The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-beta in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-beta for a minimum of 2 years and classified as responders and non-responders based on clinical criteria. A validation cohort of 30 multiple sclerosis patients was included in the study to replicate gene-expression findings. Before treatment, interferon-beta responders and non-responders were characterized by differential expression of type I interferon-induced genes with overexpression of the type interferon-induced genes in non-responders. Upon treatment the expression of these genes remained unaltered in non-responders, but was strongly upregulated in responders. Functional experiments showed a selective increase in phosphorylated STAT1 levels and interferon receptor 1 expression in monocytes of non-responders at baseline. When dissecting this type I interferon signature further, interferon-beta non-responders were characterized by increased monocyte type I interferon secretion upon innate immune stimuli via toll-like receptor 4, by increased endogenous production of type I interferon, and by an elevated activation status of myeloid dendritic cells. These findings indicate that perturbations of the type I interferon signalling pathway in monocytes are related to lack of response to interferon-beta, and type I interferon-regulated genes may be used as response markers in interferon-beta treatment.

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ObjectivesTo determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients and healthy siblings raised in the same family household. MethodsVirus antigen-specific IgG responses to Epstein-Barr virus (EBV)-derived gene products as well as to human herpersvirus-6, human cytomegalovirus, and measles virus were evaluated in 25 MS patients and compared to 49 healthy fullsiblings. ResultsIgG responses to the latent EBV-encoded nuclear antigen-1 (EBNA1) were selectively increased in individuals with MS compared with their unaffected siblings. ConclusionThe increase of IgG responses towards EBNA1 is specifically associated with the development of MS. 3.