HLA-DRB10401 and HLA-DRB10408 Are Strongly Associated with the Development of Antibodies against Interferon-β Therapy in Multiple Sclerosis

• Published in: American journal of human genetics Vol. 83; no. 2; pp. 219 - 227
• Main Authors: HOFFMANN, Steve, CEPOK, Sabine, HEMMER, Bernhard, GRUMMEL, Verena, LEHMANN-HORN, Klaus, HACKERMUELLER, Jörg, STADLER, Peter F, HARTUNG, Hans-Peter, BERTHELE, Achim, DEISENHAMMER, Florian, WASMUTH, Ralf
• Format: Journal Article
• Language: English
• Published: Chicago, IL University of Chicago Press 01.08.2008
• Subjects: Adolescent; Adult; Aged; Alleles; Biological and medical sciences; Computational Biology - methods; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; HLA Antigens - chemistry; HLA-DR Antigens - metabolism; HLA-DRB1 Chains; Humans; Interferon-beta - immunology; Interferon-beta - metabolism; Male; Medical genetics; Medical sciences; Middle Aged; Molecular and cellular biology; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; Human; HLA-System; Therapy; Nervous system diseases; Multiple sclerosis; Antibody; Major histocompatibility system; Cytokine; Inflammatory disease; Association; Treatment; Central nervous system disease; Beta interferon; Development; Genetics; Class I histocompatibility antigen
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2008.07.006

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.