| Autor: |
Wallner, Michael, Hauser, Michael, Himly, Martin, Zaborsky, Nadja, Mutschlechner, Sonja, Harrer, Andrea, Asam, Claudia, Pichler, Ulrike, van Ree, Ronald, Briza, Peter, Thalhamer, Josef, Bohle, Barbara, Achatz, Gernot, Ferreira, Fatima |
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| Zdroj: |
Journal of Allergy & Clinical Immunology; Jun2011, Vol. 127 Issue 6, p1571-1578.e9, 0p |
| Abstrakt: |
Background: Several alternative mechanisms have been proposed to explain why some proteins are able to induce a TH2-biased and IgE-mediated immune response. These include specific interactions with receptors of the innate immune system, proteolytic activities, allergen-associated carbohydrate structures, and intrinsic structural determinants. Objectives: Available data suggest that a fold-dependent allergy-promoting mechanism could be a driving force for the TH2-polarization activity of Bet v 1, the major birch pollen allergen. Methods: Computer-aided sequence and fold analysis of the Bet v 1 family identified a short stretch susceptible for mutations inducing an altered fold of the entire molecule. With this knowledge, 7 consecutive amino acids of Bet v 1 were replaced with the homologous Mal d 1 sequence, creating the derivative BM4. Results: The minimal changes of the sequence led to a loss of the Bet v 1–like fold and influenced the immunologic behavior. Compared to wild-type Bet v 1, BM4 induced elevated T-cell proliferation of human PBMCs. In the mouse model, immunization with Bet v 1 absorbed to aluminum hydroxide triggered strong TH2 polarization, whereas BM4 immunization additionally recruited TH1 cells. Furthermore, the fold variant BM4 showed enhanced uptake by dendritic cells and a decreased susceptibility to endo-/lysosomal proteolysis. Conclusion: Modifications in the 3-dimensional structure of Bet v 1.0101 resulted in a change of its immunologic properties. We observed that the fold alteration led to a modified crosstalk with dendritic cells and a shift of the immune response polarization toward a mixed TH1/TH2 cytokine production. [ABSTRACT FROM AUTHOR] |
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