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2.
Handb Exp Pharmacol ; 268: 31-41, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34255192

RESUMO

Hypersensitivity reactions are overreactions of the immune system clinically seen as allergic and autoimmune diseases. Gell and Coombs originally described four different types of hypersensitivity reactions almost 60 years ago, and their description still applies in large parts. However, some modifications and extensions have been included in original definition. Especially in allergic diseases, it became clear that often, multiple types of hypersensitivity reaction can occur simultaneously. This improved insight is not only important for a better understanding of hypersensitivity disorders, but is especially of importance for improved diagnostics and directing therapeutic interventions.


Assuntos
Hipersensibilidade , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/etiologia
6.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33798095

RESUMO

Pollen exposure weakens the immunity against certain seasonal respiratory viruses by diminishing the antiviral interferon response. Here we investigate whether the same applies to the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is sensitive to antiviral interferons, if infection waves coincide with high airborne pollen concentrations. Our original hypothesis was that more airborne pollen would lead to increases in infection rates. To examine this, we performed a cross-sectional and longitudinal data analysis on SARS-CoV-2 infection, airborne pollen, and meteorological factors. Our dataset is the most comprehensive, largest possible worldwide from 130 stations, across 31 countries and five continents. To explicitly investigate the effects of social contact, we additionally considered population density of each study area, as well as lockdown effects, in all possible combinations: without any lockdown, with mixed lockdown-no lockdown regime, and under complete lockdown. We found that airborne pollen, sometimes in synergy with humidity and temperature, explained, on average, 44% of the infection rate variability. Infection rates increased after higher pollen concentrations most frequently during the four previous days. Without lockdown, an increase of pollen abundance by 100 pollen/m3 resulted in a 4% average increase of infection rates. Lockdown halved infection rates under similar pollen concentrations. As there can be no preventive measures against airborne pollen exposure, we suggest wide dissemination of pollen-virus coexposure dire effect information to encourage high-risk individuals to wear particle filter masks during high springtime pollen concentrations.


Assuntos
COVID-19/epidemiologia , Internacionalidade , Pólen/efeitos adversos , COVID-19/virologia , Geografia , Humanos , Estudos Longitudinais , SARS-CoV-2/fisiologia
8.
Allergy ; 76(6): 1718-1730, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33037672

RESUMO

BACKGROUND: Common ragweed has been spreading as a neophyte in Europe. Elevated CO2 levels, a hallmark of global climate change, have been shown to increase ragweed pollen production, but their effects on pollen allergenicity remain to be elucidated. METHODS: Ragweed was grown in climate-controlled chambers under normal (380 ppm, control) or elevated (700 ppm, based on RCP4.5 scenario) CO2 levels. Aqueous pollen extracts (RWE) from control- or CO2 -pollen were administered in vivo in a mouse model for allergic disease (daily for 3-11 days, n = 5) and employed in human in vitro systems of nasal epithelial cells (HNECs), monocyte-derived dendritic cells (DCs), and HNEC-DC co-cultures. Additionally, adjuvant factors and metabolites in control- and CO2 -RWE were investigated using ELISA and untargeted metabolomics. RESULTS: In vivo, CO2 -RWE induced stronger allergic lung inflammation compared to control-RWE, as indicated by lung inflammatory cell infiltrate and mediators, mucus hypersecretion, and serum total IgE. In vitro, HNECs stimulated with RWE increased indistinctively the production of pro-inflammatory cytokines (IL-8, IL-1ß, and IL-6). In contrast, supernatants from CO2 -RWE-stimulated HNECs, compared to control-RWE-stimulated HNECS, significantly increased TNF and decreased IL-10 production in DCs. Comparable results were obtained by stimulating DCs directly with RWEs. The metabolome analysis revealed differential expression of secondary plant metabolites in control- vs CO2 -RWE. Mixes of these metabolites elicited similar responses in DCs as compared to respective RWEs. CONCLUSION: Our results indicate that elevated ambient CO2 levels elicit a stronger RWE-induced allergic response in vivo and in vitro and that RWE increased allergenicity depends on the interplay of multiple metabolites.


