Key result
Prolonged interferon beta is linked to decreased transmembrane and increased soluble IFNAR-2 in NAb-negative MS.
Why the study?
There is high variability in response to interferon beta therapy in multiple sclerosis, and regulation of IFNalpha/beta receptor expression may modulate this responsiveness.
How does interferon beta therapy regulate IFNalpha/beta receptor expression in patients with multiple sclerosis?
Observational (n=141)
How does interferon beta therapy regulate IFNalpha/beta receptor expression in patients with multiple sclerosis?
IFNAR-2 isoforms are important regulators of responsiveness to interferon beta in multiple sclerosis, showing both agonistic and antagonistic actions.
Prolonged interferon beta may alter IFNAR-2 dynamics in MS; hypothesis-generating for efficacy monitoring, prospective validation required.
BACKGROUND: The cytokine interferon beta (IFNbeta) is successfully used in the treatment of multiple sclerosis (MS), although there is a high degree of variability in the response. A common mechanism involved in the modulation of responsiveness to cytokines is represented by regulation of their receptor expression through autocrine ligand-mediated loops. The present study is aimed at investigating the regulation of IFNalpha/beta receptor (IFNAR) during IFNbeta therapy in patients with MS and at correlating it with the biologic responsiveness to the cytokine. METHODS: Quantitative PCR measurements of IFNAR-1 and the three IFNAR-2 isoforms were performed in 141 patients after short-term and long-term treatment. Patients were also regularly screened for anti-IFNbeta neutralizing antibodies (NAbs). IFN-inducible myxovirus resistance protein A messenger RNA was used as an indicator of bioactivity. RESULTS: Pretreatment levels of IFNAR-2 in patients were lower overall than in controls (p = 0.038), and high levels correlated with greater bioactivity. Upon prolonged treatment, NAb-negative patients displayed a state of decreased transmembrane IFNAR-2 expression (p < or = 0.025), whereas levels of soluble IFNAR-2 were slightly increased (p < 0.0001). The presence of NAbs reversed these effects (p < or = 0.0056). In NAb-positive patients, pretreatment expression levels of both transmembrane IFNAR-2 isoforms were significantly lower than in NAb-negative patients (p < or = 0.0089). CONCLUSIONS: Findings show that interferon-alpha/beta receptor (IFNAR)-2 isoforms are important regulators of the responsiveness to endogenous and systemically administered interferon beta (IFNbeta). They show a dual action, agonistic and antagonistic, that influences both the magnitude and the nature of the biologic response to IFNbeta. Levels of IFNAR-2 are regulated with the aim of keeping the body in a state of equilibrium, even when nonphysiologic stimuli are present.
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Gilli et al. (2008) conducted an observational in Multiple sclerosis (n=141). Interferon beta (IFNbeta) vs. Controls and NAb-positive patients was evaluated on IFNAR-1 and IFNAR-2 isoform expression levels. In 141 patients with multiple sclerosis, prolonged interferon beta treatment decreased transmembrane IFNAR-2 expression (p<=0.025) and increased soluble IFNAR-2 (p<0.0001) in NAb-negative patients.
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