title: HLA-DRB1*1501 risk association in multiple sclerosis may not be related to presentation of myelin epitopes.
abstract: Susceptibility to multiple sclerosis (MS) is associated genetically with human leucocyte antigen (HLA) class II alleles, including DRB1*1501, DRB5*0101, and DQB1*0602, and it is possible that these alleles contribute to MS through an enhanced ability to present encephalitogenic myelin peptides to pathogenic T cells. HLA-DRB1*1502, which contains glycine instead of valine at position 86 of the P1 peptide-binding pocket, is apparently not genetically associated with MS. To identify possible differences between these alleles in their antigen-presenting function, we determined if T-cell responses to known DRB1*1501-restricted myelin peptides might be diminished or absent in transgenic (Tg) DRB1*1502-expressing mice. We found that Tg DRB1*1502 mice had moderate to strong T-cell responses to several myelin peptides with favorable DRB1*1501 binding motifs, notably myelin oligodendrocyte glycoprotein (MOG)-35-55 (which was also encephalitogenic), proteolipid protein (PLP)-95-116, and MOG-194-208, as well as other PLP and MOG peptides. These peptides, with the exception of MOG-194-208, were also immunogenic in healthy human donors expressing either DRB1*1502 or DRB1*1501. In contrast, the DRB1*1502 mice had weak or absent responses to peptides with unfavorable DRB1*1501 binding motifs. Overall, none of the DRB1*1501-restricted myelin peptides tested selectively lacked immunogenicity in association with DRB1*1502. These results indicate that the difference in risk association with MS of DRB1*1501 versus DRB1*1502 is not due to a lack of antigen presentation by DRB1*1502, at least for this set of myelin peptides, and suggest that other mechanisms involving DRB1*1501 may account for increased susceptibility to MS.
authors.affiliation: Neuroimmunology Research, Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Finn
authors.forename: Richard E
authors.initials: RE
authors.lastname: Jones
authors.forename: Cathleen
authors.initials: C
authors.lastname: Rich
authors.forename: Rony
authors.initials: R
authors.lastname: Dahan
authors.forename: Jason
authors.initials: J
authors.lastname: Link
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Yuan K
authors.initials: YK
authors.lastname: Chou
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D059811:HLA-DRB1 Chains; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein; D012307:Risk Factors
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D016056:Immunodominant Epitopes; C571326:MOG protein, human; C571327:Mog protein, mouse; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein