title: HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis.
abstract: The formation of antibodies to interferon-beta (IFN-beta), a protein-based disease-modifying agent for multiple sclerosis (MS), is a problem in clinical practice. These antibodies may neutralize the biological effects of the protein drug, potentially decreasing its therapeutic effects. By high-resolution HLA class I and II typing we identified two HLA class II alleles associated with the development of antibodies to IFN-beta. In two independent continuous and binary-trait association studies, HLA-DRB1*0401 and HLA-DRB1*0408 (odds ratio: 5.15)--but not other HLA alleles--were strongly associated with the development of binding and neutralizing antibodies to IFN-beta. The associated HLA-DRB1*04 alleles differ from nonassociated HLA-DRB1*04 alleles by a glycine-to-valine substitution in position 86 of the epitope-binding alpha-helix of the HLA class II molecule. The peptide-binding motif of HLA-DRB1*0401 and *0408 might promote binding and presentation of an immunogenic peptide, which may eventually break T cell tolerance and facilitate antibody development to IFN-beta. In summary, we identified genetic factors determining the immunogenicity of IFN-beta, a protein-based disease-modifying agent for the treatment of MS.
authors.affiliation: Department of Bioinformatics, Interdisciplinary Center for Bioinformatics, University Leipzig, Leipzig, Germany.
authors.forename: Steve
authors.initials: S
authors.lastname: Hoffmann
authors.forename: Sabine
authors.initials: S
authors.lastname: Cepok
authors.forename: Verena
authors.initials: V
authors.lastname: Grummel
authors.forename: Klaus
authors.initials: K
authors.lastname: Lehmann-Horn
authors.forename: Jörg
authors.initials: J
authors.lastname: Hackermüller
authors.forename: Jörg
authors.initials: J
authors.lastname: Hackermueller
authors.forename: Peter F
authors.initials: PF
authors.lastname: Stadler
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Achim
authors.initials: A
authors.lastname: Berthele
authors.forename: Florian
authors.initials: F
authors.lastname: Deisenhammer
authors.forename: Ralf
authors.initials: R
authors.lastname: Wassmuth
authors.forename: Ralf
authors.initials: R
authors.lastname: Wasmuth
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019295:Computational Biology / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation; D006680:HLA Antigens / Q000737:chemistry; D006684:HLA-DR Antigens / Q000378:metabolism*; D059811:HLA-DRB1 Chains; D006801:Humans; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D016899:Interferon-beta