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1.
Annu Rev Immunol ; 38: 49-77, 2020 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-32340580

RESUMEN

Mast cells have existed long before the development of adaptive immunity, although they have been given different names. Thus, in the marine urochordate Styela plicata, they have been designated as test cells. However, based on their morphological characteristics (including prominent cytoplasmic granules) and mediator content (including heparin, histamine, and neutral proteases), test cells are thought to represent members of the lineage known in vertebrates as mast cells. So this lineage presumably had important functions that preceded the development of antibodies, including IgE. Yet mast cells are best known, in humans, as key sources of mediators responsible for acute allergic reactions, notably including anaphylaxis, a severe and potentially fatal IgE-dependent immediate hypersensitivity reaction to apparently harmless antigens, including many found in foods and medicines. In this review, we briefly describe the origins of tissue mast cells and outline evidence that these cells can have beneficial as well as detrimental functions, both innately and as participants in adaptive immune responses. We also discuss aspects of mast cell heterogeneity and comment on how the plasticity of this lineage may provide insight into its roles in health and disease. Finally, we consider some currently open questions that are yet unresolved.


Asunto(s)
Susceptibilidad a Enfermedades , Inflamación/etiología , Inflamación/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Inmunidad Adaptativa , Animales , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata , Inflamación/diagnóstico , Mediadores de Inflamación/metabolismo , Transducción de Señal
2.
Nat Immunol ; 20(11): 1435-1443, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31591569

RESUMEN

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.


Asunto(s)
Alérgenos/inmunología , Dermatitis Atópica/inmunología , Mastocitos/inmunología , Nociceptores/inmunología , Pyroglyphidae/inmunología , Animales , Comunicación Celular/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Mastocitos/metabolismo , Ratones Noqueados , Nociceptores/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Piel/citología , Piel/inmunología , Canales Catiónicos TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismo
3.
Nat Immunol ; 20(2): 129-140, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30664762

RESUMEN

Basophils are evolutionarily conserved in vertebrates, despite their small numbers and short life span, suggesting that they have beneficial roles in maintaining health. However, these roles are not fully defined. Here we demonstrate that basophil-deficient mice exhibit reduced bacterial clearance and increased morbidity and mortality in the cecal ligation and puncture (CLP) model of sepsis. Among the several proinflammatory mediators that we measured, tumor necrosis factor (TNF) was the only cytokine that was significantly reduced in basophil-deficient mice after CLP. In accordance with that observation, we found that mice with genetic ablation of Tnf in basophils exhibited reduced systemic concentrations of TNF during endotoxemia. Moreover, after CLP, mice whose basophils could not produce TNF, exhibited reduced neutrophil and macrophage TNF production and effector functions, reduced bacterial clearance, and increased mortality. Taken together, our results show that basophils can enhance the innate immune response to bacterial infection and help prevent sepsis.


Asunto(s)
Basófilos/inmunología , Endotoxemia/inmunología , Inmunidad Innata , Factor de Necrosis Tumoral alfa/inmunología , Traslado Adoptivo , Animales , Basófilos/metabolismo , Ciego/microbiología , Modelos Animales de Enfermedad , Endotoxemia/microbiología , Endotoxemia/terapia , Microbioma Gastrointestinal , Humanos , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neutrófilos/inmunología , Neutrófilos/metabolismo , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/genética
4.
Allergy ; 79(2): 445-455, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37916710

RESUMEN

BACKGROUND: Conventional basophil activation tests (BATs) measure basophil activation by the increased expression of CD63. Previously, fluorophore-labeled avidin, a positively-charged molecule, was found to bind to activated basophils, which tend to expose negatively charged granule constituents during degranulation. This study further compares avidin versus CD63 as basophil activation biomarkers in classifying peanut allergy. METHODS: Seventy subjects with either a peanut allergy (N = 47), a food allergy other than peanut (N = 6), or no food allergy (N = 17) were evaluated. We conducted BATs in response to seven peanut extract (PE) concentrations (0.01-10,000 ng/mL) and four control conditions (no stimulant, anti-IgE, fMLP (N-formylmethionine-leucyl-phenylalanine), and anti-FcεRI). We measured avidin binding and CD63 expression on basophils with flow cytometry. We evaluated logistic regression and XGBoost models for peanut allergy classification and feature identification. RESULTS: Avidin binding was correlated with CD63 expression. Both markers discriminated between subjects with and without a peanut allergy. Although small by percentage, an avidin+ /CD63- cell subset was found in all allergic subjects tested, indicating that the combination of avidin and CD63 could allow a more comprehensive identification of activated basophils. Indeed, we obtained the best classification accuracy (97.8% sensitivity, 96.7% specificity) by combining avidin and CD63 across seven PE doses. Similar accuracy was obtained by combining PE dose of 10,000 ng/mL for avidin and PE doses of 10 and 100 ng/mL for CD63. CONCLUSIONS: Avidin and CD63 are reliable BAT activation markers associated with degranulation. Their combination enhances the identification of activated basophils and improves the classification accuracy of peanut allergy.


