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1.
Gene ; 737: 144462, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32045661

RESUMO

OBJECTIVE: To investigate the association of single nucleotide polymorphisms (SNPs) at the interleukin (IL)-18 locus with wheat-dependent exercise-induced anaphylaxis (WDEIA) in the Han Chinese population. METHOD: 130 patients with WDEIA and 600 healthy subjects were recruited for this study. Three tag SNPs (rs360729, rs360717 and rs1946518) were selected and genotyped, and total IgE and specific IgE levels were measured using the ImmunoCAP system. RESULTS: After Bonferroni correction, the frequency of the G-allele in rs1946518 in the WDEIA group was significantly higher than that in control group (P = 0.0015). Genotypic distributions of rs1946518 significantly differed between WDEIA and control groups, and compared with the TT genotype, the homozygote GG genotype was associated with a higher risk of WDEIA (P = 0.0031). At position rs1946518, the log-transformed total IgE values were significantly higher in the group with the heterozygous GT genotype than in TT genotype group (P = 0.0024). Haplotype AGG formed by three SNPs alleles occurred significantly more frequently in WDEIA group than in control group (P = 0.003). CONCLUSION: The minor allele G at position rs1946518 might serve as a marker for the risk of WDEIA.


Assuntos
Anafilaxia/etiologia , Grupo com Ancestrais do Continente Asiático/genética , Grupos Étnicos/genética , Exercício Físico , Variação Genética , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Hipersensibilidade a Trigo/complicações , Adulto , Anafilaxia/genética , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
2.
Biomed Pharmacother ; 118: 109214, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31382129

RESUMO

OBJECTIVE: To investigate the effects of desmoglein 3 (DSG3) gene mediating epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling pathway on inflammatory response and immune function of anaphylactic rhinitis (AR). METHODS: Ten of the seventy male BALB/c mice were randomly selected as the normal control group, and the remaining 60 were used to construct the AR mice model. AR model mice were divided into 6 groups: model group (instilled with 5 µL saline), empty vector group (instilled with 5 µL of liposome and empty vector mixture), siRNA-DSG3 group (instilled with 5 µL of liposome and siRNA-DSG3 carrier mixture), AG1478 group (instilled with 5 µL of EGF/EGFR inhibitor AG1478), siRNA-DSG3+AG1478 group (instilled with 5 µL of liposome and siRNA-DSG3 carrier and EGF/EGFR inhibitor AG1478 mixture) and oe-DSG3 group, 10 in each group. After taking serum, each group of mice was sacrificed to get nasal mucosa tissues. HE staining was used to observe the pathological changes of nasal mucosa tissues in each group. The expression levels of DSG3, EGF and EGFR in nasal mucosa tissues of mice in each group were detected by qRT-PCR and western blot methods respectively. TUNEL staining was used to observe the apoptosis of nasal mucosa cells in mice. The expression of IgE, INF-γ, TNF-α, IL-2, IL-4 and IL-6 in serum of mice was determined by ELISA method. The immune adhesion function of red blood cells was detected by complement sensitization yeast hemagglutination method. RESULTS: All the mice with AR showed different degrees of nasal mucosa injury and inflammatory cell infiltration, and silencing DSG3 or inhibiting the activity of EGF signaling pathway could alleviate the nasal mucosa injury. Compared with control group, the INF-γ and IL-2 levels of serum in AR model mice were significantly decreased; IgE, TNF-α, IL-4 and IL-6 levels were significantly increased (all P < 0.05); the mRNA expression levels and protein levels of DSG3, EGF and EGFR were significantly increased (all P < 0.05); C3b receptor rosette rate and Ic rosette rate were significantly decreased (all P < 0.05). Detected by ELISA method, the expression levels of IgE, TNF-α, IL-4 and IL-6 were increased, while the expression levels of INF-γ and IL-2 were decreased after DSG3 silencing or using AG1478. Detected by qRT-PCR and western blot methods, the expression of DSG3, EGF and EGFR did decrease after DSG3 silencing. There was no significant difference in the EGF and EGFR expression between DSG3 silencing and using AG1478, and the expression decreased even more under the double effect. The mRNA and protein expression levels of DSG3, EGF and EGFR in the nasal mucosa tissues of mice with overexpression of DSG3 plasmid were significantly higher than those of normal mice (all P < 0.05). CONCLUSION: Silencing DSG3 gene can inhibit the activation of EGF signaling pathway, alleviate the inflammation of AR nasal mucosa, and enhance red blood cells immune adherence function.


