Bet v 1 and other birch allergens are more resistant to proteolysis and more abundant than other birch pollen proteins.
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ABSTRACT:
SUBMITTER: Cabrera A
PROVIDER: S-EPMC9132243 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
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Bet v 1 and other birch allergens are more resistant to proteolysis and more abundant than other birch pollen proteins.
Cabrera Aurora A Foo Alexander C Y ACY Fitzgerald Michael C MC Mueller Geoffrey A GA
Allergy 20220112 4
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Project description: Not available
| S-EPMC7237293 | biostudies-literature
Project description:Protein modifications such as oligomerization and tyrosine nitration alter the immune response to allergens and may contribute to the increasing prevalence of allergic diseases. In this mini-review, we summarize and discuss relevant findings for the major birch and grass pollen allergens Bet v 1 and Phl p 5 modified with tetranitromethane (laboratory studies), peroxynitrite (physiological processes), and ozone and nitrogen dioxide (environmental conditions). We focus on tyrosine nitration and the formation of protein dimers and higher oligomers via dityrosine cross-linking and the immunological effects studied.
| S-EPMC10732249 | biostudies-literature
Project description:Dendritic cells play a fundamental role in shaping the immune response to allergens. The events that lead to allergic sensitization or tolerance induction during the interaction of the major birch pollen allergen Bet v 1 and dendritic cells are not very well studied. Here, we analyzed the uptake of Bet v 1 and the cross-reactive celery allergen Api g 1 by immature monocyte-derived dendritic cells (iMoDCs) of allergic and normal donors. In addition, we characterized the allergen-triggered intracellular signaling and transcriptional events. Uptake kinetics, competitive binding, and internalization pathways of labeled allergens by iMoDCs were visualized by live-cell imaging. Surface-bound IgE was detected by immunofluorescence microscopy and flow cytometry. Allergen- and IgE-induced gene expression of early growth response genes and Th1 and Th2 related cytokines and chemokines were analyzed by real-time PCR. Phosporylation of signaling kinases was analyzed by Western blot. Internalization of Bet v 1 by iMoDCs of both donor groups, likely by receptor-mediated caveolar endocytosis, followed similar kinetics. Bet v 1 outcompeted Api g 1 in cell surface binding and uptake. MoDCs of allergic and healthy donors displayed surface-bound IgE and showed a pronounced upregulation of Th2 cytokine- and NFκB-dependent genes upon non-specific Fcε receptor cross-linking. In contrast to these IgE-mediated responses, Bet v 1-stimulation increased transcript levels of the Th2 cytokines IL-4 and IL-13 but not of NFκB-related genes in MoDCs of BP allergic donors. Cells of healthy donors were either unresponsive or showed elevated mRNA levels of Th1-promoting chemokines. Moreover, Bet v 1 was able to induce Erk1/2 and p38 MAPK activation in BP allergics but only a slight p38 activation in normal donors. In conclusion, our data indicate that Bet v 1 favors the activation of a Th2 program only in DCs of BP allergic individuals.
| S-EPMC4311984 | biostudies-literature
Project description:BackgroundIn allergic patients, clinical symptoms caused by pollen remind of symptoms triggered by viral respiratory infections, which are also the main cause of asthmatic exacerbations. In patients sensitized to birch pollen, Bet v 1 is the major symptom-causing allergen. Immune mechanisms driving Bet v 1-related responses of human blood cells have not been fully characterized.ObjectiveTo characterize the immune response to Bet v 1 in peripheral blood in patients allergic to birch pollen.MethodsThe peripheral blood mononuclear cells of birch-allergic (n = 24) and non-allergic (n = 47) adolescents were stimulated ex-vivo followed by transcriptomic profiling. Systems-biology approaches were employed to decipher disease-relevant gene networks and deconvolution of associated cell populations.ResultsSolely in birch-allergic patients, co-expression analysis revealed activation of networks of innate immunity and antiviral signalling as the immediate response to Bet v 1 stimulation. Toll-like receptors and signal transducer transcription were the main drivers of gene expression patterns. Macrophages and dendritic cells were the main cell subsets responding to Bet v 1.Conclusions and clinical relevanceIn birch-pollen-allergic patients, the activated innate immune networks seem to be, in part, the same as those activated during viral infections. This tendency of the immune system to read pollens as viruses may provide new insight to allergy prevention and treatment.
