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1. Quantification and functional characterization of antibodies to native aquaporin 4 in neuromyelitis optica.

Author

Kalluri SR, Illes Z, Srivastava R, Cree B, Menge T, Bennett JL, Berthele A, and Hemmer B

Subjects
Adult, Aged, Aquaporin 4 cerebrospinal fluid, Aquaporin 4 genetics, Biological Assay methods, Cell Line, Tumor, Cohort Studies, Cytotoxicity Tests, Immunologic methods, Female, Flow Cytometry methods, Gene Expression Regulation, Neoplastic physiology, Glioma pathology, Humans, Immunoglobulin G cerebrospinal fluid, Male, Middle Aged, Neuromyelitis Optica cerebrospinal fluid, Transfection methods, Young Adult, Aquaporin 4 blood, Aquaporin 4 immunology, Immunoglobulin G blood, Neuromyelitis Optica blood, Neuromyelitis Optica immunology
Abstract

Background: Antibodies targeting membrane proteins play an important role in various autoimmune diseases of the nervous system. So far, assays allowing proper analysis of such autoantibodies are largely missing. A serum autoantibody to aquaporin 4 (AQP4) is associated with neuromyelitis optica (NMO). Although several assays are able to detect this autoantibody, they do not allow determination of the biological activity of anti-AQP4 antibodies., Objective: To develop a bioassay for quantification and characterization of human anti-AQP4 antibodies., Design, Setting, and Participants: We developed a novel bioassay for quantification and characterization of human anti-AQP4 antibodies based on high-level expression of native AQP4 (nAQP4) protein on the surface of human astroglioma cells. The test was validated in 2 independent cohorts of patients with NMO spectrum disease., Results: We detected anti-nAQP4-IgG with a sensitivity of 57.9% and specificity of 100% in patients with NMO spectrum diseases, suggesting that our bioassay is at least as sensitive and specific as the gold-standard NMO-IgG assay. The anti-AQP4 antibodies belonged predominantly to the IgG1 isotype and bound with high affinity to the extracellular domain of nAQP4. Our data suggest that the autoantibody exerts pathological properties because nAQP4-IgG-positive sera induced cell death of nAQP4-expressing cells by antibody-dependent cellular natural killer cell cytotoxic effect and complement activation. Furthermore, nAQP4-IgG titers strongly correlated with in vitro cytotoxic effect., Conclusions: In NMO, this assay may help to unravel the biological function of anti-nAQP4-IgG. Our findings demonstrate the potential of bioassays to characterize biologically relevant antibodies in human autoimmune diseases.

Published
2010
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2. Restrictive and diversifying elements of the anti-myelin/oligodendrocyte glycoprotein antibody response in primate experimental allergic encephalomyelitis.

Author

von Büdingen HC, Menge T, Hauser SL, and Genain CP

Subjects
Animals, Animals, Outbred Strains, Autoantigens immunology, Callithrix genetics, Callithrix immunology, Encephalomyelitis, Autoimmune, Experimental immunology, Genes, Immunoglobulin genetics, Immunoglobulin Fab Fragments genetics, Immunoglobulin Heavy Chains genetics, Immunoglobulin Light Chains genetics, Immunoglobulin Variable Region genetics, Immunoglobulin kappa-Chains genetics, Molecular Sequence Data, Myelin Proteins, Myelin-Oligodendrocyte Glycoprotein, Antibody Diversity, Autoantibodies genetics, Encephalomyelitis, Autoimmune, Experimental genetics, Immunoglobulin G genetics, Myelin-Associated Glycoprotein immunology
Abstract

Autoantibody responses against conformational epitopes of myelin/oligodendrocyte glycoprotein (MOG) possess myelin destructive potential, as demonstrated in the marmoset model of human multiple sclerosis (MS) and in some rodent models of experimental allergic encephalomyelitis. We have previously characterized monoclonal Fab fragments specific for conformational epitopes of MOG that were derived from a combinatorial antibody library generated from a MOG-immune marmoset. In this paper, we address the molecular heterogeneity of humoral responses against MOG in this outbred model of MS by studying additional antibody clones derived from a genetically unrelated animal. We find that all MOG-specific IgGkappa Fab fragments, unrelated to genetic make-up, utilize a restricted set of variable region genes, IGHV1 and IGHV3 for the H chain and IGKV1, IGKV3, and IGKV5 for the L chain. Despite these restricting factors, diversity within these antibody repertoires can be observed, predominantly within the H-chain CDR3 regions. Our findings suggest that only a limited set of Ig genes is necessary to launch a diverse, destructive humoral immune response against a single CNS antigen in primates. These results are the first to contribute to a better understanding of how myelin-directed and potentially destructive autoantibody responses may develop in human MS.

