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Abstract
PurposeInterferon beta receptor 2 subunit (IFNAR2) can be produced as a transmembrane protein, but also as a soluble form (sIFNAR2) generated by alternative splicing or proteolytic cleavage, which has both agonist and antagonist activities for IFN-β. However, its role regarding the clinical response to IFN-β for relapsing-remitting multiple sclerosis (RRMS) is unknown. We aim to evaluate the in vitro short-term effects and after 6 and 12 months of IFN-β therapy on sIFNAR2 production and their association with the clinical response in MS patients.MethodsNinety-four RRMS patients were included and evaluated at baseline, 6 and 12 months from treatment onset. A subset of 41 patients were classified as responders and non-responders to IFN-β therapy. sIFNAR2 serum levels were measured by ELISA. mRNA expression for IFNAR1, IFNAR2 splice variants, MxA and proteases were assessed by RT-PCR. The short-term effect was evaluated in PBMC from RRMS patients after IFN-β stimulation in vitro.ResultsProtein and mRNA levels of sIFNAR2 increased after IFN-β treatment. According to the clinical response, only non-responders increased sIFNAR2 significantly at both protein and mRNA levels. sIFNAR2 gene expression correlated with the transmembrane isoform expression and was 2.3-fold higher. While MxA gene expression increased significantly after treatment, IFNAR1 and IFNAR2 only slightly increased. After short-term IFN-β in vitro induction of PBMC, 6/7 patients increased the sIFNAR2 expression.ConclusionsIFN-β administration induces the production of sIFNAR2 in RRMS and higher levels might be associated to the reduction of therapeutic response. Thus, levels of sIFNAR2 could be monitored to optimize an effective response to IFN-β therapy.
Highlights
Multiple sclerosis (MS) is the most prevalent chronic inflammatory autoimmune disease of the central nervous system, with a complex pathophysiology characterized by inflammation, demyelination, and axonal degeneration
Regarding sIFNAR2, we found increased levels at 6- and 12months follow-up after IFN-b exposure compared to baseline levels, with significant differences at 6 months (p=0.008)
This increase of sIFNAR2 levels was replicated in the cohort 2, being statistically significant at 6 months (p=0.0001) and at 12 months (p=0.0001)
Summary
Multiple sclerosis (MS) is the most prevalent chronic inflammatory autoimmune disease of the central nervous system, with a complex pathophysiology characterized by inflammation, demyelination, and axonal degeneration. In the last two decades the approval of several disease-modifying therapies have revolutionized the management of MS [1], IFN-b is still used as a first line therapeutic option because of benefit/risk profile and cost. Cytokine receptors are usually expressed by cells as transmembrane proteins, most of them are secreted in soluble forms and can be detected in different human body fluids including the blood, the tears, the cerebrospinal fluid or the urine [4, 5]. The generation of soluble receptors is an important mechanism by which the biological activity of cytokines is modulated due to their ability to bind them, acting as antagonists or agonists [6, 7], so that they can be used for therapeutic purposes [4]
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