title: Antigen aggregation decides the fate of the allergic immune response.
abstract: Previously, defined naturally occurring isoforms of allergenic proteins were classified as hypoallergens and therefore suggested as an agent for immunotherapy in the future. In this paper, we report for the first time the molecular background of hypoallergenicity by comparing the immunological behavior of hyperallergenic Betula verrucosa major Ag 1a (Bet v 1a) and hypoallergenic Bet v 1d, two isoforms of the major birch pollen allergen Betula verrucosa 1. Despite their cross-reactivity, Bet v 1a and Bet v 1d differ in their capacity to induce protective Ab responses in BALB/c mice. Both isoforms induced similar specific IgE levels, but only Bet v 1d expressed relevant titers of serum IgGs and IgAs. Interestingly, hypoallergenic Bet v 1d activated dendritic cells more efficiently, followed by the production of increased amounts of Th1- as well as Th2-type cytokines. Surprisingly, compared with Bet v 1a, Bet v 1d-immunized mice showed a decreased proliferation of regulatory T cells. Crystallographic studies and dynamic light scattering revealed that Bet v 1d demonstrated a high tendency to form disulfide-linked aggregates due to a serine to cysteine exchange at residue 113. We conclude that aggregation of Bet v 1d triggers the establishment of a protective Ab titer and supports a rationale for Bet v 1d being a promising candidate for specific immunotherapy of birch pollen allergy.
authors.affiliation: Department of Molecular Biology, Christian Doppler Laboratory for Allergy Diagnosis and Therapy, University of Salzburg, Salzburg, Austria.
authors.forename: Nadja
authors.initials: N
authors.lastname: Zaborsky
authors.forename: Marietta
authors.initials: M
authors.lastname: Brunner
authors.forename: Michael
authors.initials: M
authors.lastname: Wallner
authors.forename: Martin
authors.initials: M
authors.lastname: Himly
authors.forename: Tanja
authors.initials: T
authors.lastname: Karl
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: Fatima
authors.initials: F
authors.lastname: Ferreira
authors.forename: Gernot
authors.initials: G
authors.lastname: Achatz
mesh_terms: D000485:Allergens / Q000737:chemistry* / Q000276:immunology; D000818:Animals; D029662:Betula / Q000276:immunology*; D029401:Betulaceae; D003429:Cross Reactions / Q000276:immunology*; D006967:Hypersensitivity / Q000276:immunology*; D056724:Immunity, Humoral; D007132:Immunoglobulin Isotypes / Q000032:analysis; D007518:Isoantibodies / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011058:Pollen / Q000276:immunology*; D055503:Protein Multimerization / Q000276:immunology*
chemical_list: D000485:Allergens; D007132:Immunoglobulin Isotypes; D007518:Isoantibodies