Published
2006
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3. Antibodies to native myelin oligodendrocyte glycoprotein are serologic markers of early inflammation in multiple sclerosis.

Author

Lalive PH, Menge T, Delarasse C, Della Gaspera B, Pham-Dinh D, Villoslada P, von Büdingen HC, and Genain CP

Subjects
Adolescent, Adult, Aged, Animals, Antibodies blood, Biological Assay, Biomarkers blood, CHO Cells, Callithrix, Cricetinae, Cricetulus, Early Diagnosis, Female, Humans, Immunodominant Epitopes immunology, Immunoglobulin G immunology, Inflammation diagnosis, Inflammation immunology, Male, Middle Aged, Multiple Sclerosis immunology, Myelin Proteins, Myelin-Oligodendrocyte Glycoprotein, Immunoglobulin G blood, Multiple Sclerosis diagnosis, Myelin-Associated Glycoprotein immunology
Abstract

Myelin oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed in CNS oligodendrocytes and outermost myelin lamellae. Anti-MOG Abs cause myelin destruction (demyelination) in animal models of multiple sclerosis (MS); however, such pathogenic Abs have not yet been characterized in humans. Here, a method that specifically detects IgG binding to human MOG in its native, membrane-embedded conformation on MOG-transfected mammalian cells was used to evaluate the significance of these auto Abs. Compared with healthy controls, native MOG-specific IgGs were most frequently found in serum of clinically isolated syndromes (P < 0.001) and relapsing-remitting MS (P < 0.01), only marginally in secondary progressive MS (P < 0.05), and not at all in primary progressive MS. We demonstrate that epitopes exposed in this cell-based assay are different from those exposed on the refolded, extracellular domain of human recombinant MOG tested by solid-phase ELISA. In marmoset monkeys induced to develop MS-like CNS inflammatory demyelination, IgG reactivity against the native membrane-bound MOG is always detected before clinical onset of disease (P < 0.0001), unlike that against other myelin constituents. We conclude that (i) epitopes displayed on native, glycosylated MOG expressed in vivo are early targets for pathogenic Abs; (ii) these Abs, which are not detected in solid-phase assays, might be the ones to play a pathogenic role in early MS with predominant inflammatory activity; and (iii) the cell-based assay provides a practical serologic marker for early detection of CNS autoimmune demyelination including its preclinical stage at least in the primate MS model.

Published
2006
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4. Antibody responses against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis.

Author

Menge T, Lalive PH, von Büdingen HC, Cree B, Hauser SL, and Genain CP

Subjects
Adult, Aged, Animals, Biomarkers, Callithrix, Encephalomyelitis, Autoimmune, Experimental immunology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Male, Middle Aged, Multiple Sclerosis diagnosis, Galactosylceramides immunology, Immunoglobulin G blood, Multiple Sclerosis immunology
Abstract

Background: Galactocerebroside, the major glycolipid of central nervous system myelin, is a known target for pathogenic demyelinating antibody responses in experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis (MS)., Objective: To address the importance of anti-galactocerebroside (alpha-GalC) antibodies in MS and to evaluate them as biomarkers of disease., Methods: alpha-GalC IgGs were quantified from sera of patients with MS and in marmoset EAE by a new immunosorbent assay., Results: We report a significant difference in serum alpha-GalC IgG titers between patients with relapsing-remitting (RR)-MS and healthy controls (HCs; P < .001). The frequencies of alpha-GalC antibody-positive subjects (alpha-GalC titers > or = mean HC titers+3 SD) are also significantly elevated in RR-MS compared with HC (40% vs 0%; P = .0033). Immunoaffinity purified alpha-GalC IgGs from human serum bind to cultured human oligodendrocytes, indicating that the ELISA detects a biologically relevant epitope. Corroborating these findings, alpha-GalC antibody responses in marmoset EAE were similarly found to be specifically associated with the RR forms and not the peracute or progressive forms, in contrast with other anti-myelin antibodies (P = .0256)., Conclusion: (1) alpha-GalC antibodies appear MS-specific and are not found in healthy subjects, unlike antibodies against myelin proteins; (2) when present, alpha-GalC antibodies identify mostly RR-MS and may be an indicator of ongoing disease activity. This novel assay is a suitable and valuable method to increase accuracy of diagnosis and disease staging in MS.

