We have recently studied biomarkers related to the response to interferon-ß (IFN-ß) treatment in patients with multiple sclerosis (MS). In a cohort of 55 clinically well-defined IFN good responders (GR) and bad responders (BR), we employed gene expression profiling of all known human genes by whole genome oligonucleotide microarrays. Prominent among the genes differentially expressed in GR versus BR at baseline and at various time points during treatment were both HLA-DQ-α and –DQ-ß, but no other polymorphic or non-polymorphic HLA-class I or –class II gene. IFN-GR demonstrated higher HLA-DQ expression at baseline and each subsequent time point. HLA-class II genes confer by far the largest part of the genetic risk for MS, and certain HLA-DR alleles and –DQ alleles, which are in close linkage disequilibrium, have been associated with the disease. However, it is at present not clear, how HLA-class II molecules contribute to the autoimmune process.
Studies of autoantigen-specific CD4+ T cell responses in MS suggest that HLA-DR molecules are more important as restriction elements of proinflammatory autoimmune T cells. Very few autoreactive T cells that are restricted by HLA-DQ have been described in MS, and data from a number of infectious diseases, but also from transplantation, allergic diseases, and autoimmune processes indicate that HLA-DQ may be more important for regulatory than effector T cell responses.
Since type I interferons, i.e. the different α-interferons and ß-interferon, are critical for anti-viral responses, we speculate that the differential expression of HLA-DQ-α/β in IFN-ß-treated non/poor-responding MS patients will provide important clues not only with regard to this particular treatment in MS, but also with respect to the role of HLA-DQ in controlling immune responsiveness and in the role of differential IFN-ß expression for the host response to viral agents in MS etiology or pathogenesis.
We will combine various methodologies, including flow cytometry, cellular immunology techniques, single nucleotide polymorphism mapping of the HLA region on chromosome 6p21, high resolution HLA typing, the isolation and functional testing of various immune populations, and viral stimulation assays to investigate the potential role of the differential HLA-DQ expression in IFN-GR and IFN-BR.