Introduction
Multiple sclerosis (MS [MIM 126200]) is a chronic inflammatory disease of the central nervous system. Whereas the etiology of MS is likely to be heterogeneous, the influence of genetic factors in the development of MS has been confirmed by association and linkage studies.1, 2, 3, 4 The crucial role of HLA alleles in the susceptibility to MS is well established. Whereas HLA-DRB1∗15 alleles are strongly associated with MS in Europeans, DRB1∗0301 and DRB1∗0401 are overrepresented in MS patients from southern Europe.5, 6 Overrepresentation of DRB1∗04 alleles was reported for patients from Turkey and the Canary Islands. Although the genetic association of susceptibility to MS with loci outside the HLA complex has been confirmed in some cases, the search for susceptibility genes continues.4
Interferon-β is the most widely used immunomodulatory drug for MS therapy. It is approved for treatment of clinically isolated syndrome and relapsing-remitting MS. Furthermore, it has antiviral activity and remains an option in the therapy of diseases such as Hepatitis-C (HCV [MIM 609532]) or the severe acute respiratory syndrome (SARS).7, 8, 9 Like other protein-based disease-modifying agents, IFN-β exhibits immunogenicity.10 Even though the technical improvement of purification processes and the introduction of recombinant preparations have helped to reduce the immunogenicity of IFN-β, up to 50% of patients may develop antibodies to IFN-β (binding antibodies [BABs]), of which a significant proportion neutralize the activity of IFN-β (neutralizing antibodies [NABs]) in vitro and vivo.11 Currently, three distinct recombinant preparations of IFN-β are in use for the treatment of MS. Interferon β-1b (165 residues) is modified from naturally occurring IFN-β by deletion of the leading methionine and a single amino acid substitution (C17S).12 It is recombinantly expressed in Escherichia coli (IFN-β-1b; Betaferon or Betaseron). IFN-β-1a, recombinantly expressed in Chinese hamster ovary cells, is identical to natural human interferon beta (166 residues) (IFN-β-1a; Avonex, Rebif). Although preparation and administration influence the immunogenic properties and the rate of antibody development, little is known about host factors that determine immune responses to IFN-β.13
Antibody production and generation of B cell responses to proteins depend on the help of antigen-specific CD4+ T cells.14 The development of antigen-specific CD4+ T cell responses itself is strongly influenced by the individual repertoire of HLA class II molecules, which present peptide antigens for recognition to the T cell receptor.15, 16 Given the central role of CD4+ T cells for the development of antigen-specific B cell responses, we performed high-resolution typing for HLA-A, -B, -C, -DRB1, and -DQB1 alleles in MS patients receiving long-term IFN-β therapy.