title: BoLA-DR peptide binding pockets are fundamental for foot-and-mouth disease virus vaccine design in cattle.
abstract: This large study investigates the associations between bovine major histocompatibility complex DRB3 alleles and their binding pockets with the immune response to a 40-mer peptide derived from foot-and-mouth disease virus (FMDV) VP1. A crossbred (Charolais and Holstein) cattle population (n=197) was immunised with the FMDV peptide and specific IgG1 and IgG2 responses were measured. Eighteen different DRB3 alleles were detected in this population, with several exhibiting highly significant associations with antibody response. Allele DRB3*1601 was correlated with relatively low IgG1 and IgG2 responses (p<0.001), whereas DRB3*1001 was associated with relatively high IgG1 and IgG2 responses (p<0.001). In contrast the allele *0901 which ranked highest for IgG1 response, only came 14th for IgG2 response. The amino acids at several positions within the peptide binding cleft of the DR molecule showed significant associations (p<0.001) with the level of antibody response. Further analysis showed that specific residues within binding pockets are likely to be crucial to vaccine design. In particular, polymorphisms at position beta70 in pocket 4 were strongly linked to the magnitude of response and highly significant associations were found for position beta57 in pocket 9 and position beta56 in pocket 10. Glutamic acid at position beta70 was associated with low FMDV peptide specific IgG1 and IgG2 response, whereas arginine at beta70 was associated (p<0.001) with a high FMDV peptide specific IgG1 and IgG2 levels. The data indicates that the amino acids within the binding pockets of the DRB3 alleles are critical for determining the degree of immune response and in addition may affect the ratio of IgG1/IgG2, which in turn will influence the efficacy of the peptide to induce protective immunity.
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin Biocentre, Midlothian, EH25 9PS, United Kingdom. rebecca.baxter@roslin.ed.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Baxter
authors.forename: S C
authors.initials: SC
authors.lastname: Craigmile
authors.forename: C
authors.initials: C
authors.lastname: Haley
authors.forename: A J
authors.initials: AJ
authors.lastname: Douglas
authors.forename: J L
authors.initials: JL
authors.lastname: Williams
authors.forename: E J
authors.initials: EJ
authors.lastname: Glass
mesh_terms: D000483:Alleles; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D000917:Antibody Formation; D000918:Antibody Specificity; D019540:Area Under Curve; D001665:Binding Sites; D036022:Capsid Proteins / Q000276:immunology; D002417:Cattle / Q000235:genetics* / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D005536:Foot-and-Mouth Disease / Q000276:immunology / Q000517:prevention & control*; D005787:Gene Frequency; D005838:Genotype; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011110:Polymorphism, Genetic; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D036022:Capsid Proteins; D000939:Epitopes; C094837:FMDV 15 peptide; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D010446:Peptide Fragments; D014765:Viral Vaccines