| S-EPMC9540660 | biostudies-literature
Project description:The term allergy was coined in 1906 by the Austrian scientist and pediatrician Clemens Freiherr von Pirquet. In 1976, Dietrich Kraft became the head of the Allergy and Immunology Research Group at the Department of General and Experimental Pathology of the University of Vienna. In 1983, Kraft proposed to replace natural extracts used in allergy diagnostic tests and vaccines with recombinant allergen molecules and persuaded Michael Breitenbach to contribute his expertise in molecular cloning as one of the mentors of this project. Thus, the foundation for the Vienna School of Molecular Allergology was laid. With the recruitment of Heimo Breiteneder as a young molecular biology researcher, the work began in earnest, resulting in the publication of the cloning of the first plant allergen Bet v 1 in 1989. Bet v 1 has become the subject of a very large number of basic scientific as well as clinical studies. Bet v 1 is also the founding member of the large Bet v 1-like superfamily of proteins with members-based on the ancient conserved Bet v 1 fold-being present in all three domains of life, i.e., archaea, bacteria and eukaryotes. This suggests that the Bet v 1 fold most likely already existed in the last universal common ancestor. The biological function of this protein was probably related to lipid binding. However, during evolution, a functional diversity within the Bet v 1-like superfamily was established. The superfamily comprises 25 families, one of which is the Bet v 1 family, which in turn is composed of 11 subfamilies. One of these, the PR-10-like subfamily of proteins, contains almost all of the Bet v 1 homologous allergens from pollen and plant foods. Structural and functional comparisons of Bet v 1 and its non-allergenic homologs of the superfamily will pave the way for a deeper understanding of the allergic sensitization process.
| S-EPMC10377203 | biostudies-literature
Project description:Proteolytic susceptibility during endolysosomal degradation is decisive for allergic sensitization. In the major birch pollen allergen Bet v 1 most protease cleavage sites are located within its secondary structure elements, which are inherently inaccessible to proteases. The allergen thus must unfold locally, exposing the cleavage sites to become susceptible to proteolysis. Hence, allergen cleavage rates are presumed to be linked to their fold stability, i.e., unfolding probability. Yet, these locally unfolded structures have neither been captured in experiment nor simulation due to limitations in resolution and sampling time, respectively. Here, we perform classic and enhanced molecular dynamics (MD) simulations to quantify fold dynamics on extended timescales of Bet v 1a and two variants with higher and lower cleavage rates. Already at the nanosecond-timescale we observe a significantly higher flexibility for the destabilized variant compared to Bet v 1a and the proteolytically stabilized mutant. Estimating the thermodynamics and kinetics of local unfolding around an initial cleavage site, we find that the Bet v 1 variant with the highest cleavage rate also shows the highest probability for local unfolding. For the stabilized mutant on the other hand we only find minimal unfolding probability. These results strengthen the link between the conformational dynamics of allergen proteins and their stability during endolysosomal degradation. The presented approach further allows atomistic insights in the conformational ensemble of allergen proteins and provides probability estimates below experimental detection limits.
| S-EPMC7045072 | biostudies-literature
Project description:Each spring millions of patients suffer from allergies when birch pollen is released into the air. In most cases, the major pollen allergen Bet v 1 is the elicitor of the allergy symptoms. Bet v 1 comes in a variety of isoforms that share virtually identical conformations, but their relative concentrations are plant-specific. Glycosylated flavonoids, such as quercetin-3-O-sophoroside, are the physiological ligands of Bet v 1, and here we found that three isoforms differing in their allergenic potential also show an individual, highly specific binding behaviour for the different ligands. This specificity is driven by the sugar moieties of the ligands rather than the flavonols. While the influence of the ligands on the allergenicity of the Bet v 1 isoforms may be limited, the isoform and ligand mixtures add up to a complex and thus individual fingerprint of the pollen. We suggest that this mixture is not only acting as an effective chemical sunscreen for pollen DNA, but may also play an important role in recognition processes during pollination.
