Allergens and their associated small molecule ligands—their dual role in sensitization

Chruszcz, M.; Chew, Fook Tim; Hoffmann‐Sommergruber, Karin; Hurlburt, Barry K.; Mueller, Geoffrey A.; Pomés, Anna; Rouvinen, Juha; Villalba, Mayte; Wöhrl, Birgitta M.; Breiteneder, Heimo

doi:10.1111/all.14861

Cited by 48 publications

(51 citation statements)

References 193 publications

(496 reference statements)

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“…In fact, the nsLTP fold enables the formation of a hydrophobic tunnel-like cavity where hydrophobic ligands with different sizes can be accommodated (31,37). Similar to nsLTP, a GRP structure is predicted to form a cavity (12) where a ligand, such as biological lipids/membranes, can be bound (1).…”

Section: Discussionmentioning

confidence: 99%

“…nsLTP was described as the most frequent sensitizer in the Italian subjects with food-dependent exercise-induced anaphylaxis (FDEAIA) ( 35 ). It was reported that the allergenicity of nsLTP, as well as that of other allergens with the function of hydrophobic molecule carrier, could be influenced by the bound ligand which may act as an adjuvant and drives the immune system toward a type 2 (pro-allergenic) response ( 36 , 37 ). For instance, the interaction of Pru p 3 with selected fatty acids was described to increase its IgE binding capacity, whereas the binding of some other lipids did not have the same effect ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

“…Different hydrophobic molecules have been suggested to bind nsLTP from several sources ( 39 , 40 ). In fact, the nsLTP fold enables the formation of a hydrophobic tunnel-like cavity where hydrophobic ligands with different sizes can be accommodated ( 31 , 37 ).…”

Section: Discussionmentioning

confidence: 99%

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When the Frequencies of Sensitization and Elicitation of Allergic Reaction Do Not Correlate—The Case of Apple Gibberellin-Regulated Protein Tested in an Italian Population

Tuppo

Alessandri²,

Giangrieco

et al. 2021

Front. Allergy

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Background: The literature reports describing allergic symptoms against apples in the patients sensitized to the gibberellin-regulated proteins (GRPs) suggested the presence of an allergenic GRP in this fruit.Objective: This study aimed to assess the presence of a GRP protein in apples and investigate its allergenicity.Methods: The protein was isolated and identified by the classical biochemical methods. The bioinformatics tools were used for similar searches and molecular modeling. The immunological features were investigated using the multiplex FABER test. Clinical data were collected by the allergy specialists.Results: A GRP was detected in the apple peel and pulp and it was named applemaclein. This protein displays 94% of sequence identity with peamaclein, Pru p 7, representing the prototype of this allergen family. The applemaclein molecular model shows a very irregular surface with grooves/clefts that may potentially accommodate small molecular ligands. In a population of 4,721 patients in Italy, 187 (4.0%) were sensitized to any allergenic GPR. Of those, 115 (61.5%), 61 (32.6%), 30 (16.0%), and 99 (52.9%) had immunoglobulin E (IgE) to apple, peach, pomegranate, and cypress GRP, respectively. However, in a cohort of the patients in Italy, most individuals IgE positive to the apple GRP did not report allergic reactions against this fruit.Conclusion: Compared with the peach Pru p 7, applemaclein shows some different structural features and higher sensitization frequency, which is often not associated with allergic reactions against apple. Further studies are needed to understand a possible correlation between the applemaclein structural properties, the interaction with still unknown molecules, and immunological behavior.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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When the Frequencies of Sensitization and Elicitation of Allergic Reaction Do Not Correlate—The Case of Apple Gibberellin-Regulated Protein Tested in an Italian Population

Tuppo

Alessandri²,

Giangrieco

et al. 2021

Front. Allergy

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“…However, some exceptions have been reported, as is the case of wheat LTP, whose ligand binding properties enhanced its conformational flexibility resulting in increased susceptibility to gastroduodenal proteolysis (Abdullah et al, 2016 ). Moreover, ligand‐binding allergens expose the immune system to a variety of biologically active small molecules that could play important and still not well‐understood roles in the sensitisation process in addition to the allergenic protein itself (Chruszcz et al, 2021 ).…”

Section: Assessmentmentioning

confidence: 99%

Scientific Opinion on development needs for the allergenicity and protein safety assessment of food and feed products derived from biotechnology

Mullins¹,

Bresson²,

Dalmay³

et al. 2022

EFS2

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This Scientific Opinion addresses the formulation of specific development needs, including research requirements for allergenicity assessment and protein safety, in general, which is urgently needed in a world that demands more sustainable food systems. Current allergenicity risk assessment strategies are based on the principles and guidelines of the Codex Alimentarius for the safety assessment of foods derived from 'modern' biotechnology initially published in 2003. The core approach for the safety assessment is based on a 'weight-of-evidence' approach because no single piece of information or experimental method provides sufficient evidence to predict allergenicity. Although the Codex Alimentarius and EFSA guidance documents successfully addressed allergenicity assessments of single/ stacked event GM applications, experience gained and new developments in the field call for a modernisation of some key elements of the risk assessment. These should include the consideration of clinical relevance, route of exposure and potential threshold values of food allergens, the update of in silico tools used with more targeted databases and better integration and standardisation of test materials and in vitro/in vivo protocols. Furthermore, more complex future products will likely challenge the overall practical implementation of current guidelines, which were mainly targeted to assess a few newly expressed proteins. Therefore, it is timely to review and clarify the main purpose of the allergenicity risk assessment and the vital role it plays in protecting consumers' health. A roadmap to (re)define the allergenicity safety objectives and risk assessment needs will be required to inform a series of key questions for risk assessors and risk managers such as 'what is the purpose of the allergenicity risk assessment?' or 'what level of confidence is necessary for the predictions?'.

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“…Notably, the majority of studies for the time being has employed allergen extracts which are known to contain LPS and other contaminating material (220)(221)(222). In case of mite Der p 2, a non-lipocalin allergen, the proposed [and debated (223,224)] allergenic mechanism is though interesting because the allergen exhibits structural homology with MD-2, a LPS-binding component of the TLR4 signaling complex (221). Thereby, it was found to facilitate signaling through direct interactions with the complex (221).…”

Section: Receptors Of Innate Immunity Recognizing Lipocalin Allergensmentioning

confidence: 99%

Inhalant Mammal-Derived Lipocalin Allergens and the Innate Immunity

Virtanen

2022

Front. Allergy

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A major part of important mammalian respiratory allergens belongs to the lipocalin family of proteins. By this time, 19 respiratory mammalian lipocalin allergens have been registered in the WHO/IUIS Allergen Nomenclature Database. Originally, lipocalins, small extracellular proteins (molecular mass ca. 20 kDa), were characterized as transport proteins but they are currently known to exert a variety of biological functions. The three-dimensional structure of lipocalins is well-preserved, and lipocalin allergens can exhibit high amino acid identities, in several cases more than 50%. Lipocalins contain an internal ligand-binding site where they can harbor small principally hydrophobic molecules. Another characteristic feature is their capacity to bind to specific cell-surface receptors. In all, the physicochemical properties of lipocalin allergens do not offer any straightforward explanations for their allergenicity. Allergic sensitization begins at epithelial barriers where diverse insults through pattern recognition receptors awaken innate immunity. This front-line response is manifested by epithelial barrier-associated cytokines which together with other components of immunity can initiate the sensitization process. In the following, the crucial factor in allergic sensitization is interleukin (IL)-4 which is needed for stabilizing and promoting the type 2 immune response. The source for IL-4 has been searched widely. Candidates for it may be non-professional antigen-presenting cells, such as basophils or mast cells, as well as CD4+ T cells. The synthesis of IL-4 by CD4+ T cells requires T cell receptor engagement, i.e., the recognition of allergen peptides, which also provides the specificity for sensitization. Lipocalin and innate immunity-associated cell-surface receptors are implicated in facilitating the access of lipocalin allergens into the immune system. However, the significance of this for allergic sensitization is unclear, as the recognition by these receptors has been found to produce conflicting results. As to potential adjuvants associated with mammalian lipocalin allergens, the hydrophobic ligands transported by lipocalins have not been reported to enhance sensitization while it is justified to suppose that lipopolysaccharide plays a role in it. Taken together, type 2 immunity to lipocalin allergens appears to be a harmful immune response resulting from a combination of signals involving both the innate and adaptive immunities.

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Allergens and their associated small molecule ligands—their dual role in sensitization

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 48 publications

References 193 publications

When the Frequencies of Sensitization and Elicitation of Allergic Reaction Do Not Correlate—The Case of Apple Gibberellin-Regulated Protein Tested in an Italian Population

When the Frequencies of Sensitization and Elicitation of Allergic Reaction Do Not Correlate—The Case of Apple Gibberellin-Regulated Protein Tested in an Italian Population

Scientific Opinion on development needs for the allergenicity and protein safety assessment of food and feed products derived from biotechnology

Inhalant Mammal-Derived Lipocalin Allergens and the Innate Immunity

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