title: Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands.
abstract: Allergic responses can be triggered by structurally diverse allergens. Most allergens are proteins, yet extensive research has not revealed how they initiate the allergic response and why the myriad of other inhaled proteins do not. Among these allergens, the cat secretoglobulin protein Fel d 1 is a major allergen and is responsible for severe allergic responses. In this study, we show that similar to the mite dust allergen Der p 2, Fel d 1 substantially enhances signaling through the innate receptors TLR4 and TLR2. In contrast to Der p 2, however, Fel d 1 does not act by mimicking the TLR4 coreceptor MD2 and is not able to bind stably to the TLR4/MD2 complex in vitro. Fel d 1 does, however, bind to the TLR4 agonist LPS, suggesting that a lipid transfer mechanism may be involved in the Fel d 1 enhancement of TLR signaling. We also show that the dog allergen Can f 6, a member of a distinct class of lipocalin allergens, has very similar properties to Fel d 1. We propose that Fel d 1 and Can f 6 belong to a group of allergen immunomodulatory proteins that enhance innate immune signaling and promote airway hypersensitivity reactions in diseases such as asthma.
authors.affiliation: Department of Medicine, University of Cambridge School of Medicine, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Herre
authors.forename: Hans
authors.initials: H
authors.lastname: Grönlund
authors.forename: Heather
authors.initials: H
authors.lastname: Brooks
authors.forename: Lee
authors.initials: L
authors.lastname: Hopkins
authors.forename: Lisa
authors.initials: L
authors.lastname: Waggoner
authors.forename: Ben
authors.initials: B
authors.lastname: Murton
authors.forename: Monique
authors.initials: M
authors.lastname: Gangloff
authors.forename: Olaniyi
authors.initials: O
authors.lastname: Opaleye
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chilvers
authors.forename: Kate
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Nick
authors.initials: N
authors.lastname: Gay
authors.forename: Tom
authors.initials: T
authors.lastname: Monie
authors.forename: Clare
authors.initials: C
authors.lastname: Bryant
mesh_terms: D000485:Allergens / Q000737:chemistry / Q000276:immunology*; D000818:Animals; D002415:Cats / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004285:Dogs; D005408:Flagellin / Q000276:immunology; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology*; D006031:Glycosylation; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008024:Ligands; D054834:Lipocalins / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D046911:Macromolecular Substances; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000209:etiology / Q000276:immunology*; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D013329:Structure-Activity Relationship; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D000485:Allergens; C587009:Can f 6 allergen, Canis familiaris; D016207:Cytokines; D006023:Glycoproteins; C495377:LY96 protein, human; D008024:Ligands; D054834:Lipocalins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C440499:lipopolysaccharide, Escherichia coli O111 B4; D005408:Flagellin; C059296:Fel d 1 protein, Felis domesticus