Assuntos
Anafilaxia/imunologia , Desmogleína 3/genética , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Rinite Alérgica/imunologia , Anafilaxia/genética , Anafilaxia/metabolismo , Animais , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/genética , Receptores ErbB/genética , Regulação da Expressão Gênica , Inflamação , Camundongos Endogâmicos BALB C , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Rinite Alérgica/genética , Rinite Alérgica/metabolismo , Transdução de Sinais
3.
Curr Allergy Asthma Rep ; 19(6): 31, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31028494

RESUMO

PURPOSE OF REVIEW: Gain of function KIT mutations are detected in clonal mast cell diseases, namely mastocytosis and monoclonal mast cell activation syndrome. Timely diagnosis and treatment of these disorders are crucial because of their association with severe and life-threatening anaphylaxis. KIT mutations also have implications for targeted therapies of mast cell disorders. This review article strives to serve as an overview of the role of clonal mast cell disorders in anaphylaxis while elucidating current and future therapies. RECENT FINDINGS: Clonal mast cell disease has been increasingly diagnosed in patients with severe hymenoptera allergy and those with recurrent unexplained anaphylaxis. The current state of knowledge of the epidemiology, pathophysiology, diagnosis, and treatment of mastocytosis with a particular focus on anaphylaxis and its triggers which are described in this context. Novel and forthcoming treatments are discussed including the relevance of KIT mutation status. This review provides an overview of the role of KIT mutations in mastocytosis and anaphylaxis, and highlights emerging therapies for mastocytosis, targeting these mutations.


Assuntos
Anafilaxia/genética , Mastocitose/genética , Proteínas Proto-Oncogênicas c-kit/genética , Anafilaxia/imunologia , Anafilaxia/terapia , Humanos , Mastócitos/imunologia , Mastocitose/imunologia , Mastocitose/terapia , Mutação
4.
Int Immunopharmacol ; 70: 417-427, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856392

RESUMO

Fluoroquinolones trigger anaphylaxis during clinical applications, affecting the safety of their administration. Mast cells are immune cells that act as sentinels during host defenses, mediating hypersensitivity and anaphylactic reactions. Mas-related G protein-coupled receptor X2 (MRGPRX2) is a mast cell-specific receptor that mediates cell degranulation in anaphylactic reactions. In this study, the mechanism underpinning the anaphylactic reactions caused by fluoroquinolones was investigated. Hypersensitivity was assessed through hindpaw swelling, tissue fluid leakage assays, in vivo and body temperature measurements assay in vivo, and cell calcium mobilization assays, and mast cell degranulation assays in vitro. Mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice and MrgprB2 (the orthologous receptor of MRGPRX2 in mice) knockout mice exhibited reduced fluoroquinolone-induced anaphylactic effects. Fluoroquinolones activated mast cells in a dose-dependent manner and reduced degranulation was observed following MRGPRX2 silencing. These results reveal that fluoroquinolone-induced anaphylactic reactions are mediated by mast cells through MRGPRX2.


Assuntos
Anafilaxia/metabolismo , Fluoroquinolonas/metabolismo , Hipersensibilidade/metabolismo , Mastócitos/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Anafilaxia/induzido quimicamente , Anafilaxia/genética , Animais , Temperatura Corporal , Sinalização do Cálcio , Degranulação Celular/genética , Permeabilidade da Membrana Celular/genética , Fluoroquinolonas/química , Células HEK293 , Humanos , Hipersensibilidade/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Proteínas do Tecido Nervoso/genética , RNA Interferente Pequeno/genética , Receptores Acoplados a Proteínas-G/genética , Receptores de Neuropeptídeos/genética
5.
J Clin Invest ; 129(3): 1387-1401, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30645205

RESUMO

Allergen immunotherapy for patients with allergies begins with weekly escalating doses of allergen under medical supervision to monitor and treat IgE mast cell-mediated anaphylaxis. There is currently no treatment to safely desensitize mast cells to enable robust allergen immunotherapy with therapeutic levels of allergen. Here, we demonstrated that liposomal nanoparticles bearing an allergen and a high-affinity glycan ligand of the inhibitory receptor CD33 profoundly suppressed IgE-mediated activation of mast cells, prevented anaphylaxis in Tg mice with mast cells expressing human CD33, and desensitized mice to subsequent allergen challenge for several days. We showed that high levels of CD33 were consistently expressed on human skin mast cells and that the antigenic liposomes with CD33 ligand prevented IgE-mediated bronchoconstriction in slices of human lung. The results demonstrated the potential of exploiting CD33 to desensitize mast cells to provide a therapeutic window for administering allergen immunotherapy without triggering anaphylaxis.