Asunto(s)
Prueba de Desgranulación de los Basófilos , Hipersensibilidad al Cacahuete , Humanos , Hipersensibilidad al Cacahuete/diagnóstico , Hipersensibilidad al Cacahuete/metabolismo , Avidina/metabolismo , Inmunoglobulina E/metabolismo , Basófilos/metabolismo , Citometría de Flujo , Arachis , Tetraspanina 30/metabolismo
5.
J Allergy Clin Immunol ; 149(6): 1845-1854, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35469840

RESUMEN

The discovery in 1987/1988 and 1990 of the cell surface receptor KIT and its ligand, stem cell factor (SCF), was a critical achievement in efforts to understand the development and function of multiple distinct cell lineages. These include hematopoietic progenitors, melanocytes, germ cells, and mast cells, which all are significantly affected by loss-of-function mutations of KIT or SCF. Such mutations also influence the development and/or function of additional cells, including those in parts of the central nervous system and the interstitial cells of Cajal (which control gut motility). Many other cells can express KIT constitutively or during immune responses, including dendritic cells, eosinophils, type 2 innate lymphoid cells, and taste cells. Yet the biological importance of KIT in many of these cell types largely remains to be determined. We here review the history of work investigating mice with mutations affecting the white spotting locus (which encodes KIT) or the steel locus (which encodes SCF), focusing especially on the influence of such mutations on mast cells. We also briefly review efforts to target the KIT/SCF pathway with anti-SCF or anti-Kit antibodies in mouse models of allergic disorders, parasite immunity, or fibrosis in which mast cells are thought to play significant roles.


Asunto(s)
Mastocitos , Proteínas Proto-Oncogénicas c-kit , Animales , Linaje de la Célula , Humanos , Inmunidad Innata , Linfocitos/citología , Linfocitos/inmunología , Linfocitos/metabolismo , Mastocitos/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Factor de Células Madre/genética , Factor de Células Madre/metabolismo
6.
J Allergy Clin Immunol ; 150(5): 1228-1231.e5, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35561839

RESUMEN

BACKGROUND: The mitochondrial fission protein dynamin-related protein 1 (Drp1) has been suggested to regulate mast cell (MC) activation by certain stimuli in vitro, but its functions in MCs activated by various stimuli in vivo have not yet been examined. OBJECTIVE: We sought to analyze Drp1 function in both mouse and human MCs. METHODS: We used human peripheral blood-derived cultured MCs and 2 genetic mouse models in which MCs were depleted of Drp1: Drp1fl/flMcpt5cre+/- mice and Drp1fl/flCpa3cre+/- mice. RESULTS: In mice, Drp1 depletion enhanced FcεRI-induced MC activation while suppressing substance P-stimulated MC activation in vitro and in vivo. This was also true in human peripheral blood-derived cultured MCs in vitro after pharmacologic inhibition of Drp1. CONCLUSION: Drp1 differentially regulates MC activation by various stimuli. Promoting Drp1 activation might therefore represent a novel therapy for suppressing IgE-dependent MC activation. Further, inhibiting Drp1 activation might mitigate other MC-dependent responses, such as those induced by substance P.