Assuntos
Ambrosia , Dióxido de Carbono , Alérgenos , Europa (Continente) , Pólen
10.
Front Allergy ; 2: 680937, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35386993

RESUMO

Seasonal exposure to birch pollen (BP) is a major cause of pollinosis. The specific role of Toll-like receptor 4 (TLR4) in BP-induced allergic inflammation and the identification of key factors in birch pollen extracts (BPE) initiating this process remain to be explored. This study aimed to examine (i) the importance of TLR4 for dendritic cell (DC) activation by BPE, (ii) the extent of the contribution of BPE-derived lipopolysaccharide (LPS) and other potential TLR4 adjuvant(s) in BPE, and (iii) the relevance of the TLR4-dependent activation of BPE-stimulated DCs in the initiation of an adaptive immune response. In vitro, activation of murine bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs by BPE or the equivalent LPS (nLPS) was analyzed by flow cytometry. Polymyxin B (PMB), a TLR4 antagonist and TLR4-deficient BMDCs were used to investigate the TLR4 signaling in DC activation. The immunostimulatory activity of BPE was compared to protein-/lipid-depleted BPE-fractions. In co-cultures of BPE-pulsed BMDCs and Bet v 1-specific hybridoma T cells, the influence of the TLR4-dependent DC activation on T cell activation was analyzed. In vivo immunization of IL-4 reporter mice was conducted to study BPE-induced Th2 polarization upon PMB pre-treatment. Murine and human DC activation induced by either BPE or nLPS was inhibited by the TLR4 antagonist or by PMB, and abrogated in TLR4-deficient BMDCs compared to wild-type BMDCs. The lipid-free but not the protein-free fraction showed a reduced capacity to activate the TLR4 signaling and murine DCs. In human DCs, nLPS only partially reproduced the BPE-induced activation intensity. BPE-primed BMDCs efficiently stimulated T cell activation, which was repressed by the TLR4 antagonist or PMB, and the addition of nLPS to Bet v 1 did not reproduce the effect of BPE. In vivo, immunization with BPE induced a significant Th2 polarization, whereas administration of BPE pre-incubated with PMB showed a decreased tendency. These findings suggest that TLR4 is a major pathway by which BPE triggers DC activation that is involved in the initiation of adaptive immune responses. Further characterization of these BP-derived TLR4 adjuvants could provide new candidates for therapeutic strategies targeting specific mechanisms in BP-induced allergic inflammation.

11.
Clin Transl Allergy ; 10: 36, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884636

RESUMO

The mechanisms involved in the induction of allergic sensitization by pollen are not fully understood. Within the last few decades, findings from epidemiological and experimental studies support the notion that allergic sensitization is not only dependent on the genetics of the host and environmental factors, but also on intrinsic features of the allergenic source itself. In this review, we summarize the current concepts and newest advances in research focusing on the initial mechanisms inducing pollen sensitization. Pollen allergens are embedded in a complex and heterogeneous matrix composed of a myriad of bioactive molecules that are co-delivered during the allergic sensitization. Surprisingly, several purified allergens were shown to lack inherent sensitizing potential. Thus, growing evidence supports an essential role of pollen-derived components co-delivered with the allergens in the initiation of allergic sensitization. The pollen matrix, which is composed by intrinsic molecules (e.g. proteins, metabolites, lipids, carbohydrates) and extrinsic compounds (e.g. viruses, particles from air pollutants, pollen-linked microbiome), provide a specific context for the allergen and has been proposed as a determinant of Th2 polarization. In addition, the involvement of various pattern recognition receptors (PRRs), secreted alarmins, innate immune cells, and the dependency of DCs in driving pollen-induced Th2 inflammatory processes suggest that allergic sensitization to pollen most likely results from particular combinations of pollen-specific signals rather than from a common determinant of allergenicity. The exact identification and characterization of such pollen-derived Th2-polarizing molecules should provide mechanistic insights into Th2 polarization and pave the way for novel preventive and therapeutic strategies against pollen allergies.