Assuntos
Alérgenos/imunologia , Anafilaxia/prevenção & controle , Dessensibilização Imunológica , Imunoglobulina E/imunologia , Mastócitos/imunologia , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Anafilaxia/genética , Anafilaxia/imunologia , Anafilaxia/patologia , Animais , Broncoconstrição/genética , Broncoconstrição/imunologia , Humanos , Imunoglobulina E/genética , Mastócitos/patologia , Camundongos , Camundongos Transgênicos , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética
6.
J Innate Immun ; 11(1): 63-73, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30189430

RESUMO

BACKGROUND: We have previously identified the upregulation of the innate immune response, neutrophil activation, and apoptosis during anaphylaxis using a microarray approach. This study aimed to validate the differential gene expression and investigate protein concentrations of "hub genes" and upstream regulators during anaphylaxis. METHODS: Samples were collected from patients with anaphylaxis on their arrival at the emergency department, and after 1 and 3 h. mRNA levels of 11 genes (interleukin-6 [IL-6], IL-10, oncostatin M [OSM], S100A8, S100A9, matrix metalloproteinase 9 [MMP9], FASL, toll-like receptor 4 [TLR4], MYD88, triggering receptor expressed on myeloid cells 1 [TREM1], and cluster of differentiation 64 [CD64]) were measured in peripheral blood leucocytes using qPCR. Serum protein concentrations were measured by ELISA or cytometric bead array for 6 of these candidates. RESULTS: Of 69 anaphylaxis patients enrolled, 36 (52%) had severe reactions, and 38 (55%) were female. Increases in both mRNA and protein of IL-10, S100A9, MMP9, and TREM1 were observed. OSM, S100A8, TLR4, and CD64 were upregulated and IL-6 protein concentrations were increased during anaphylaxis. Both FASL and soluble Fas ligand decreased during anaphylaxis. CONCLUSION: These results provide evidence for the involvement of innate immune pathways and myeloid cells during human anaphylaxis, validating previous microarray findings. Elevated S100A8, S100A9, TLR4, and TREM1 expression, and increased S100A9 and soluble TREM1 protein concentrations strongly suggest that neutrophils are activated during acute anaphylaxis.


Assuntos
Anafilaxia/imunologia , Imunidade Inata , Células Mieloides/imunologia , Ativação de Neutrófilo , Neutrófilos/imunologia , Adulto , Anafilaxia/sangue , Anafilaxia/genética , Citocinas/genética , Citocinas/metabolismo , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Proteínas Inflamatórias de Macrófagos/genética , Proteínas Inflamatórias de Macrófagos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Adulto Jovem
7.
Ann Allergy Asthma Immunol ; 122(2): 148-155, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30465863

RESUMO

OBJECTIVE: This article reviews the latest science and epidemiologic studies related to drug allergy in children and adults to explore possible mechanisms related to female propensity for drug allergy. DATA SOURCES: PubMed literature review, focusing primarily on the last 5 years. STUDY SELECTIONS: Articles reviewing the science behind female predisposition to atopic and asthmatic conditions and epidemiologic studies reviewing drug allergy and drug-induced anaphylaxis. RESULTS: Despite adult female predilection for atopic conditions, few laboratory studies explore sex-specific mechanisms in atopic/allergic diseases, and most are focused on autoimmunity and asthma. Drug allergy is more frequently reported in adult females compared with adult males. Adult females are also more likely to have drug-induced anaphylaxis (DIA), although no clear sex predominance has been reported in fatal or severe DIA. Studies in children suggest the reverse picture, with prepubertal males more likely to have drug allergy and DIA than prepubertal girls. CONCLUSION: Possible explanations for female predisposition for drug allergy are multifactorial and include disproportionate utilization of health care with more exposure to antibiotics or medications, genetic factors related to the X chromosome, epigenetic changes, and discrepant hormonal interactions with immune cells.