Asunto(s)
Dinaminas , Receptores de IgE , Sustancia P , Animales , Humanos , Ratones , Células Cultivadas , Dinaminas/metabolismo , Mastocitos/metabolismo , Receptores de IgE/metabolismo , Sustancia P/farmacología , Sustancia P/metabolismo
7.
Allergy ; 77(2): 499-512, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-33840121

RESUMEN

BACKGROUND: In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research supports the toxin hypothesis, showing that MCs and IgE-related type 2 immune responses can enhance host defense against certain noxious substances, including honeybee venom (BV). However, the mechanisms by which MCs can interfere with BV toxicity are unknown. In this study, we assessed the role of IgE and certain MC products in MC-mediated BV detoxification. METHODS: We applied in vitro and in vivo fluorescence microscopyimaging, and flow cytometry, fibroblast-based toxicity assays and mass spectrometry to investigate IgE-mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC-derived heparin and proteases helped to define the importance of specific detoxification mechanisms. RESULTS: Venom-specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE-activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin-related interference with toxicity. Mediators released by IgE-activated human MCs efficiently degraded multiple BV toxins. CONCLUSIONS: Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin-neutralizing activity to MC-derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV.


Asunto(s)
Venenos de Abeja , Mastocitos , Alérgenos/metabolismo , Animales , Degranulación de la Célula , Heparina/metabolismo , Humanos , Inmunoglobulina E , Ratones , Péptido Hidrolasas/metabolismo
8.
Immunity ; 39(5): 963-75, 2013 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-24210352

RESUMEN

Allergies are widely considered to be misdirected type 2 immune responses, in which immunoglobulin E (IgE) antibodies are produced against any of a broad range of seemingly harmless antigens. However, components of insect venoms also can sensitize individuals to develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. We found that mice injected with amounts of honeybee venom similar to that which could be delivered in one or two stings developed a specific type 2 immune response that increased their resistance to subsequent challenge with potentially lethal amounts of the venom. Our data indicate that IgE antibodies and the high affinity IgE receptor, FcεRI, were essential for such acquired resistance to honeybee venom. The evidence that IgE-dependent immune responses against venom can enhance survival in mice supports the hypothesis that IgE, which also contributes to allergic disorders, has an important function in protection of the host against noxious substances.


Asunto(s)
Venenos de Abeja/toxicidad , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Anafilaxia/etiología , Anafilaxia/inmunología , Anafilaxia/prevención & control , Animales , Venenos de Abeja/administración & dosificación , Venenos de Abeja/inmunología , Venenos de Abeja/uso terapéutico , Desensibilización Inmunológica , Relación Dosis-Respuesta Inmunológica , Epítopos , Femenino , Inmunización Pasiva , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/inmunología , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Inmunológicos , Receptores de IgE/inmunología , Daboia , Células Th2/inmunología , Venenos de Víboras/inmunología , Venenos de Víboras/toxicidad
9.
Immunol Rev ; 282(1): 121-150, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29431212

RESUMEN

Mast cells are hematopoietic cells that reside in virtually all vascularized tissues and that represent potential sources of a wide variety of biologically active secreted products, including diverse cytokines and growth factors. There is strong evidence for important non-redundant roles of mast cells in many types of innate or adaptive immune responses, including making important contributions to immediate and chronic IgE-associated allergic disorders and enhancing host resistance to certain venoms and parasites. However, mast cells have been proposed to influence many other biological processes, including responses to bacteria and virus, angiogenesis, wound healing, fibrosis, autoimmune and metabolic disorders, and cancer. The potential functions of mast cells in many of these settings is thought to reflect their ability to secrete, upon appropriate activation by a range of immune or non-immune stimuli, a broad spectrum of cytokines (including many chemokines) and growth factors, with potential autocrine, paracrine, local, and systemic effects. In this review, we summarize the evidence indicating which cytokines and growth factors can be produced by various populations of rodent and human mast cells in response to particular immune or non-immune stimuli, and comment on the proven or potential roles of such mast cell products in health and disease.


Asunto(s)
Quimiocinas/metabolismo , Citocinas/metabolismo , Hipersensibilidad/inmunología , Mastocitos/inmunología , Animales , Comunicación Celular , Humanos , Inmunidad Innata
10.
Clin Gastroenterol Hepatol ; 19(6): 1151-1159.e14, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-32434067