Published
2005
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5. Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

Author

Ruth Dobson, P. Kleinova, Tessel F. Runia, H.-P. Hartung, Maria Trojano, A.D. Martinez, Viviana Annibali, Sreeram V. Ramagopalan, Florian Deisenhammer, Mohsen Khademi, Jens Kuhle, Jan Lycke, Mar Tintoré, Ludwig Kappos, Pietro Iaffaldano, Antonio Uccelli, Dana Horakova, Kjell-Morten Myhr, Cecilia Rajda, Konrad Rejdak, Stig Wergeland, Monica Marta, Roberto Furlan, Florian Lauda, Jean Pelletier, Romain Marignier, G. Comi, Giulio Disanto, Romy Roesler, Vita Direnzo, Özgür Yaldizli, N. Moll, Silvia Romano, Sergey V. Lapin, Sylvain Lehmann, Irena Dujmovic, Elio Scarpini, Tomas Olsson, Rogier Q. Hintzen, Raija L.P. Lindberg, E. P. Evdoshenko, Siegrid Fuchs, B. C. Kieseier, Henrik Larsson, Eric Thouvenot, Jonathan P. Bestwick, Maurizio Leone, László Vécsei, S. Saip, Pablo Villoslada, Roberto Bergamaschi, Xavier Montalban, Øivind Torkildsen, José C. Álvarez-Cermeño, Joanne Topping, Albert Saiz, Isabel Bosca, Hayrettin Tumani, Adriana Carrá, Joep Killestein, Sara Llufriu, N. Barizzone, Ute-Christiane Meier, Diego Franciotta, David Brassat, Christian Enzinger, Michael Khalil, Gavin Giovannoni, Timucin Avsar, Scott L. Rauch, Aksel Siva, N. Lazareva, Clas Malmeström, Jette L. Frederiksen, Harald Hegen, Ugur Uygunoglu, Luisa M. Villar, Lucia Bianchi, Marco Salvetti, Tobias Derfuss, Giovanni Castelnovo, Ayse Altintas, Rocco Adiutori, E. Colombo, G. Dalla Costa, Daniela Galimberti, Madeleine H. Sombekke, Vittorio Martinelli, Sandra D'Alfonso, Manuel Comabella, Eva Havrdova, Fredrik Piehl, Charlotte E. Teunissen, Til Menge, Jelena Drulovic, C. Picard, Alice Laroni, Christian Confavreux, Chiara Fenoglio, Neurology, Laboratory Medicine, NCA - Neuroinflamation, Direction des Applications Militaires (DAM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), National Oceanography Centre (NOC), Department of Anatomy and Structural Biology Albert Einstein College of Medicine, Albert Einstein College of Medicine [New York], Department of public health, University of Turin, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Water Environment Technology, Chalmers University of Technology [Göteborg], Department of Neurology, A.O.U. Maggiore della Carità, and IRCAD, Novara, Leibniz-Institut für Gewässerökologie und Binnenfischerei (IGB), Leibniz Association, Department of Neurology, University of California [San Francisco] (UCSF), University of California-University of California, Center for Neuroimmunology, Service of Neurology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Université européenne de Bretagne - European University of Brittany (UEB), Laboratoire de l'intégration, du matériau au système (IMS), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Azm Center for Biotechnology Research, Agence universitaire de la Francophonie (Beyrouth, Lebanon)-Lebanese University [Beirut] (LU), FOI, Linköping University (LIU), Centro Dino Ferrari [Milano], Università degli Studi di Milano [Milano] (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, IRMP-Louvain, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Dipartimento Ingegneria Aerospaziale 'Lucio Lazzarino' (DIA), University of Pisa - Università di Pisa, International Centre for Hydrology 'Dino Tonini' and Dipartimento IMAGE, Universita degli Studi di Padova, Dept. of Neurology, University Hospital Rigshospitalet, University of California [Berkeley], University of California, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, The Weizmann Institute, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Laboratory of Neuroimmunology, IRCCS, Neurological Institute 'C. Mondino', University of Pavia, Pa, University of Pavia, Department of Neurology, Albert Szent-Gyorgyi Clinical Centre, University of Szeged [Szeged], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Universitat de Barcelona (UB)-Hospital Clinic, University of Ulm, Department of Neurology, Service Anesthésie et Réanimation [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], University of Eastern Piedmont, Department of Medical Sciences, IRCAD, Novara, Vall d'Hebron University Hospital [Barcelona], Department of Public Health and Clinical Medicine, Umeå University, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Universitaire de Bâle, Laboratory of Molecular Virology, Université