Assuntos
Cromossomos Humanos X , Hipersensibilidade a Drogas/etiologia , Imunidade Adaptativa , Adulto , Anafilaxia/etiologia , Anafilaxia/genética , Anti-Inflamatórios não Esteroides/efeitos adversos , Criança , Hipersensibilidade a Drogas/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Hormônios Esteroides Gonadais/fisiologia , Humanos , Imunidade Inata , Masculino , Caracteres Sexuais
8.
Pharmacogenomics J ; 19(2): 191-199, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30093714

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions. Such reactions can be pharmacologically or immunologically mediated, but in both cases individual susceptibility can be influenced by genetic factors. Polymorphisms in centrosomal protein of 68 kDa (CEP68) have been associated with pharmacologically mediated NSAIDs reactions. Here, we evaluated this gene in immunologically mediated single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) by analyzing 52 single nucleotide polymorphisms in CEP68 in 176 patients and 363 NSAIDs-tolerant controls. Two intronic variants (rs2241160 and rs2241161) were significantly associated with an increased risk of SNIUAA, suggesting CEP68 to be a key player in both types of NSAIDs hypersensitivity. However, we found no overlap with genetic variants previously associated with pharmacologically mediated hypersensitivity, pointing to a complex role for this gene and its potential use in the development of biomarkers of clinical utility to diagnose patients at risk of these reactions and to differentiate entities.


Assuntos
Anafilaxia/genética , Anti-Inflamatórios não Esteroides/efeitos adversos , Hipersensibilidade a Drogas/genética , Proteínas Associadas aos Microtúbulos/genética , Urticária/genética , Adulto , Anafilaxia/induzido quimicamente , Anafilaxia/patologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Hipersensibilidade a Drogas/patologia , Feminino , Estudos de Associação Genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Urticária/induzido quimicamente , Urticária/patologia
9.
Int J Rheum Dis ; 21(12): 2071-2078, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30556363

RESUMO

AIM: Allergy inhibitory receptor-1 (Allergin-1) is a newly identified immune regulatory molecule thought to influence autoantibody production. Autoantibody production, like that observed in Allergin-1-deficient mice, is crucial in the pathogenesis of several autoimmune diseases such as systemic lupus erythematosus. The purpose of this study is to clarify the regulatory role of Allergin-1-mediated autoantibody production using a murine model of thymocytic anaphylaxis. METHODS: C57BL/6 (WT) and Allergin-1-deficient mice were treated with apoptotic cells from naive thymocytes stimulated by dexamethasone. Antibody titers of total or immunoglobulin G (IgG) subclass of anti-double-stranded DNA (anti-dsDNA) and anti-histone antibody from serum were measured using an enzyme-linked immunosorbent assay. Macrophages from wild-type (WT) or Allergin-1-deficient mice were co-cultured with fluorescence-labeled apoptotic thymocytes or fluorogenic reagent and resultant phagocytic activity was quantified by with flow cytometry. RESULTS: After apoptotic cells injection, antibody titers of total and IgG3 anti-dsDNA and total anti-histone from serum were significantly increased in Allergin-1-deficient versus WT mice. Phagocytic activity was significantly lower in macrophages from Allergin-1-deficient mice versus WT mice. CONCLUSION: Allergin-1 might play an inhibitory role in autoantibody production via upregulation of macrophage phagocytosis.


Assuntos
Anafilaxia/imunologia , Apoptose , Autoanticorpos/imunologia , Macrófagos/imunologia , Fagocitose , Receptores Imunológicos/metabolismo , Timócitos/imunologia , Anafilaxia/genética , Anafilaxia/metabolismo , Anafilaxia/patologia , Animais , Autoanticorpos/sangue , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/deficiência , Receptores Imunológicos/genética , Timócitos/patologia
10.
Front Immunol ; 9: 1809, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30177930

RESUMO

FcγRIIa is an activating FcγR, unique to humans and non-human primates. It induces antibody-dependent proinflammatory responses and exists predominantly as FcγRIIa1. A unique splice variant, we designated FcγRIIa3, has been reported to be associated with anaphylactic reactions to intravenous immunoglobulins (IVIg) therapy. We aim to define the functional consequences of this FcγRIIa variant associated with adverse responses to IVIg therapy and evaluate the frequency of associated SNPs. FcγRIIa forms from macaque and human PBMCs were investigated for IgG-subclass specificity, biochemistry, membrane localization, and functional activity. Disease-associated SNPs were analyzed by sequencing genomic DNA from 224 individuals with immunodeficiency or autoimmune disease. FcγRIIa3 was identified in macaque and human PBMC. The FcγRIIa3 is distinguished from the canonical FcγRIIa1 by a unique 19-amino acid cytoplasmic insertion and these two FcγRIIa forms responded distinctly to antibody ligation. Whereas FcγRIIa1 was rapidly internalized, FcγRIIa3 was retained longer at the membrane, inducing greater calcium mobilization and cell degranulation. Four FCGR2A SNPs were identified including the previously reported intronic SNP associated with anaphylaxis, but in only 1 of 224 individuals. The unique cytoplasmic element of FcγRIIa3 delays internalization and is associated with enhanced cellular activation. The frequency of the immunodeficiency-associated SNP varies between disease populations but interestingly occurred at a lower frequency than previously reported. None-the-less enhanced FcγRIIa3 function may promote a proinflammatory environment and predispose to pathological inflammatory responses.