RESUMEN

BACKGROUND & AIMS: Gastrointestinal side effects are common during oral immunotherapy (OIT) and eosinophilic esophagitis (EoE) is a potential complication. We aimed to characterize eosinophilic gastrointestinal responses to peanut OIT, in which peanut protein is given orally, with incremental increases in dose over time. METHODS: Twenty adults with IgE-mediated peanut allergy were randomly assigned to groups given peanut OIT (n = 15) or placebo (n = 5); 1 additional subject withdrew before randomization. Serial gastrointestinal biopsies were collected at baseline (n = 21, 0 weeks), following dose escalation (n = 10, 52 weeks), and during the maintenance phase (n = 11, 104 weeks). Endoscopic findings were characterized using the EoE endoscopic reference score. Biopsies were assessed for eosinophils per high-power field (eos/hpf) and other pathology features using EoE histologic scoring system scores. We performed immunohistochemical analyses of eosinophil peroxidase deposition, quantified using automated image analysis. RESULTS: At baseline, no subjects reported current gastrointestinal symptoms. However, 3 of the 21 subjects (14%) had esophageal peak eosinophil counts ≥15 eos/hpf and all subjects had dilated intercellular spaces (DIS). OIT induced or exacerbated esophageal eosinophilia (EE) at 52 weeks in most subjects (peak eosinophil counts >5 eos/hpf in 6 of 7 patients [86%]; peak eosinophil counts ≥15 eos/hpf in 4 of 7 patients [57%]). One subject met clinicopathologic criteria for EoE and withdrew; no significant changes in esophageal peak eosinophil counts were observed in the placebo group. EE in the OIT group corresponded with significant increases in EoE histologic scoring system scores and deposition of eosinophil peroxidase. In 4 of 6 participants (67%), OIT-induced EE and gastrointestinal eosinophilia resolved by the end of the maintenance phase. Gastrointestinal symptoms were not clearly associated with EE or gastrointestinal eosinophilia. CONCLUSIONS: In this pilot study, we found that peanut OIT-induced EE and gastrointestinal eosinophilia are usually transient and are not always associated with gastrointestinal symptoms. Clinicaltrials.gov no: NCT02103270.


Asunto(s)
Esofagitis Eosinofílica , Hipersensibilidad al Cacahuete , Adulto , Arachis , Eosinófilos , Humanos , Inmunoterapia/efectos adversos , Hipersensibilidad al Cacahuete/terapia , Proyectos Piloto
11.
Allergy ; 76(6): 1800-1812, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33300157

RESUMEN

BACKGROUND: Peanut and tree nut allergies are the most important causes of anaphylaxis. Co-reactivity to more than one nut is frequent, and co-sensitization in the absence of clinical data is often obtained. Confirmatory oral food challenges (OFCs) are inconsistently performed. OBJECTIVE: To investigate the utility of the basophil activation test (BAT) in diagnosing peanut and tree nut allergies. METHODS: The Markers Of Nut Allergy Study (MONAS) prospectively enrolled patients aged 0.5-17 years with confirmed peanut and/or tree nut (almond, cashew, hazelnut, pistachio, walnut) allergy or sensitization from Canadian (n = 150) and Austrian (n = 50) tertiary pediatric centers. BAT using %CD63+ basophils (SSClow/CCR3pos) as outcome was performed with whole blood samples stimulated with allergen extracts of each nut (0.001-1000 ng/mL protein). BAT results were assessed against confirmed allergic status in a blinded fashion to develop a generalizable statistical model for comparison to extract and marker allergen-specific IgE. RESULTS: A mixed effect model integrating BAT results for 10 and 100 ng/mL of peanut and individual tree nut extracts was optimal. The area under the ROC curve (AUROC) was 0.98 for peanut, 0.97 for cashew, 0.92 for hazelnut, 0.95 for pistachio, and 0.97 for walnut. The BAT outperformed sIgE testing for peanut or hazelnut and was comparable for walnut (AUROC 0.95, 0.94, 0.92) in a sub-analysis in sensitized patients undergoing OFC. CONCLUSIONS: Basophil activation test can predict allergic clinical status to peanut and tree nuts in multi-nut-sensitized children and may reduce the need for high-risk OFCs in patients.


