Elevated type I interferon-like activity in a subset of multiple sclerosis patients: molecular basis and clinical relevance.

BACKGROUND: A subset of patients with multiple sclerosis (MS) shows an increased endogenous IFN-like activity before initiation of IFN-beta treatment. The molecular basis of this phenomenon and its relevance to predict individual therapy outcomes are not yet fully understood. We studied the expression patterns of these patients, the prognostic value of an elevated IFN-like activity, and the gene regulatory effects of exogenously administered IFN-beta. METHODS: Microarray gene expression profiling was performed for 61 MS patients using peripheral blood mononuclear cells obtained before and after 1 month of IFN-beta therapy. Expression levels of genes involved in pathways either inducing or being activated by IFN-beta were compared between patients with high (MX1(high) cohort) and low (MX1(low) cohort) endogenous IFN-like activity. Patients were followed for 5 years and relapses as well as progression on the expanded disability status scale (EDSS) were documented. RESULTS: Before the start of therapy, 11 patients presented elevated mRNA levels of IFN-stimulated genes indicative of a relatively high endogenous IFN-like activity (MX1(high)). In these patients, pathogen receptors (for example, TLR7, RIG-I and IFIH1) and transcription factors were also expressed more strongly, which could be attributed to an overactivity of IFN-stimulated gene factor 3 (ISGF3, a complex formed by STAT1, STAT2 and IFN regulatory factor 9). After 1 month of IFN-beta therapy, the expression of many pathway genes was significantly induced in MX1(low) patients, but remained unaltered in MX1(high) patients. During follow-up, relapse rate and changes in EDSS were comparable between both patient groups, with differences seen between different types of IFN-beta drug application. CONCLUSIONS: Therapeutic IFN-beta induces the transcription of several genes involved in IFN-related pathways. In a subgroup of MS patients, the expression of these genes is already increased before therapy initiation, possibly driven by an overexpression of ISGF3. Patients with high and low endogenous IFN-like activity showed similar clinical long-term courses of disease. Different results were obtained for different IFN-beta drug preparations, and this merits further investigation.

An inventory of short term and long term changes in gene expression under interferon ß treatment of relapsing remitting MS patients.

Multiple sclerosis (MS) is a chronic immune modulated disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal injury. Currently relapsing remitting type of MS patients are most commonly treated with immune- modulators like interferon ß (IFN ß) or glatiramer acetate (GA). However, while the majority of patients respond well to therapy others do not. Gene expression profiles in blood samples taken over the course of IFN ß treatment can document changes in the biology of the patients in response to the drug and disease activity. During the last decade quite a few of such studies profiling expression in response to IFN ß treatment had been done. Here, we combine the results of these studies to outline common differential expression patterns in peripheral blood mononuclear cells (PBMCs) over the course of time under IFN ß treatment. We set these profiles into the picture of current knowledge about IFN ß pathway, MS immunology and IFN ß mechanisms of action. IFN ß modulates hundreds of genes. In most of the studies the prominent ones like MX 1, OAS 1, and CXCL 10 had been found to be influenced by IFN ß drug treatment. We show examples of short term and long term induced expressional changes, up and down regulated genes (STAT1 and IL8), and explain how under drug treatment feedback loops of type I IFN (IFN α and IFN ß) regulated genes may be modulated and changes in expression patterns may result in cytological changes.