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HLA-DRBI*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis

: Hoffmann, S.; Cepok, S.; Grummel, V.; Lehmann-Horn, K.; Hackermüller, J.; Stadler, P.F.; Hartung, H.-P.; Berthele, A.; Deisenhammer, F.; Wasmuth, R.; Hemmer, B.


American journal of human genetics 83 (2008), Nr.2, S.219-227
ISSN: 0002-9297
ISSN: 1537-6605
Fraunhofer IZI ()
multiple sklerosis

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.