Asunto(s)
Hipersensibilidad a la Nuez , Hipersensibilidad al Cacahuete , Alérgenos , Arachis , Austria , Basófilos , Canadá , Niño , Humanos , Hipersensibilidad a la Nuez/diagnóstico , Nueces , Hipersensibilidad al Cacahuete/diagnóstico , Pruebas Cutáneas
12.
J Allergy Clin Immunol ; 145(3): 885-896.e6, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31805311

RESUMEN

BACKGROUND: Oral immunotherapy (OIT) can successfully desensitize many peanut-allergic subjects, but clinical tolerance diminishes over time on discontinuation, or low-dose maintenance, of peanut. Therefore, to improve the efficacy and sustainability of such therapy, we sought to identify biomarkers and clinical tools that can predict therapeutic outcomes and monitor treatment responses. OBJECTIVE: We evaluated whether basophil activation in whole blood, and plasma levels of peanut-specific immunoglobulins, are useful biomarkers for peanut OIT. METHODS: We longitudinally measured, before, during, and after OIT, basophil activation in whole blood ex vivo in response to peanut stimulation, and peanut-specific IgE (sIgE) and peanut-specific IgG4 (sIgG4), in a large, single-site, double-blind, randomized, placebo-controlled, phase 2 peanut OIT study. We compared basophil responsiveness and peanut-specific immunoglobulins between those who were clinically reactive and those who were tolerant to peanut oral challenges. RESULTS: Peanut OIT significantly decreased basophil activation, peanut sIgE, Ara h 1, Ara h 2, and Ara h 3 IgE levels, and sIgE/total IgE, but increased sIgG4/sIgE. Participants who became reactive to 4 g of peanut 13 weeks off active OIT exhibited higher peanut-induced basophil activation ex vivo and higher peanut sIgE levels and sIgE/total IgE, but lower sIgG4/sIgE. Notably, participants entering the study with low basophil responsiveness were more likely to achieve treatment success. Substantial suppression of basophil activation was required to maintain long-term clinical tolerance after peanut OIT. CONCLUSIONS: Assessments of peanut-induced basophil activation and peanut-specific immunoglobulins can help to predict treatment outcomes, and to differentiate transient desensitization versus sustained unresponsiveness after OIT.


Asunto(s)
Basófilos/inmunología , Biomarcadores/análisis , Desensibilización Inmunológica/métodos , Inmunoglobulina E/sangre , Hipersensibilidad al Cacahuete/inmunología , Administración Oral , Alérgenos/administración & dosificación , Método Doble Ciego , Humanos , Inmunoglobulina E/inmunología , Hipersensibilidad al Cacahuete/sangre
13.
Lab Invest ; 100(4): 516-526, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31857699

RESUMEN

Mast cell-deficient mice are widely used to identify and quantify contributions of mast cells to diverse biological responses in vivo, including allergic inflammation. However, despite the fact that scores of genes have been identified as modifiers of allergic inflammation, most mast cell-deficient models have been available only on a single genetic background. We transferred the KitW-sh allele onto the BALB/c background to generate BALB/c mast cell-deficient mice (BALB/c-KitW-sh/W-sh). BALB/c-KitW-sh/W-sh mice have dramatically reduced mast cell numbers (0-2% of wild type) in all tissues examined, as well as subtle hematologic differences from the corresponding wild type mice, including splenomegaly with evidence of increased splenic hematopoiesis. We examined in BALB/c-KitW-sh/W-sh mice models of allergic inflammation that are substantially diminished in C57BL/6-KitW-sh/W-sh mast cell-deficient mice. In a model of acute allergic inflammation, i.e., IgE-dependent passive cutaneous anaphylaxis, both ear swelling and leukocyte infiltration were largely or entirely absent in BALB/c-KitW-sh/W-sh mice. In contrast, in two different models of allergic airway inflammation, airway hyperresponsiveness, lung inflammation, and airway remodeling developed robustly in mast cell-deficient BALB/c-KitW-sh/W-sh mice. These results support the conclusion that the importance of mast cell contributions in various models of allergic inflammation may be at least partially determined by genetic background.


Asunto(s)
Asma , Modelos Animales de Enfermedad , Animales , Asma/inducido químicamente , Asma/patología , Asma/fisiopatología , Mastocitos/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-kit/genética
14.
Lancet ; 394(10207): 1437-1449, 2019 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-31522849

