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.
Department of Neurology, Division of Neuroimmunology, University of Rostock, Germany.
Alexander
A
Hundeshagen
Michael
M
Hecker
Brigitte Katrin
BK
Paap
Charlotte
C
Angerstein
Ole
O
Kandulski
Christian
C
Fatum
Christiane
C
Hartmann
Dirk
D
Koczan
Hans-Juergen
HJ
Thiesen
Uwe Klaus
UK
Zettl
D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks / Q000276:immunology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
D007370:Interferon Type I; D016899:Interferon-beta