12.
J Allergy Clin Immunol ; 146(3): 583-594.e6, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32272131

RESUMO

BACKGROUND: Pollen exposure induces local and systemic allergic immune responses in sensitized individuals, but nonsensitized individuals also are exposed to pollen. The kinetics of symptom expression under natural pollen exposure have never been systematically studied, especially in subjects without allergy. OBJECTIVE: We monitored the humoral immune response under natural pollen exposure to potentially uncover nasal biomarkers for in-season symptom severity and identify protective factors. METHODS: We compared humoral immune response kinetics in a panel study of subjects with seasonal allergic rhinitis (SAR) and subjects without allergy and tested for cross-sectional and interseasonal differences in levels of serum and nasal, total, and Betula verrucosa 1-specific immunoglobulin isotypes; immunoglobulin free light chains; cytokines; and chemokines. Nonsupervised principal component analysis was performed for all nasal immune variables, and single immune variables were correlated with in-season symptom severity by Spearman test. RESULTS: Symptoms followed airborne pollen concentrations in subjects with SAR, with a time lag between 0 and 13 days depending on the pollen type. Of the 7 subjects with nonallergy, 4 also exhibited in-season symptoms whereas 3 did not. Cumulative symptoms in those without allergy were lower than in those with SAR but followed the pollen exposure with similar kinetics. Nasal eotaxin-2, CCL22/MDC, and monocyte chemoattactant protein-1 (MCP-1) levels were higher in subjects with SAR, whereas IL-8 levels were higher in subjects without allergy. Principal component analysis and Spearman correlations identified nasal levels of IL-8, IL-33, and Betula verrucosa 1-specific IgG4 (sIgG4) and Betula verrucosa 1-specific IgE (sIgE) antibodies as predictive for seasonal symptom severity. CONCLUSIONS: Nasal pollen-specific IgA and IgG isotypes are potentially protective within the humoral compartment. Nasal levels of IL-8, IL-33, sIgG4 and sIgE could be predictive biomarkers for pollen-specific symptom expression, irrespective of atopy.


Assuntos
Alérgenos/imunologia , Antígenos de Plantas/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Adulto , Biomarcadores , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interleucina-33/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/imunologia , Rinite Alérgica Sazonal/sangue , Estações do Ano , Adulto Jovem
13.
World Allergy Organ J ; 13(3): 100109, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32180893

RESUMO

The epithelial cell-derived cytokine milieu has been discussed as a "master switch" in the development of allergic disease. To understand the role of innate immune response in nasal epithelial cells during allergic inflammation, we created and established a fast and minimally invasive method to isolate and culture human nasal epithelial cells from clinically and immunologically well characterized patients. Human nasal epithelial cells from non-atopic volunteers and from allergic rhinitis patients were compared in respect to their growth, barrier integrity, pattern recognition, receptor expression, and immune responses to allergens and an array of pathogen-associated molecular patterns and inflammasome activators. Cells from nasal scrapings were clearly identified as nasal epithelial cells by staining of pan-Cytokeratin, Cytokeratin-14 and Tubulin. Additionally, Mucin 5AC staining revealed the presence of goblet cells, while staining of tight-junction protein Claudin-1, Occludin and ZO-1 showed the ability of the cells to form a tight barrier. Cells of atopic donors grew slower than cells of non-atopic donors. All nasal epithelial cells expressed TLR1-6 and 9, yet the expression of TLR-9 was lower in cells from allergic rhinitis (AR) donors. Additionally, epithelial cells from AR donors responded with a different TLR expression pattern to stimulation with TLR ligands. TLR-3 was the most potent modulator of cytokine and chemokine secretion in all human nasal epithelial cells (HNECs). The secretion of IL-1ß, CCL-5, IL-8, IL-18 and IL-33 was elevated in HNECs of AR donors as compared to cells of non-atopic donors. This was observed in the steady-state (IL-18, IL-33) as well as under stimulation with TLR ligands (IL-18, IL-33, CCL-5, IL-8), aqueous pollen extracts (IL-18, IL-33), or the inflammasome activator Nigericin (IL-1ß). In conclusion, nasal epithelial cells of AR donors show altered physical barrier responses in steady-state and in response to allergen stimulation. Cells of AR donors show increased expression of pro-inflammatory and IL-1 family cytokines at baseline and under stimulation, which could contribute to a micromilieu which is favorable for Th2.