RESUMEN

BACKGROUND: Dietary avoidance is recommended for peanut allergies. We evaluated the sustained effects of peanut allergy oral immunotherapy (OIT) in a randomised long-term study in adults and children. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we enrolled participants at the Sean N Parker Center for Allergy and Asthma Research at Stanford University (Stanford, CA, USA) with peanut allergy aged 7-55 years with a positive result from a double-blind, placebo-controlled, food challenge (DBPCFC; ≤500 mg of peanut protein), a positive skin-prick test (SPT) result (≥5 mm wheal diameter above the negative control), and peanut-specific immunoglobulin (Ig)E concentration of more than 4 kU/L. Participants were randomly assigned (2·4:1·4:1) in a two-by-two block design via a computerised system to be built up and maintained on 4000 mg peanut protein through to week 104 then discontinued on peanut (peanut-0 group), to be built up and maintained on 4000 mg peanut protein through to week 104 then to ingest 300 mg peanut protein daily (peanut-300 group) for 52 weeks, or to receive oat flour (placebo group). DBPCFCs to 4000 mg peanut protein were done at baseline and weeks 104, 117, 130, 143, and 156. The pharmacist assigned treatment on the basis of a randomised computer list. Peanut or placebo (oat) flour was administered orally and participants and the study team were masked throughout by use of oat flour that was similar in look and feel to the peanut flour and nose clips, as tolerated, to mask taste. The statistician was also masked. The primary endpoint was the proportion of participants who passed DBPCFCs to a cumulative dose of 4000 mg at both 104 and 117 weeks. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02103270. FINDINGS: Between April 15, 2014, and March 2, 2016, of 152 individuals assessed, we enrolled 120 participants, who were randomly assigned to the peanut-0 (n=60), peanut-300 (n=35), and placebo groups (n=25). 21 (35%) of peanut-0 group participants and one (4%) placebo group participant passed the 4000 mg challenge at both 104 and 117 weeks (odds ratio [OR] 12·7, 95% CI 1·8-554·8; p=0·0024). Over the entire study, the most common adverse events were mild gastrointestinal symptoms, which were seen in 90 of 120 patients (50/60 in the peanut-0 group, 29/35 in the peanut-300 group, and 11/25 in the placebo group) and skin disorders, which were seen in 50/120 patients (26/60 in the peanut-0 group, 15/35 in the peanut-300 group, and 9/25 in the placebo group). Adverse events decreased over time in all groups. Two participants in the peanut groups had serious adverse events during the 3-year study. In the peanut-0 group, in which eight (13%) of 60 participants passed DBPCFCs at week 156, higher baseline peanut-specific IgG4 to IgE ratio and lower Ara h 2 IgE and basophil activation responses were associated with sustained unresponsiveness. No treatment-related deaths occurred. INTERPRETATION: Our study suggests that peanut OIT could desensitise individuals with peanut allergy to 4000 mg peanut protein but discontinuation, or even reduction to 300 mg daily, could increase the likelihood of regaining clinical reactivity to peanut. Since baseline blood tests correlated with week 117 treatment outcomes, this study might aid in optimal patient selection for this therapy. FUNDING: National Institute of Allergy and Infectious Diseases.


Asunto(s)
Arachis , Desensibilización Inmunológica/métodos , Hipersensibilidad al Cacahuete/terapia , Proteínas de Plantas/administración & dosificación , Administración Oral , Adolescente , Niño , Desensibilización Inmunológica/efectos adversos , Método Doble Ciego , Femenino , Enfermedades Gastrointestinales/etiología , Humanos , Inmunoglobulina E/sangre , Masculino , Hipersensibilidad al Cacahuete/diagnóstico , Hipersensibilidad al Cacahuete/inmunología , Proteínas de Plantas/efectos adversos , Pruebas Cutáneas , Resultado del Tratamiento
15.
J Allergy Clin Immunol ; 142(5): 1618-1627.e9, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29678746

RESUMEN

BACKGROUND: Thirdhand smoke (THS) represents the accumulation of secondhand smoke on indoor surfaces and in dust, which, over time, can become more toxic than secondhand smoke. Although it is well known that children of smokers are at increased risk for asthma or asthma exacerbation if the disease is already present, how exposure to THS can influence the development or exacerbation of asthma remains unknown. OBJECTIVE: We investigated whether epicutaneous exposure to an important component of THS, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), can influence asthma pathology in a mouse model elicited by means of repeated intranasal challenge with cockroach antigen (CRA). METHODS: Wild-type mice, α7 nicotinic acetylcholine receptor (nAChR)- or mast cell (MC)-deficient mice, and mice with MCs that lacked α7 nAChRs or were the host's sole source of α7 nAChRs were subjected to epicutaneous NNK exposure, intranasal CRA challenge, or both, and the severity of features of asthma pathology, including airway hyperreactivity, airway inflammation, and airway remodeling, was assessed. RESULTS: We found that α7 nAChRs were required to observe adverse effects of epicutaneous NNK exposure on multiple features of CRA-induced asthma pathology. Moreover, MC expression of α7 nAChRs contributed significantly to the ability of epicutaneous NNK exposure to exacerbate airway hyperreactivity to methacholine, airway inflammation, and airway remodeling in this model. CONCLUSION: Our results show that skin exposure to NNK, a component of THS, can exacerbate multiple features of a CRA-induced model of asthma in mice and define MCs as key contributors to these adverse effects of NNK.