Assuntos
Anafilaxia/genética , Anafilaxia/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Anafilaxia/diagnóstico , Anafilaxia/imunologia , Animais , Biomarcadores , Degranulação Celular/imunologia , Suscetibilidade a Doenças , Imunofluorescência , Expressão Gênica , Loci Gênicos , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macaca , Mastócitos/imunologia , Mastócitos/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Isoformas de Proteínas , Análise de Sequência de DNA
11.
Sci Rep ; 8(1): 11628, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072729

RESUMO

The study of anaphylactoid reactions during perioperative procedures and anaesthesia represents a diagnostic challenge for allergists, as many drugs are administered simultaneously, and approximately half of them trigger allergic reactions without a verifiable IgE-mediated mechanism. Recently, mast cell receptor MRGPRX2 has been identified as a cause of pseudo-allergic drug reactions. In this study, we analyse the ability of certain drugs used during perioperative procedures and anaesthesia to induce MRGPRX2-dependent degranulation in human mast cells and sera from patients who experienced an anaphylactoid reaction during the perioperative procedure. Using a ß-hexosaminidase release assay, several drugs were seen to cause mast cell degranulation in vitro in comparison with unstimulated cells, but only morphine, vancomycin and cisatracurium specifically triggered this receptor, as assessed by the release of ß-hexosaminidase in the control versus the MRGPRX2-silenced cells. The same outcome was seen when measuring degranulation based on the percentage of CD63 expression at identical doses. Unlike that of the healthy controls, the sera of patients who had experienced an anaphylactoid reaction induced mast-cell degranulation. The degranulation ability of these sera decreased when MRGPRX2 was silenced. In conclusion, MRGPRX2 is a candidate for consideration in non-IgE-mediated allergic reactions to some perioperative drugs, reinforcing its role in mast cell responses and their pathophysiology.


Assuntos
Anafilaxia/metabolismo , Atracúrio/análogos & derivados , Degranulação Celular/efeitos dos fármacos , Hipersensibilidade a Drogas/metabolismo , Mastócitos/metabolismo , Morfina/efeitos adversos , Proteínas do Tecido Nervoso/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Vancomicina/efeitos adversos , Anafilaxia/induzido quimicamente , Anafilaxia/genética , Anafilaxia/patologia , Anestesia/efeitos adversos , Atracúrio/efeitos adversos , Atracúrio/farmacologia , Hipersensibilidade a Drogas/genética , Hipersensibilidade a Drogas/patologia , Células HEK293 , Humanos , Mastócitos/patologia , Morfina/farmacologia , Proteínas do Tecido Nervoso/genética , Assistência Perioperatória/efeitos adversos , Receptores Acoplados a Proteínas-G/genética , Receptores de Neuropeptídeos/genética , Vancomicina/farmacologia
12.
Immunol Allergy Clin North Am ; 38(3): 365-377, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30007457

RESUMO

Mast cell activation disorders is a term proposed to cover diseases and conditions related to activation of mast cells and effects of mast cell mediators. In its broadest sense, the term encompasses a wide range of diseases from allergic asthma to rhinoconjunctivitis, urticaria, food allergy, anaphylaxis, mastocytosis, and other conditions where MC activation is contributing to the pathogenesis. This article focuses on clinical presentations, challenges, and controversies in pediatric mastocytosis and gives an overview of current knowledge and areas in need of further research.