15.
Allergy ; 75(3): 576-587, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31512243

RESUMO

BACKGROUND: Hundreds of plant species release their pollen into the air every year during early spring. During that period, pollen allergic as well as non-allergic patients frequently present to doctors with severe respiratory tract infections. Our objective was therefore to assess whether pollen may interfere with antiviral immunity. METHODS: We combined data from real-life human exposure cohorts, a mouse model and human cell culture to test our hypothesis. RESULTS: Pollen significantly diminished interferon-λ and pro-inflammatory chemokine responses of airway epithelia to rhinovirus and viral mimics and decreased nuclear translocation of interferon regulatory factors. In mice infected with respiratory syncytial virus, co-exposure to pollen caused attenuated antiviral gene expression and increased pulmonary viral titers. In non-allergic human volunteers, nasal symptoms were positively correlated with airborne birch pollen abundance, and nasal birch pollen challenge led to downregulation of type I and -III interferons in nasal mucosa. In a large patient cohort, numbers of rhinoviruspositive cases were correlated with airborne birch pollen concentrations. CONCLUSION: The ability of pollen to suppress innate antiviral immunity, independent of allergy, suggests that high-risk population groups should avoid extensive outdoor activities when pollen and respiratory virus seasons coincide.


Assuntos
Imunidade Inata , Pólen/efeitos adversos , Vírus Sinciciais Respiratórios , Rhinovirus , Animais , Humanos , Interferons , Camundongos , Mucosa Nasal
16.
Allergy ; 74(12): 2382-2393, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31230350

RESUMO

BACKGROUND: Over 100 million people worldwide suffer from birch pollen allergy. Bet v 1 has been identified as the major birch pollen allergen. However, the molecular mechanisms of birch allergic sensitization, including the roles of Bet v 1 and other components of the birch pollen extract, remain incompletely understood. Here, we examined how known birch pollen-derived molecules influence the endolysosomal processing of Bet v 1, thereby shaping its allergenicity. METHODS: We analyzed the biochemical and immunological interaction of ligands with Bet v 1. We then investigated the proteolytic processing of Bet v 1 by endosomal extracts in the presence and absence of ligands, followed by a detailed kinetic analysis of Bet v 1 processing by individual endolysosomal proteases as well as the T-cell epitope presentation in BMDCs. RESULTS: We identified E1 phytoprostanes as novel Bet v 1 ligands. Pollen-derived ligands enhanced the proteolytic resistance of Bet v 1, affecting degradation kinetics and preferential cleavage sites of the endolysosomal proteases cathepsin S and legumain. E1 phytoprostanes exhibited a dual role by stabilizing Bet v 1 and inhibiting cathepsin protease activity. CONCLUSION: Bet v 1 can serve as a transporter of pollen-derived, bioactive compounds. When carried to the endolysosome, such compounds can modulate the proteolytic activity, including its processing by cysteine cathepsins. We unveil a paradigm shift from an allergen-centered view to a more systemic view that includes the host endolysosomal enzymes.


Assuntos
Alérgenos/imunologia , Antígenos de Plantas/imunologia , Endossomos/enzimologia , Peptídeo Hidrolases/metabolismo , Basófilos/imunologia , Basófilos/metabolismo , Betula/imunologia , Degranulação Celular/imunologia , Ativação Enzimática , Humanos , Imunoglobulina E/imunologia , Ligantes , Pólen/imunologia , Ligação Proteica , Proteínas Recombinantes
17.
Sci Total Environ ; 653: 190-199, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30408667

RESUMO

Pollen exposure is a major cause of respiratory allergies worldwide. However, it is unclear how everyday exposure is related to symptoms and how allergic patients may be affected spatially and temporally. Hence, we investigated the relationship of pollen, symptoms and immune responses under a controlled regime of 'high-low-moderate' pollen exposure in urban versus alpine environment. The research was conducted in 2016 in two locations in Germany: urban Augsburg (494 m) and Schneefernerhaus (UFS) on Zugspitze mountain (2656 m). Monitoring of airborne pollen took place using Hirst-type volumetric traps. On UFS, both indoor and outdoor samples were taken. Grass pollen allergic human volunteers were monitored daily during the peak of the grass pollen season, in Augsburg, on UFS, then again in Augsburg. Nasal biosamples were obtained throughout the study to investigate immune responses. All symptoms decreased significantly during the stay on UFS and remained low even after the return to Augsburg. The same was observed for nasal total IgE and IgM levels and for nasal type 2 cytokines and chemokines. Augsburg showed higher pollen concentrations than those on UFS. At all sites, pollen were present throughout each day, but were more abundant in Augsburg during morning. On UFS, outdoor pollen levels were up to 6-fold higher than those indoors. Nasal, ocular and pulmonary symptoms correlated with current and previous days' pollen concentrations and relative humidity. Stays in low-exposure environments during the peak pollen season can be an efficient means of reducing allergic symptoms and immune responses. However, in alpine environments, even occasional pollen exposure during short intervals may still trigger symptoms because of the additional environmental stress posed onto allergics. This highlights the need for the consideration of additional environmental factors, apart from symptom diaries and immune responses, so as to efficiently predict high-risk allergy periods.


