title: Reshaping the Bet v 1 fold modulates T(H) polarization.
abstract: BACKGROUND
  Several alternative mechanisms have been proposed to explain why some proteins are able to induce a T(H)2-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.
  
  
  OBJECTIVE
  Available data suggest that a fold-dependent allergy-promoting mechanism could be a driving force for the T(H)2-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 T(H)2 polarization, whereas BM4 immunization additionally recruited T(H)1 cells. Furthermore, the fold variant BM4 showed enhanced uptake by dendritic cells and a decreased susceptibility to endo-/lysosomal proteolysis.
  
  
  CONCLUSIONS
  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 T(H)1/T(H)2 cytokine production.
authors.affiliation: Christian Doppler Laboratory for Allergy Diagnosis and Therapy, Department of Molecular Biology, University of Salzburg, Salzburg, Austria. michael.wallner@sbg.ac.at
authors.forename: Michael
authors.initials: M
authors.lastname: Wallner
authors.forename: Michael
authors.initials: M
authors.lastname: Hauser
authors.forename: Martin
authors.initials: M
authors.lastname: Himly
authors.forename: Nadja
authors.initials: N
authors.lastname: Zaborsky
authors.forename: Sonja
authors.initials: S
authors.lastname: Mutschlechner
authors.forename: Andrea
authors.initials: A
authors.lastname: Harrer
authors.forename: Claudia
authors.initials: C
authors.lastname: Asam
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pichler
authors.forename: Ronald
authors.initials: R
authors.lastname: van Ree
authors.forename: Peter
authors.initials: P
authors.lastname: Briza
authors.forename: Josef
authors.initials: J
authors.lastname: Thalhamer
authors.forename: Barbara
authors.initials: B
authors.lastname: Bohle
authors.forename: Gernot
authors.initials: G
authors.lastname: Achatz
authors.forename: Fatima
authors.initials: F
authors.lastname: Ferreira
mesh_terms: D000485:Allergens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D000937:Antigen-Antibody Reactions; D052179:Antigens, Plant / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D029662:Betula / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007114:Immunization; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017510:Protein Folding; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000485:Allergens; D052179:Antigens, Plant; D000939:Epitopes; C061312:Bet v 1 allergen, Betula