Assuntos
Anafilaxia/imunologia , Degranulação Celular , Mastócitos/fisiologia , Mastocitose/imunologia , Proteínas Proto-Oncogênicas c-kit/genética , Urticária/imunologia , Adulto , Anafilaxia/genética , Criança , Humanos , Mastocitose/genética , Triptases/metabolismo , Urticária/genética
13.
Front Immunol ; 9: 1244, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29928276

RESUMO

Immediate hypersensitivity reactions are induced by the interaction of allergens with specific IgE antibodies bound via FcεRI to mast cells and basophils. While these specific IgE antibodies are needed to trigger such reactions, not all individuals harboring IgE exhibit symptoms of allergy. The lack of responsiveness seen in some subjects correlates with the presence of IgG antibodies of the same specificity. In cell culture studies and in vivo animal models of food allergy and anaphylaxis such IgG antibodies have been shown to exert suppression via FcγRIIb. However, the reported absence of this inhibitory receptor on primary mast cells derived from human skin has raised questions about the role of IgG-mediated inhibition of immediate hypersensitivity in human subjects. Here, we tested the hypothesis that mast cell FcγRIIb expression might be tissue specific. Utilizing a combination of flow cytometry, quantitative PCR, and immunofluorescence staining of mast cells derived from the tissues of humanized mice, human skin, or in fixed paraffin-embedded sections of human tissues, we confirm that FcγRIIb is absent from dermal mast cells but is expressed by mast cells throughout the gastrointestinal tract. IgE-induced systemic anaphylaxis in humanized mice is strongly inhibited by antigen-specific IgG. These findings support the concept that IgG, signaling via FcγRIIb, plays a physiological role in suppressing hypersensitivity reactions.


Assuntos
Regulação da Expressão Gênica , Mastócitos/imunologia , Mastócitos/metabolismo , Receptores de IgG/genética , Alérgenos/imunologia , Anafilaxia/genética , Anafilaxia/imunologia , Anafilaxia/metabolismo , Animais , Citometria de Fluxo , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Imunofenotipagem , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Receptores de IgG/metabolismo
14.
J Agric Food Chem ; 66(22): 5581-5592, 2018 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-29763312

RESUMO

Deep-sea-derived butyrolactone I (BTL-I), which was identified as a type of butanolide, was isolated from Aspergillus sp. Ovalbumin (OVA)-induced BALB/c anaphylaxis was established to explore the antifood allergic activity of BTL-I. As a result, BTL-I was able to alleviate OVA-induced allergy symptoms, reduce the levels of histamine and mouse mast cell proteinases, inhibit OVA-specific IgE, and decrease the population of mast cells in the spleen and mesenteric lymph nodes. BTL-I also significantly suppressed mast-dependent passive cutaneous anaphylaxis. Additionally, the maturation of bone marrow-derived mast cells (BMMCs) declined as BTL-I caused down-regulation of c-KIT receptors. Furthermore, molecular docking analyses revealed that BTL-I interacted with the inhibitory receptor, FcγRIIB. In conclusion, the reduction of mast cell function by deep-sea-derived BTL-I as well as its interactions with the inhibitory receptor, FcγRIIB, may contribute to BTL-I-related protection against food anaphylaxis.


Assuntos
4-Butirolactona/análogos & derivados , Anafilaxia/tratamento farmacológico , Aspergillus/química , Hipersensibilidade Alimentar/tratamento farmacológico , Mastócitos/imunologia , 4-Butirolactona/administração & dosagem , Anafilaxia/genética , Anafilaxia/imunologia , Animais , Aspergillus/genética , Aspergillus/isolamento & purificação , Células Cultivadas , Modelos Animais de Doenças , Feminino , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/imunologia , Histamina/imunologia , Humanos , Imunoglobulina E/imunologia , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/efeitos adversos , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/imunologia , Água do Mar/microbiologia
15.
Clin Exp Allergy ; 48(7): 846-861, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29779231