Assuntos
Alérgenos/imunologia , Exposição Ambiental , Hipersensibilidade/imunologia , Poaceae , Pólen/imunologia , Adulto , Idoso , Feminino , Alemanha , Humanos , Hipersensibilidade/etiologia , Masculino , Pessoa de Meia-Idade , Poaceae/efeitos adversos , Estações do Ano , Adulto Jovem
18.
Exp Dermatol ; 27(11): 1193-1200, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30099779

RESUMO

Allergies are usually referred to as type I hypersensitivity reactions against innocuous environmental antigens, characterized by a Th2/IgE-dominated inflammation. They can manifest themselves in various organs, such as skin, gastrointestinal and respiratory tract, and comprise diseases as diverse as allergic rhinitis and conjunctivitis, bronchial asthma, oral allergy syndrome, food allergy, urticaria and atopic eczema, but also anaphylactic shock. Within the last decades, there was a significant global increase in allergy prevalence, which has been mostly attributed to changes in environment and lifestyle. But which, among all factors discussed, are the most relevant, and what are the mechanisms by which these factors promote or prevent the development of allergic diseases? To answer this, it is necessary to go back to the two key questions that have occupied allergy researchers for the last decades: Firstly, what makes an allergen an allergen? Secondly, why are more and more individuals affected? Within the last decade, we have made considerable progress in answering these questions. This review gives an overview over scientific progress in the field, summarizes latest findings and points out future prospective and research needs.


Assuntos
Poluentes Atmosféricos/imunologia , Meio Ambiente , Hipersensibilidade/imunologia , Estresse Fisiológico/imunologia , Dermatite Atópica , Poeira/imunologia , Humanos , Hipersensibilidade/genética , Imunidade Inata , Pólen/imunologia
20.
Biofactors ; 43(3): 388-399, 2017 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-28139053

RESUMO

Ze339, an herbal extract from Petasites hybridus leaves is effective in treatment of allergic rhinitis by inhibition of a local production of IL-8 and eicosanoid LTB4 in allergen-challenged patients. However, the mechanism of action and anti-inflammatory potential in virally induced exacerbation of the upper airways is unknown. This study investigates the anti-inflammatory mechanisms of Ze339 on primary human nasal epithelial cells (HNECs) upon viral, bacterial and pro-inflammatory triggers. To investigate the influence of viral and bacterial infections on the airways, HNECs were stimulated with viral mimics, bacterial toll-like-receptor (TLR)-ligands or cytokines, in presence or absence of Ze339. The study uncovers Ze339 modulated changes in pro-inflammatory mediators and decreased neutrophil chemotaxis as well as a reduction of the nuclear translocation and phosphorylation of STAT molecules. Taken together, this study suggests that phyto drug Ze339 specifically targets STAT-signalling pathways in HNECs and has high potential as a broad anti-inflammatory drug that exceeds current indication. © 2016 BioFactors, 43(3):388-399, 2017.


Assuntos
Células Epiteliais/efeitos dos fármacos , Petasites/química , Extratos Vegetais/farmacologia , Fatores de Transcrição STAT/antagonistas & inibidores , Sesquiterpenos/farmacologia , Movimento Celular/efeitos dos fármacos , Quimiocinas/antagonistas & inibidores , Quimiocinas/biossíntese , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Flagelina/antagonistas & inibidores , Flagelina/farmacologia , Regulação da Expressão Gênica , Humanos , Interferon gama/antagonistas & inibidores , Interferon gama/farmacologia , Interleucina-4/antagonistas & inibidores , Interleucina-4/farmacologia , Lipopeptídeos/antagonistas & inibidores , Lipopeptídeos/farmacologia , Cavidade Nasal/citologia , Cavidade Nasal/efeitos dos fármacos , Cavidade Nasal/metabolismo , Neutrófilos/efeitos dos fármacos , Folhas de Planta/química , Poli I-C/antagonistas & inibidores , Poli I-C/farmacologia , Cultura Primária de Células , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
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