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

Journal of Neuroinflammation

Uwe Klaus Zettl¹  Hans-Juergen Thiesen²  Dirk Koczan²  Christiane Hartmann¹  Christian Fatum¹  Ole Kandulski¹  Charlotte Angerstein¹  Brigitte Katrin Paap²  Michael Hecker²  Alexander Hundeshagen¹ 

[1] Department of Neurology, Division of Neuroimmunology, University of Rostock, Gehlsheimer Str. 20, 18147, Rostock, Germany;Institute of Immunology, University of Rostock, Schillingallee 68, 18057, Rostock, Germany

关键词: Therapy response;    Signaling pathway;    Pharmacological effects;    MX1;    Multiple sclerosis;    IFN-beta;    Blood biomarker;   

Others  :  1212497
DOI  :  10.1186/1742-2094-9-140

 received in 2012-01-23, accepted in 2012-06-22,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Hundeshagen et al.; licensee BioMed Central Ltd.

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