title: Bet v 1 from birch pollen is a lipocalin-like protein acting as allergen only when devoid of iron by promoting Th2 lymphocytes.
abstract: It is hypothesized that allergens are at the borderline of self and non-self and, through as yet elusive circumstances, mount a Th2 response for allergic sensitization. The major birch pollen allergen Bet v 1 is considered the prototype for the PR-10 protein family causing respiratory allergy. Here, we give structural evidence that Bet v 1 is a lipocalin-like protein with a striking structural resemblance to human lipocalin 2. Lipocalin 2 is highly expressed in the lung where it exerts immunoregulatory functions dependent on being loaded with siderophore-bound iron (holo-form) or not (apo-form). We demonstrate that similar to lipocalin 2, Bet v 1 is capable of binding iron via catechol-based siderophores. Thereby, calculated Kd values of 66 nm surpassed affinities to known ligands nearly by a power of 10. Moreover, we give functional evidence of the immunomodulatory capacity of Bet v 1 being dependent on its iron-loaded state. When incubated to human immune cells, only the apo-form of Bet v 1, but not the holo-form, was able to promote Th2 cells secreting IL13. These results provide for the first time a functional understanding on the allergenicity of Bet v 1 and a basis for future allergen immunotherapies counteracting Th2 immune responses on a molecular basis.
authors.affiliation: From the Comparative Medicine Unit, Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University of Vienna, and University of Vienna, A-1210 Vienna, Austria.
authors.forename: Franziska
authors.initials: F
authors.lastname: Roth-Walter
authors.affiliation: the Biotechnology Department, Center for Plant Biotechnology and Genomics, Technical University of Madrid, 28040 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gomez-Casado
authors.affiliation: the Biotechnology Department, Center for Plant Biotechnology and Genomics, Technical University of Madrid, 28040 Madrid, Spain.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Pacios
authors.affiliation: AllergyCare, 1220 Vienna, Austria.
authors.forename: Nadine
authors.initials: N
authors.lastname: Mothes-Luksch
authors.affiliation: the Department of Anesthesiology, General Intensive Care and Pain Medicine, Medical University of Vienna, Austria, and.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Roth
authors.affiliation: the Unit of Comparative Immunology and Oncology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Singer
authors.affiliation: the Biotechnology Department, Center for Plant Biotechnology and Genomics, Technical University of Madrid, 28040 Madrid, Spain.
authors.forename: Araceli
authors.initials: A
authors.lastname: Diaz-Perales
authors.affiliation: From the Comparative Medicine Unit, Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University of Vienna, and University of Vienna, A-1210 Vienna, Austria, the Unit of Comparative Immunology and Oncology, Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria erika.jensen-jarolim@meduniwien.ac.at.
authors.forename: Erika
authors.initials: E
authors.lastname: Jensen-Jarolim
mesh_terms: D000209:Acute-Phase Proteins; D052179:Antigens, Plant / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D029662:Betula / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology; D007501:Iron / Q000737:chemistry / Q000276:immunology; D000071068:Lipocalin-2; D054834:Lipocalins; D008297:Male; D011518:Proto-Oncogene Proteins; D040681:Structural Homology, Protein; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D000209:Acute-Phase Proteins; D052179:Antigens, Plant; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; C061312:Bet v 1 allergen, Betula; D007501:Iron
keywords: Allergen; Allergic Sensitization; Allergy; Apo- and Holo-form; Bet v 1; Immunosuppression; Iron; Mucosal Immunology; Siderophore; Th2 Skewing