Asunto(s)
Asma/inmunología , Mastocitos/efectos de los fármacos , Nitrosaminas/toxicidad , Piel/efectos de los fármacos , Humo/efectos adversos , Contaminación por Humo de Tabaco , Receptor Nicotínico de Acetilcolina alfa 7/inmunología , Administración Intranasal , Alérgenos/administración & dosificación , Animales , Cucarachas/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Pulmón/efectos de los fármacos , Pulmón/inmunología , Mastocitos/inmunología , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovalbúmina/administración & dosificación , Piel/inmunología , Receptor Nicotínico de Acetilcolina alfa 7/genética
16.
J Allergy Clin Immunol ; 139(3): 889-899.e11, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27527263

RESUMEN

BACKGROUND: Basophil activation tests (BATs) have promise for research and for clinical monitoring of patients with allergies. However, BAT protocols vary in blood anticoagulant used and temperature and time of storage before testing, complicating comparisons of results from various studies. OBJECTIVE: We attempted to establish a BAT protocol that would permit analysis of blood within 24 hours of obtaining the sample. METHODS: Blood from 46 healthy donors and 120 patients with peanut allergy was collected into EDTA or heparin tubes, and samples were stored at 4°C or room temperature for 4 or 24 hours before performing BATs. RESULTS: Stimulation with anti-IgE or IL-3 resulted in strong upregulation of basophil CD203c in samples collected in EDTA or heparin, stored at 4°C, and analyzed 24 hours after sample collection. However, a CD63hi population of basophils was not observed in any conditions in EDTA-treated samples unless exogenous calcium/magnesium was added at the time of anti-IgE stimulation. By contrast, blood samples collected in heparin tubes were adequate for quantification of upregulation of basophil CD203c and identification of a population of CD63hi basophils, irrespective of whether the specimens were analyzed by means of conventional flow cytometry or cytometry by time-of-flight mass spectrometry, and such tests could be performed after blood was stored for 24 hours at 4°C. CONCLUSION: BATs to measure upregulation of basophil CD203c and induction of a CD63hi basophil population can be conducted with blood obtained in heparin tubes and stored at 4°C for 24 hours.


Asunto(s)
Prueba de Desgranulación de los Basófilos/métodos , Manejo de Especímenes/métodos , Adolescente , Adulto , Anticuerpos Antiidiotipos/farmacología , Anticoagulantes/farmacología , Basófilos/efectos de los fármacos , Niño , Ácido Edético/farmacología , Femenino , Citometría de Flujo , Heparina/farmacología , Humanos , Interleucina-3/farmacología , Masculino , Persona de Mediana Edad , Hipersensibilidad al Cacahuete/sangre , Hipersensibilidad al Cacahuete/inmunología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/metabolismo , Temperatura , Factores de Tiempo , Adulto Joven
17.
J Allergy Clin Immunol ; 139(2): 584-596.e10, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27555460

RESUMEN

BACKGROUND: Conflicting results have been obtained regarding the roles of Fc receptors and effector cells in models of active systemic anaphylaxis (ASA). In part, this might reflect the choice of adjuvant used during sensitization because various adjuvants might differentially influence the production of particular antibody isotypes. OBJECTIVE: We developed an "adjuvant-free" mouse model of ASA and assessed the contributions of components of the "classical" and "alternative" pathways in this model. METHODS: Mice were sensitized intraperitoneally with ovalbumin at weekly intervals for 6 weeks and challenged intraperitoneally with ovalbumin 2 weeks later. RESULTS: Wild-type animals had immediate hypothermia and late-phase intraperitoneal inflammation in this model. These features were reduced in mice lacking the IgE receptor FcεRI, the IgG receptor FcγRIII or the common γ-chain FcRγ. FcγRIV blockade resulted in a partial reduction of inflammation without any effect on hypothermia. Depletion of monocytes/macrophages with clodronate liposomes significantly reduced the hypothermia response. By contrast, depletion of neutrophils or basophils had no significant effects in this ASA model. Both the hypothermia and inflammation were dependent on platelet-activating factor and histamine and were reduced in 2 types of mast cell (MC)-deficient mice. Finally, engraftment of MC-deficient mice with bone marrow-derived cultured MCs significantly exacerbated the hypothermia response and restored inflammation to levels similar to those observed in wild-type mice. CONCLUSION: Components of the classical and alternative pathways contribute to anaphylaxis in this adjuvant-free model, with key roles for MCs and monocytes/macrophages.


