title: The HLA-DP2 protein binds the immunodominant epitope from myelin basic protein, MBP85-99, with high affinity.
abstract: Myelin basic protein (MBP) is a candidate autoantigen in multiple sclerosis (MS). The immunodominant epitope for T-cell responses is assigned to the amino acid sequence MBP84-102, which binds to human leukocyte antigen (HLA)-DR2a (DRB5*0101) and HLA-DR2b (DRB1*1501) of the HLA-DR2 haplotype carrying the strongest genetic association with MS. In contrast with HLA-DR and -DQ molecules, HLA-DP molecules are poorly characterized with respect to the binding of self-peptides. We show here that HLA-DP2 binds MBP85-99 with high affinity, and that the amino acid residues in position MBP91, MBP92 and MBP93 are influencing the binding, as shown by alanine scans. We further used a series of truncated peptides to identify the core of the binding. Moving the frame along the peptide from residues 87-97 to 89-99 progressively decreased the binding affinity for HLA-DP2, while moving further towards the C-terminal completely abrogated the binding of peptides to HLA-DP2. The data suggest that the docking of the MBP85-99 peptide into the HLA-DP2 groove is dependent on MBP88V and MBP89V and may use either of them as primary anchor for the p1 position. HLA-DP2 might thus present the MBP85-99 peptide in the same register as the HLA-DRB1*1501, where the MBP89V is preferred as the p1 anchor. Notably, full-length MBP was able to compete for peptide binding with an affinity similar to that seen for the high-affinity binding peptides, DRα170-83 and IIP53-65. In summary, the HLA-DP2 molecule binds the immunodominant epitope in MS, MBP85-99, possibly in more than one register.
authors.affiliation: Department of Rheumatology, Institute for Inflammation Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. behmail@get2net.dk
authors.forename: B E
authors.initials: BE
authors.lastname: Hansen
authors.forename: C H
authors.initials: CH
authors.lastname: Nielsen
authors.forename: H O
authors.initials: HO
authors.lastname: Madsen
authors.forename: L P
authors.initials: LP
authors.lastname: Ryder
authors.forename: B K
authors.initials: BK
authors.lastname: Jakobsen
authors.forename: A
authors.initials: A
authors.lastname: Svejgaard
mesh_terms: D020001:1-Butanol / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D004331:Drosophila melanogaster; D004797:Enzyme-Linked Immunosorbent Assay; D006682:HLA-DP Antigens / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D059868:HLA-DP beta-Chains; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011994:Recombinant Proteins; C107908:myelin basic protein 85-99; D020001:1-Butanol