title: Role of Anti-Osteopontin Antibodies in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.
abstract: Osteopontin (OPN) is highly expressed in demyelinating lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). OPN is cleaved by thrombin into N- (OPN-N) and C-terminal (OPN-C) fragments with different ligands and functions. In EAE, administering recombinant OPN induces relapses, whereas treatment with anti-OPN antibodies ameliorates the disease. Anti-OPN autoantibodies (autoAbs) are spontaneously produced during EAE but have never been detected in MS. The aim of the study was to evaluate anti-OPN autoAbs in the serum of MS patients, correlate them with disease course, and recapitulate the human findings in EAE. We performed ELISA in the serum of 122 patients collected cross-sectionally, and 50 patients with relapsing-remitting (RR) disease collected at diagnosis and followed longitudinally for 10 years. In the cross-sectional patients, the autoAb levels were higher in the RR patients than in the primary- and secondary-progressive MS and healthy control groups, and they were highest in the initial stages of the disease. In the longitudinal group, the levels at diagnosis directly correlated with the number of relapses during the following 10 years. Moreover, in patients with active disease, who underwent disease-modifying treatments, autoAbs were higher than in untreated patients and were associated with low MS severity score. The autoAb displayed neutralizing activity and mainly recognized OPN-C rather than OPN-N. To confirm the clinical effect of these autoAbsin vivo, EAE was induced using myelin oligodendrocyte glycoprotein MOG35-55in C57BL/6 mice pre-vaccinated with ovalbumin (OVA)-linked OPN or OVA alone. We then evaluated the titer of antibodies to OPN, the clinical scores andin vitrocytokine secretion by spleen lymphocytes. Vaccination significantly induced antibodies against OPN during EAE, decreased disease severity, and the protective effect was correlated with decreased T cell secretion of interleukin 17 and interferon-γex vivo. The best effect was obtained with OPN-C, which induced significantly faster and more complete remission than other OPN vaccines. In conclusion, these data suggest that production of anti-OPN autoAbs may favor remission in both MS and EAE. Novel strategies boosting their levels, such as vaccination or passive immunization, may be proposed as a future strategy in personalized MS therapy.
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Clemente
authors.affiliation: Department of Translational Medicine, IRCAD, Neurology Unit, University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Comi
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Raineri
authors.affiliation: Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck , Innsbruck , Austria.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cappellano
authors.affiliation: Department of Translational Medicine, IRCAD, Neurology Unit, University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Domizia
authors.initials: D
authors.lastname: Vecchio
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Casimiro L
authors.initials: CL
authors.lastname: Gigliotti
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.affiliation: Department of Drug Science and Technology, University of Turin , Torino , Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dianzani
authors.affiliation: Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute , Milano , Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: Laboratory of Human Genetics of Neurological Disorders, CNS Inflammatory Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute , Milano , Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli-Boneschi
authors.affiliation: Neurology Unit 2, Centro Riferimento Regionale Sclerosi Multipla (CRESM), Azienda Ospedaliero-Universitaria San Luigi , Orbassano , Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Caldano
authors.affiliation: Neurology Unit 2, Centro Riferimento Regionale Sclerosi Multipla (CRESM), Azienda Ospedaliero-Universitaria San Luigi , Orbassano , Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertolotto
authors.affiliation: ASO Neurologia, Azienda Ospedaliera S. Croce e Carle , Cuneo , Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ambrogio
authors.affiliation: Department of Life Science, University of Trieste , Trieste , Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Sblattero
authors.affiliation: Department of Translational Medicine, Medical Statistics Unit, University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cena
authors.affiliation: IRCAD, Neurology Unit, Scientific Institute, Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo , Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Leone
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale (UPO) , Novara , Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
keywords: autoantibodies; experimental autoimmune encephalomyelitis; multiple sclerosis; osteopontin; vaccination