Asunto(s)
Anafilaxia/inmunología , Movimiento Celular , Hipotermia/inmunología , Leucocitos/inmunología , Macrófagos/inmunología , Mastocitos/inmunología , Adyuvantes Inmunológicos , Animales , Células Cultivadas , Vía Alternativa del Complemento , Vía Clásica del Complemento , Modelos Animales de Enfermedad , Humanos , Inmunización , Mastocitos/trasplante , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de IgE/genética , Receptores de IgE/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo
18.
Trans Am Clin Climatol Assoc ; 128: 193-221, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28790503

RESUMEN

Mast cells and immunoglobulin E (IgE) antibodies are thought to promote health by contributing to host responses to certain parasites, but other beneficial functions have remained obscure. Venoms provoke innate inflammatory responses and pathology reflecting the activities of the contained toxins. Venoms also can induce allergic sensitization and development of venom-specific IgE antibodies, which can predispose some subjects to exhibit anaphylaxis upon subsequent exposure to the relevant venom. We found that innate functions of mast cells, including degradation of venom toxins by mast cell-derived proteases, enhanced survival in mice injected with venoms from the honeybee, two species of scorpion, three species of poisonous snakes, or the Gila monster. We also found that mice injected with sub-lethal amounts of honeybee or Russell's viper venom exhibited enhanced survival after subsequent challenge with potentially lethal amounts of that venom, and that IgE antibodies, FcεRI, and probably mast cells contributed to such acquired resistance.


Asunto(s)
Inmunidad Adaptativa/fisiología , Inmunidad Innata/fisiología , Inmunoglobulina E/fisiología , Mastocitos/fisiología , Ponzoñas/toxicidad , Animales , Anticuerpos/inmunología
19.
J Allergy Clin Immunol ; 137(1): 246-257.e11, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26410782

RESUMEN

BACKGROUND: Type 2 cytokine-related immune responses associated with development of antigen-specific IgE antibodies can contribute to pathology in patients with allergic diseases and to fatal anaphylaxis. However, recent findings in mice indicate that IgE also can enhance defense against honeybee venom. OBJECTIVE: We tested whether IgE antibodies, IgE-dependent effector mechanisms, and a local anaphylactic reaction to an unrelated antigen can enhance defense against Russell viper venom (RVV) and determined whether such responses can be influenced by immunization protocol or mouse strain. METHODS: We compared the resistance of RVV-immunized wild-type, IgE-deficient, and Fcer1a-deficient mice after injection of a potentially lethal dose of RVV. RESULTS: A single prior exposure to RVV enhanced the ability of wild-type mice, but not mice lacking IgE or functional FcεRI, to survive challenge with a potentially lethal amount of RVV. Moreover, IgE-dependent local passive cutaneous anaphylaxis in response to challenge with an antigen not naturally present in RVV significantly enhanced resistance to the venom. Finally, we observed different effects on resistance to RVV or honeybee venom in BALB/c versus C57BL/6 mice that had received a second exposure to that venom before challenge with a high dose of that venom. CONCLUSION: These observations illustrate the potential benefit of IgE-dependent effector mechanisms in acquired host defense against venoms. The extent to which type 2 immune responses against venoms can decrease pathology associated with envenomation seems to be influenced by the type of venom, the frequency of venom exposure, and the genetic background of the host.


Asunto(s)
Anafilaxia/inmunología , Inmunoglobulina E/inmunología , Receptores de IgE/inmunología , Venenos de Víboras/inmunología , Animales , Venenos de Abeja/inmunología , Degranulación de la Célula , Femenino , Inmunización , Mastocitos/inmunología , Mastocitos/fisiología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de IgE/genética
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