPLA2s. Furthermore, IgE, IgA, and IgG1 cross-reactivities against BT, DR, and NM sPLA2s were also detectable in the range of 22.2-44.8%. Allergic patients showed significant T-cell proliferative response to NM sPLA2 together with increased IFN-γ and IL-13 production even though they had never been exposed to cobra venom. Although nonallergic healthy controls show no cross-reactivity at T-cell level, they did have low levels of IgG4 and IgA against BT, DR, and NM sPLA2s. Human TCC spanning three major T-cell epitopes of AM sPLA2 showed minor proliferative response to NM and hGIII sPLA2s. CONCLUSIONS: This study shows that T cells and antibodies may show cross-reactivity between different species without being naturally exposed to sPLA2s.