Abstract
BackgroundA relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment.MethodsTwenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays.Results and discussionPurified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb.
Highlights
Interferon-beta (IFNb), a first-line disease modifying therapy for relapsing-remitting multiple sclerosis (RRMS), has demonstrated beneficial effects on reducing clinical and radiological disease activity [1,2,3]
Several lines of evidence support an important role of monocytes in MS pathogenesis: (i) circulating monocytes from MS patients are more active and they are present in brain active lesions [13]; (ii) monocytes from MS patients secrete more quantity of hydrogen peroxide and superoxide [14] and express more proinflammatory cytokines (TNFa, IL1b and IL6) during acute disease relapses upon stimulation [15]; (iii) MS patients have a higher percentage of monocytes secreting IL6 and IL12, and IL12secreting monocytes are associated with higher disease activity when measured by magnetic resonance imaging [16]; (iv) nonclassical type CD14+CD16+ (CCR5+) monocytes go through the blood brain barrier during acute phases of neuroinflammation [17]
In a later study by our group, we identified a baseline overexpression of type I IFN responsive genes in peripheral blood mononuclear cells (PBMC) from a subgroup of RRMS patients who showed a lack of response to IFNb [5], which was in part explained by the presence of an increased baseline expression of endogenous IFNb in nonresponders [10]
Summary
Interferon-beta (IFNb), a first-line disease modifying therapy for relapsing-remitting multiple sclerosis (RRMS), has demonstrated beneficial effects on reducing clinical and radiological disease activity [1,2,3]. Previous studies performed by our group revealed a baseline type I IFN signature in peripheral blood mononuclear cells (PBMC) from a subgroup of IFNb non-responders selected by stringent clinical response criteria after two years of treatment [5]. A relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. We aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
