Dataset Information

Computationally grafting an IgE epitope onto a scaffold: Implications for a pan anti-allergy vaccine design.

ABSTRACT: Allergy is becoming an intensifying disease among the world population, particularly in the developed world. Once allergy develops, sufferers are permanently trapped in a hyper-immune response that makes them sensitive to innocuous substances. The immune pathway concerned with developing allergy is the Th₂ immune pathway where the IgE antibody binds to its Fc ∊ RI receptor on Mast and Basophil cells. This paper discusses a protocol that could disrupt the binding between the antibody and its receptor for a potential permanent treatment. Ten proteins were computationally designed to display a human IgE motif very close in proximity to the IgE antibody's Fc ∊ RI receptor's binding site in an effort for these proteins to be used as a vaccine against our own IgE antibody. The motif of interest was the FG loop motif and it was excised and grafted onto a Staphylococcus aureus protein (PDB ID 1YN3), then the motif + scaffold structure had its sequence re-designed around the motif to find an amino acid sequence that would fold to the designed structure correctly. These ten computationally designed proteins showed successful folding when simulated using Rosetta's AbinitioRelax folding simulation and the IgE epitope was clearly displayed in its native three-dimensional structure in all of them. These designed proteins have the potential to be used as a pan anti-allergy vaccine. This work employedin silicobased methods for designing the proteins and did not include any experimental verifications.

SUBMITTER: Sabban SS

PROVIDER: S-EPMC8403545 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundThe distribution of Pooideae species varies across Europe. Especially, Timothy is less represented in Southern than in Northern Europe. Since allergenic cross-reactivity between pollens from different grasses is only partial, grass pollen-allergic patients are expected to display different sensitization profiles, with specific IgE directed against different combinations of allergenic epitopes, depending on their living places in Europe and the grasses they are exposed to. In this context, this study aimed at comparing two tablets commercially available for allergy immunotherapy, namely a 5-grass (Cocksfoot, Meadow-grass, Rye-grass, Sweet vernal-grass and Timothy) and a 1-grass (Timothy) pollen tablets, for their ability to represent the sensitization profiles of patients, depending on whether they live in Southern or Northern Europe.MethodsSera were collected from adult patients living in Spain (n?=?19) and Sweden (n?=?22). Tablets were compared for their ability to inhibit the binding of patient serum IgE to pollen allergens from twelve grasses commonly distributed throughout Europe, as determined by the areas under the curves obtained by ELISA-inhibition. Tablets were adjusted to an equivalent allergenic activity, based on the CBER/FDA bioequivalent allergy unit.ResultsInhibition of the IgE binding to pollen allergens from twelve grasses was significantly stronger with the 5-grass than with the 1-grass pollen tablet (p?<?0.0001), regardless of whether patients were considered as a whole or by geographical area. This difference between tablets was significantly greater for Southern than Northern European patients (p?<?0.05).ConclusionsCompared to the 1-grass tablet, the 5-grass tablet generally covers better the sensitization profiles of European patients, especially patients from Southern Europe, in principle less exposed to pollen from Timothy than from other grasses. The 5-grass tablet is therefore expected to elicit larger spectra of blocking antibodies, which might have implications in light of the generally accepted mechanisms of allergy immunotherapy.

Project description:Background: Although adverse food reactions are commonly divided into immunoglobulin E (IgE) mediated food allergy (FA), and non-IgE FA, the current literature is providing support for the role of innate immune responses as an important component of non-IgE FA. Using a commercially available leukocyte activation (LA) assay, a recent quantitative study of total extracellular DNA released in cellular supernatants of human peripheral blood mononuclear cells exposed either to positive or negative tested foods demonstrated that leukocytes exposed to foods with positive LA test results showed higher DNA content than those exposed to foods with negative LA test results. In humans, the origin of DNA might be either the nucleus or the mitochondria. Analysis of emerging data from several laboratories, including our own, suggests that mitochondrial DNA induces inflammatory responses through induction of proinflammatory cytokines. Objective: This pilot study was designed primarily to convey the finding, and relevance of, mitochondrial DNA in the form of neutrophil extracellular traps (NET) as a new pathogenetic mechanism for innate immune-mediated non-IgE FA. Methods: The study population consisted of a total of six subjects, four in a major FA study group and two in a subgroup. Neutrophils were isolated and treated with food antigens that elicited positive and negative LA responses, and the released free DNA was analyzed for the cellular site of origin by using real-time polymerase chain reaction and for leukocyte calprotectin and S100 calcium-binding protein A12 (S100A12) proteins as markers of NETs. Results: We showed that cellular supernatants from neutrophils treated with foods that elicit positive LA responses can contain increased DNA levels of nuclear as well as mitochondrial origin. Supernatants from neutrophils treated with negative tested food (LA) responses did not induce the release of nuclear or mitochondrial DNA. Conclusion: Analysis of our data suggested that the induction of NETs that contain proinflammatory mitochondrial DNA may provide the critical link necessary for a better understanding of the pathogenesis of non-IgE-mediated FA. These discoveries may not only facilitate better diagnostic tests of FA but should also improve clinical management of allergic and other inflammatory diseases.

Dataset Information

Computationally grafting an IgE epitope onto a scaffold: Implications for a pan anti-allergy vaccine design.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets