Endolysosomal protease susceptibility of Amb a 1 as a determinant of allergenicity

Wolf, Martin; Aglas, Lorenz; Twaroch, Teresa E; Steiner, Markus J.; Huber, Sara; Hauser, Michael; Hofer, Heidi; Parigiani, Maria Alejandra; Ebner, Christof; Bohle, Barbara; Briza, Peter; Neubauer, A.; Stolz, Frank; Wallner, Michael; Ferreira, Fátima

doi:10.1016/j.jaci.2017.10.027

Cited by 8 publications

(8 citation statements)

References 13 publications

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“…This feature may influence allergen processing and, in turn, determine allergenicity through increasing the intensity and polarization of TH2 responses. 6,7 Our results showed that the shortening of Blo t 5 led to a reduced susceptibility to endolysosomal proteolysis ( Figure 1E). We hypothesize that the absence of the disordered N-terminal region in rBlo t 5 short has reduced the flexibility of the molecule and, in association with the higher temporal folding capacity, the profile of endolysosomal degradation was then modified.…”

Section: N-terminal Peptide Deletion Influences Immunological and Strmentioning

confidence: 70%

N‐terminal peptide deletion influences immunological and structural features of Blo t 5

Silva

Huber

Alcantara-Neves

et al. 2020

Allergy

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LETTERS TO THE EDITOR in infrequent phenotypes such as isolated angioedema by SRs and multiple SRs, which may be misdiagnosed as CRs. This procedure is useful not only for reducing the number of patients who are unnecessarily avoiding NSAIDs but also for extending their therapeutic possibilities. Although such accurate diagnosis requires facilities and trained personal in this field, it will improve the allergological workup and, consequently, patients' management.

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Section: N-terminal Peptide Deletion Influences Immunological and Strmentioning

confidence: 70%

N‐terminal peptide deletion influences immunological and structural features of Blo t 5

Silva

Huber

Alcantara-Neves

et al. 2020

Allergy

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“…Thus, the allergenic potential of a protein often cannot be rationalized, nor predicted, based on sequence or structural similarity to known allergens (Lu et al, 2018). However, one decisive feature biasing the immunologic response to a protein antigen is its proteolytic susceptibility (Toda et al, 2011;Apostolovic et al, 2016;Machado et al, 2016;Scheiblhofer et al, 2017;Wolf et al, 2018). Hence, reliable experimental and computational models of proteolytic susceptibility in the endosome represent promising tools to understand, and possibly even predict, what makes a protein an allergen.…”

Section: Introductionmentioning

confidence: 99%

“…The recognition of this MHC2-peptide complex by Thelper cells then determines the subsequent immune response (Watts, 2004;Valenta et al, 2010). Thus, proteolytic cleavage of the exogenous antigen is a crucial step in this mechanism and is discussed as the origin of the varying allergenic potential of the studied Bet v 1 variants (Thai et al, 2004;Machado et al, 2016;Wolf et al, 2018). Only antigens with an "optimal" stability are able to induce an allergic response on T-cell level.…”

Section: Introductionmentioning

confidence: 99%

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

Kamenik

Hofer

Handle

et al. 2020

Front. Mol. Biosci.

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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.

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“…In contrast, if the same proteins are applied within their natural “matrix,” that is within an aqueous pollen extract, allergic sensitization results even in the absence of external adjuvants such as alum. Recently, however, a highly immunogenic Amb a 1 isoform was described to potently sensitize mice in the absence of adjuvant, presumably due to its stability to endolysosomal degradation in dendritic cells …”

Section: Matrix Matters: Lessons To Be Learned From Pollenmentioning

confidence: 99%

The role of environmental factors in allergy: A critical reappraisal

Gilles

Akdiş

Lauener

et al. 2018

Experimental Dermatology

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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.

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Endolysosomal protease susceptibility of Amb a 1 as a determinant of allergenicity

Cited by 8 publications

References 13 publications

N‐terminal peptide deletion influences immunological and structural features of Blo t 5

N‐terminal peptide deletion influences immunological and structural features of Blo t 5

Dynamics Rationalize Proteolytic Susceptibility of the Major Birch Pollen Allergen Bet v 1

The role of environmental factors in allergy: A critical reappraisal

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