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/β receptor in IFNβ-treated patients with multiple sclerosisFrom Centro Riferimento Regionale Sclerosi Multipla (CRESM) and Neurobiologia Clinica, ASO S. Luigi Gonzaga, Orbassano, Torino, Italy.
Address correspondence and reprint requests to Dr. Francesca Gilli, Centro di Riferimento Regionale Sclerosi Multipla (CRESM) & Neurobiologia Clinica, ASO S. Luigi Gonzaga, Regione Gonzole 10, I-10043, Orbassano (Torino) Italy neurobiologia{at}sanluigi.piemonte.it
Background: The cytokine interferon beta (IFNβ) 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 IFN
/β receptor (IFNAR) during IFNβ 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-IFNβ 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 
0.025), whereas levels of soluble IFNAR-2 were slightly increased (p < 0.0001). The presence of NAbs reversed these effects (p 0.0056). In NAb-positive patients, pretreatment expression levels of both transmembrane IFNAR-2 isoforms were significantly lower than in NAb-negative patients (p 0.0089).
Conclusions: Findings show that interferon-/β receptor (IFNAR)-2 isoforms are important regulators of the responsiveness to endogenous and systemically administered interferon beta (IFNβ). They show a dual action, agonistic and antagonistic, that influences both the magnitude and the nature of the biologic response to IFNβ. Levels of IFNAR-2 are regulated with the aim of keeping the body in a state of equilibrium, even when nonphysiologic stimuli are present.
Abbreviations: AUC = area under the curve; BAB = binding antibody; CRESM = Centro Riferimento Regionale Sclerosi Multipla; GAPDH = glyceraldehyde phosphate dehydrogenase; IFNβ = interferon beta; IFNAR = interferon-/β receptor; iNAb+ = isolated neutralizing antibody positive; mRNA = messenger RNA; MS = multiple sclerosis; MxA = myxovirus resistance protein A; NAb = neutralizing antibody; NAb+ = neutralizing antibody positive; NAb– = neutralizing antibody negative; NAb-DFS = neutralizing antibody development–free survival; NS = not significant; PBMC = peripheral blood mononuclear cell; pNAb+ = persistent neutralizing antibody positive; RE = relative expression; ROC = receiver operating characteristic; sc = subcutaneous; TRU = 10-fold reduction unit.
Supplemental data at www.neurology.org
Editorial, page 1936
e-Pub ahead of print on October 29, 2008, at www.neurology.org.
This study was supported by a grant from the "Fondazione Italiana Sclerosi Multipla" (FISM contract 2007/R/6). Also, financial support was obtained from the FORB (Fondazione per la Ricerca Biomedica, ONLUS) and from the S. Luigi Gonzaga ONLUS. Finally, authors participate in NABINMS, a specific targeted research project on neutralizing antibodies to interferon beta in multiple sclerosis, established by the European Commission under its 6th Framework Programme (contract number 018926).
Disclosure: The authors report no disclosures.
Received November 19, 2007. Accepted in final form June 3, 2008.
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Neurology 2008 71: 1936-1937.
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