title: Heligmosomoides polygyrus elicits a dominant nonprotective antibody response directed against restricted glycan and peptide epitopes.
abstract: Heligmosomoides polygyrus is a widely used gastrointestinal helminth model of long-term chronic infection in mice, which has not been well-characterized at the antigenic level. We now identify the major targets of the murine primary Ab response as a subset of the secreted products in H. polygyrus excretory-secretory (HES) Ag. An immunodominant epitope is an O-linked glycan (named glycan A) carried on three highly expressed HES glycoproteins (venom allergen Ancylostoma-secreted protein-like [VAL]-1, -2, and -5), which stimulates only IgM Abs, is exposed on the adult worm surface, and is poorly represented in somatic parasite extracts. A second carbohydrate epitope (glycan B), present on both a non-protein high molecular mass component and a 65-kDa molecule, is widely distributed in adult somatic tissues. Whereas the high molecular mass component and 65-kDa molecules bear phosphorylcholine, the glycan B epitope itself is not phosphorylcholine. Class-switched IgG1 Abs are found to glycan B, but the dominant primary IgG1 response is to the polypeptides of VAL proteins, including also VAL-3 and VAL-4. Secondary Ab responses include the same specificities while also recognizing VAL-7. Although vaccination with HES conferred complete protection against challenge H. polygyrus infection, mAbs raised against each of the glycan epitopes and against VAL-1, VAL-2, and VAL-4 proteins were unable to do so, even though these specificities (with the exception of VAL-2) are also secreted by tissue-phase L4 larvae. The primary immune response in susceptible mice is, therefore, dominated by nonprotective Abs against a small subset of antigenic epitopes, raising the possibility that these act as decoy specificities that generate ineffective humoral immunity.
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.
authors.forename: James P
authors.initials: JP
authors.lastname: Hewitson
authors.forename: Kara J
authors.initials: KJ
authors.lastname: Filbey
authors.forename: John R
authors.initials: JR
authors.lastname: Grainger
authors.forename: Adam A
authors.initials: AA
authors.lastname: Dowle
authors.forename: Mark
authors.initials: M
authors.lastname: Pearson
authors.forename: Janice
authors.initials: J
authors.lastname: Murray
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Harcus
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
mesh_terms: D000818:Animals; D000909:Antibodies, Helminth / Q000096:biosynthesis*; D000918:Antibody Specificity / Q000276:immunology; D000947:Antigens, Helminth / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005260:Female; D007106:Immune Sera / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009351:Nematospiroides dubius / Q000276:immunology*; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011134:Polysaccharides / Q000276:immunology* / Q000378:metabolism; D011487:Protein Conformation; D017206:Strongylida Infections / Q000276:immunology / Q000469:parasitology
chemical_list: D000909:Antibodies, Helminth; D000947:Antigens, Helminth; D000939:Epitopes; D007106:Immune Sera; D010455:Peptides; D011134:Polysaccharides