HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis.
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.
Hoffmann
Steve
S
Department of Bioinformatics, Interdisciplinary Center for Bioinformatics, University Leipzig, Leipzig, Germany.
Cepok
Sabine
S
Grummel
Verena
V
Lehmann-Horn
Klaus
K
Hackermüller
Jörg
J
Hackermueller
Jörg
J
Stadler
Peter F
PF
Hartung
Hans-Peter
HP
Berthele
Achim
A
Deisenhammer
Florian
F
Wassmuth
Ralf
R
Wasmuth
Ralf
R
Hemmer
Bernhard
B
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
D006680:HLA Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D016899:Interferon-beta