RESUMO

BACKGROUND: The Royal College of Anaesthetists 6th National Audit Project examined Grade 3-5 perioperative anaphylaxis for 1 year in the UK. OBJECTIVE: To describe the causes and investigation of anaphylaxis in the NAP6 cohort, in relation to published guidance and previous baseline survey results. METHODS: We used a secure registry to gather details of Grade 3-5 perioperative anaphylaxis. Anonymous reports were aggregated for analysis and reviewed in detail. Panel consensus diagnosis, reaction grade, review of investigations and clinic assessment are reported and compared to the prior NAP6 baseline clinic survey. RESULTS: A total of 266 cases met inclusion criteria between November 2015 and 2016, detailing reactions and investigations. One hundred and ninety-two of 266 (72%) had anaphylaxis with a trigger identified, of which 140/192 (75%) met NAP6 criteria for IgE-mediated allergic anaphylaxis, 13% lacking evidence of positive IgE tests were labelled "non-allergic anaphylaxis". 3% were non-IgE-mediated anaphylaxis. Adherence to guidance was similar to the baseline survey for waiting time for clinic assessment. However, lack of testing for chlorhexidine and latex, non-harmonized testing practices and poor coverage of all possible culprits was confirmed. Challenge testing may be underused and many have unacceptably delayed assessments, even in urgent cases. Communication or information provision for patients was insufficient, especially for avoidance advice and communication of test results. Insufficient detail regarding skin test methods was available to draw conclusions regarding techniques. CONCLUSION AND CLINICAL RELEVANCE: Current clinical assessment in the UK is effective but harmonization of approach to testing, access to services and MHRA reporting is needed. Expert anaesthetist involvement should increase to optimize diagnostic yield and advice for future anaesthesia. Dynamic tryptase evaluation improves detection of tryptase release where peak tryptase is <14 µg/L and should be adopted. Standardized clinic reports containing appropriate details of tests, conclusions, avoidance, cross-reactivity and suitable alternatives are required to ensure effective, safe future management options.


Assuntos
Serviços de Saúde , Hipersensibilidade/epidemiologia , Especialização , Anafilaxia/epidemiologia , Anafilaxia/genética , Biomarcadores , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/etiologia , Imunoglobulina E/imunologia , Período Perioperatório , Qualidade da Assistência à Saúde , Índice de Gravidade de Doença , Triptases/metabolismo , Reino Unido/epidemiologia
16.
Curr Opin Allergy Clin Immunol ; 18(3): 190-197, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29601357

RESUMO

PURPOSE OF REVIEW: Recognize the presentation of anaphylaxis for prompt management and treatment and to provide tools for the diagnosis of the underlying cause(s) and set up a long-term treatment to prevent recurrence of anaphylaxis. RECENT FINDINGS: The recent description of phenotypes provides new insight and understanding into the mechanisms and causes of anaphylaxis through a better understanding of endotypes and biomarkers for broad clinical use. SUMMARY: Anaphylaxis is the most severe hypersensitivity reaction and can lead to death. Epinephrine is the first-line treatment of anaphylaxis and it is life-saving. Patients with first-line therapy-induced anaphylaxis are candidates for desensitization to increase their quality of life and life expectancy. Desensitization is a breakthrough novel treatment for patients with anaphylaxis in need of first-line therapy, including chemotherapy, mAbs, aspirin and others. Ultrarush with venom immunotherapy should be considered in patients who present with life-threatening anaphylaxis after Hymenoptera sting with evidence of IgE-mediated mechanisms. Food desensitization is currently being expanded to provide increased safety to adults and children with food-induced anaphylaxis.


Assuntos
Anafilaxia/terapia , Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/terapia , Hipersensibilidade Alimentar/terapia , Medicina de Precisão/métodos , Adulto , Alérgenos/administração & dosagem , Alérgenos/imunologia , Anafilaxia/genética , Anafilaxia/imunologia , Anafilaxia/mortalidade , Animais , Venenos de Artrópodes/administração & dosagem , Venenos de Artrópodes/imunologia , Biomarcadores/análise , Anticoncepcionais Orais Hormonais/administração & dosagem , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepcionais Orais Hormonais/imunologia , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Epinefrina/uso terapêutico , Feminino , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/imunologia , Humanos , Himenópteros/imunologia , Imunoglobulina E/imunologia , Mordeduras e Picadas de Insetos/complicações , Mordeduras e Picadas de Insetos/imunologia , Expectativa de Vida , Fenótipo , Progestinas/administração & dosagem , Progestinas/efeitos adversos , Progestinas/imunologia , Qualidade de Vida , Recidiva
18.
Adv Med Sci ; 63(2): 265-277, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29486376

RESUMO

Anaphylaxis is defined as severe, life-threatening, systemic or general, immediate reaction of hypersensitivity, with repeatable symptoms caused by the dose of stimulus which is well tolerated by healthy persons. The proper diagnosis, immediate treatment and differential diagnosis are crucial for saving patient's life. However, anaphylaxis is relatively frequently misdiagnosed or confused with other clinical entities. Thus, there is a continuous need for identifying detectable markers improving the proper diagnosis of anaphylaxis. Here we presented currently known markers of anaphylaxis and discussed in more detail the most clinically valuable ones: tryptase, platelet activacting factor (PAF), PAF-acethylhydrolase, histamine and its metabolites.


Assuntos
Anafilaxia/metabolismo , Biomarcadores/metabolismo , Anafilaxia/diagnóstico , Anafilaxia/genética , Histamina/metabolismo , Humanos , Fator de Ativação de Plaquetas/metabolismo , Triptases/metabolismo
19.
J Allergy Clin Immunol ; 141(5): 1711-1725.e9, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29454836

RESUMO

BACKGROUND: Mechanisms for the development of food allergy in neonates are unknown but clearly linked in patient populations to a genetic predisposition to skin barrier defects. Whether skin barrier defects contribute functionally to development of food allergy is unknown. OBJECTIVE: The purpose of the study was to determine whether skin barrier mutations, which are primarily heterozygous in patient populations, contribute to the development of food allergy. METHODS: Mice heterozygous for the filaggrin (Flg)ft and Tmem79ma mutations were skin sensitized with environmental and food allergens. After sensitization, mice received oral challenge with food allergen, and then inflammation, inflammatory mediators, and anaphylaxis were measured. RESULTS: We define development of inflammation, inflammatory mediators, and food allergen-induced anaphylaxis in neonatal mice with skin barrier mutations after brief concurrent cutaneous exposure to food and environmental allergens. Moreover, neonates of allergic mothers have increased responses to suboptimal sensitization with food allergens. Importantly, responses to food allergens by these neonatal mice were dependent on genetic defects in skin barrier function and on exposure to environmental allergens. ST2 blockade during skin sensitization inhibited the development of anaphylaxis, antigen-specific IgE, and inflammatory mediators. Neonatal anaphylactic responses and antigen-specific IgE were also inhibited by oral pre-exposure to food allergen, but interestingly, this was blunted by concurrent pre-exposure of the skin to environmental allergen. CONCLUSION: These studies uncover mechanisms for food allergy sensitization and anaphylaxis in neonatal mice that are consistent with features of human early-life exposures and genetics in patients with clinical food allergy and demonstrate that changes in barrier function drive development of anaphylaxis to food allergen.


Assuntos
Hipersensibilidade Alimentar/imunologia , Mutação/imunologia , Pele/imunologia , Alérgenos/imunologia , Anafilaxia/genética , Anafilaxia/imunologia , Animais , Antígenos/imunologia , Feminino , Hipersensibilidade Alimentar/genética , Imunoglobulina E/imunologia , Inflamação/genética , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética
20.
Proc Natl Acad Sci U S A ; 115(7): E1550-E1559, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29386381

RESUMO

There is a growing appreciation for the contribution of platelets to immunity; however, our knowledge mostly relies on platelet functions associated with vascular injury and the prevention of bleeding. Circulating immune complexes (ICs) contribute to both chronic and acute inflammation in a multitude of clinical conditions. Herein, we scrutinized platelet responses to systemic ICs in the absence of tissue and endothelial wall injury. Platelet activation by circulating ICs through a mechanism requiring expression of platelet Fcγ receptor IIA resulted in the induction of systemic shock. IC-driven shock was dependent on release of serotonin from platelet-dense granules secondary to platelet outside-in signaling by αIIbß3 and its ligand fibrinogen. While activated platelets sequestered in the lungs and leaky vasculature of the blood-brain barrier, platelets also sequestered in the absence of shock in mice lacking peripheral serotonin. Unexpectedly, platelets returned to the blood circulation with emptied granules and were thereby ineffective at promoting subsequent systemic shock, although they still underwent sequestration. We propose that in response to circulating ICs, platelets are a crucial mediator of the inflammatory response highly relevant to sepsis, viremia, and anaphylaxis. In addition, platelets recirculate after degranulation and sequestration, demonstrating that in adaptive immunity implicating antibody responses, activated platelets are longer lived than anticipated and may explain platelet count fluctuations in IC-driven diseases.


Assuntos
Anafilaxia/imunologia , Complexo Antígeno-Anticorpo/imunologia , Plaquetas/imunologia , Serotonina/imunologia , Choque Séptico/imunologia , Adulto , Anafilaxia/sangue , Anafilaxia/genética , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ativação Plaquetária , Contagem de Plaquetas , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Receptores de IgG/genética , Receptores de IgG/imunologia , Choque Séptico/sangue , Choque Séptico/genética , Adulto Jovem
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