| S-EPMC4456386 | biostudies-literature
Project description:Many allergens share several biophysical characteristics, including the capability to undergo oligomerization. The dimerization mechanism in Bet v 1 and its allergenic properties are so far poorly understood. Here, we report crystal structures of dimeric Bet v 1, revealing a noncanonical incorporation of cysteine at position 5 instead of genetically encoded tyrosine. Cysteine polysulfide bridging stabilized different dimeric assemblies, depending on the polysulfide linker length. These dimers represent quaternary arrangements that are frequently observed in related proteins, reflecting their prevalence in unmodified Bet v 1. These conclusions were corroborated by characteristic immunologic properties of monomeric and dimeric allergen variants. Hereby, residue 5 could be identified as an allergenic hot spot in Bet v 1. The presented results refine fundamental principles in protein chemistry and emphasize the importance of protein modifications in understanding the molecular basis of allergenicity.
| S-EPMC3879576 | biostudies-literature
Project description:BackgroundIn the temperate climate zone of the Northern hemisphere, Fagales pollen allergy represents the main cause of winter/spring pollinosis. Among Fagales trees, pollen allergies are strongly associated within the Betulaceae and the Fagaceae families. It is widely accepted that Fagales pollen allergies are initiated by sensitization against Bet v 1, the birch pollen major allergen, although evidence is accumulating that the allergenic activity of some Bet v 1-like molecules has been underestimated.ObjectiveTo investigate the allergenic potential of the clinically most important Fagales pollen allergens from birch, alder, hazel, hornbeam, hop-hornbeam, oak, beech and chestnut.MethodsTo obtain the full spectrum of allergens, the three previously unavailable members of the Bet v 1-family, hop-hornbeam Ost c 1, chestnut Cas s 1 and beech Fag s 1, were identified in the respective pollen extracts, cloned and produced as recombinant proteins in E. coli. Together with recombinant Bet v 1, Aln g 1, Car b 1, Cor a 1 and Que a 1, the molecules were characterized physicochemically, mediator release assays were performed and IgE cross-reactivity was evaluated by ELISA and Immuno Solid-phase Allergen Chip (ISAC) IgE inhibition assays.ResultsAll allergens showed the typical Bet v 1-like secondary structure elements, and they were all able to bind serum IgE from Fagales allergic donors. Strong IgE binding was observed for Betuloideae and Coryloideae allergens, however, cross-reactivity between the two subfamilies was limited as explored by inhibition experiments. In contrast, IgE binding to members of the Fagaceae could be strongly inhibited by serum pre-incubation with allergens of the Betuloideae subfamily.Conclusions and clinical relevanceThe data suggest that Bet v 1-like allergens of the Betuloideae and Coryloideae subfamily might have the potential to induce IgE antibodies with different specificities, while allergic reactions towards Fagaceae allergens are the result of IgE cross-reactivity.
| S-EPMC5689382 | biostudies-literature
Project description:IgE-mediated allergy to birch pollen affects more than 100 million patients world-wide. Bet v 1, a 17 kDa protein is the major allergen in birch pollen responsible for allergic rhinoconjunctivitis and asthma in birch pollen allergic patients. Allergen-specific immunotherapy (AIT) based on therapeutic administration of Bet v 1-containing vaccines is an effective treatment for birch pollen allergy but no allergen-specific forms of prevention are available. We developed a mouse model for IgE sensitization to Bet v 1 based on subcutaneous injection of aluminum-hydroxide adsorbed recombinant Bet v 1 and performed a detailed characterization of the specificities of the IgE, IgG and CD4+ T cell responses in sensitized mice using seven synthetic peptides of 31-42 amino acids length which comprised the Bet v 1 sequence and the epitopes recognized by human CD4+ T cells. We then demonstrate that preventive systemic administration of a mix of synthetic non-allergenic Bet v 1 peptides to 3-4 week old mice significantly reduced allergic immune responses, including IgE, IgG, IgE-mediated basophil activation, CD4+ T cell and IL-4 responses to the complete Bet v 1 allergen but not to the unrelated major grass pollen allergen Phl p 5, without inducing Bet v 1-specific allergic sensitization or adaptive immunity. Our results thus demonstrate that early preventive administration of non-allergenic synthetic T cell epitope-containing allergen peptides could be a safe strategy for the prevention of allergen-specific IgE sensitization.
| S-EPMC8594376 | biostudies-literature