libre de Bruxelles (ULB), Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Department of Atmospheric, Oceanic and Planetary Physics [Oxford] (AOPP), University of Oxford [Oxford], Blizard Institute of Cell and Molecular Science, Università degli studi di Torino = University of Turin (UNITO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Padova = University of Padua (Unipd), University of California [Berkeley] (UC Berkeley), University of California (UC), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia = University of Pavia (UNIPV), University of Oxford, Direction des Applications Militaires ( DAM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), National Oceanography Centre, University of Southampton [Southampton], Albert Einstein College of Medicine, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Neuropsychiatrie : recherche épidémiologique et clinique, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Leibniz-Institute, University of California [San Francisco] ( UCSF ), Université européenne de Bretagne ( UEB ), Laboratoire de l'intégration, du matériau au système ( IMS ), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique ( CNRS ), Agence universitaire de la Francophonie (Beyrouth, Lebanon)-Lebanese University [Beirut], Linköping University ( LIU ), Department of Neurological Sciences, Dino Ferrari Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy, Università di Bologna [Bologna] ( UNIBO ), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Dipartimento Ingegneria Aerospaziale 'Lucio Lazzarino' ( DIA ), Università di Pisa, Universita degli Studi di Padova = University of Padua = Université de Padoue, Educational Testing Service, Graduate School of Education, University of California at Berkeley, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Universitat de Barcelona ( UB ) -Hospital Clinic, Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Institut de recherche en biothérapie ( IRB ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Université de Montpellier ( UM ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Department of Atmospheric, Oceanic and Planetary Physics [Oxford] ( AOPP ), Kuhle, J., Disanto, G., Dobson, R., Adiutori, R., Bianchi, L., Topping, J., Bestwick, J. P., Meier, U. -C., Marta, M., Dalla Costa, G, Runia, T., Evdoshenko, E., Lazareva, N., Thouvenot, E., Iaffaldano, P., Direnzo, V., Khademi, M., Piehl, F., Comabella, M., Sombekke, M., Killestein, J., Hegen, H., Rauch, S., Dalfonso, S., Alvarez-Cermeno, J. C., Kleinova, P., Horakova, D., Roesler, R., Lauda, F., Llufriu, S., Avsar, T., Uygunoglu, U., Altintas, A., Saip, S., Menge, T., Rajda, C., Bergamaschi, R., Moll, N., Khalil, M., Marignier, R., Dujmovic, I., Larsson, H., Malmestrom, C., Scarpini, E., Fenoglio, C., Wergeland, S., Laroni, A., Annibali, V., Romano, S., Martinez, A. D., Carra, A., Salvetti, M., Uccelli, A., Torkildsen, O., Myhr, K. M., Galimberti, D., Rejdak, K., Lycke, J., Frederiksen, J. L., Drulovic, J., Confavreux, C., Brassat, D., Enzinger, C., Fuchs, S., Bosca, I., Pelletier, J., Picard, C., Colombo, E., Franciotta, D., Derfuss, T., Lindberg, R. L. P., Yaldizli, O., Vecsei, L., Kieseier, B. C., Hartung, H. P., Villoslada, P., Siva, A., Saiz, A., Tumani, H., Havrdova, E., Villar, L. M., Leone, M., Barizzone, N., Deisenhammer, F., Teunissen, C., Montalban, X., Tintore, M., Olsson, T., Trojano, M., Lehmann, S., Castelnovo, G., Lapin, S., Hintzen, R., Kappos, L., Furlan, R., Martinelli, V., Comi, G., Ramagopalan, S. V., and Giovannoni, G.

Subjects
Male, Pathology, serum 25-hydroxyvitamin D3 (25-OH-D), [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Gastroenterology, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, sclerosis, clinically isolated syndrome (CIS), Vitamin D, 0303 health sciences, Clinically isolated syndrome, Nuclear Proteins, Prognosis, Magnetic Resonance Imaging, Neurology, Clinically definite multiple sclerosis (CDMS), Epstein-Barr nuclear antigen 1 (EBNA-1), oligoclonal bands (OCBs), Predictive value of tests, Cohort, Disease Progression, Female, Cohort study, Adult, medicine.medical_specialty, Multiple Sclerosis, clinic study, Risk Assessment, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Vitamin D and neurology, Humans, Survival analysis, 030304 developmental biology, business.industry, Multiple sclerosis, Oligoclonal Bands, Endonucleases, medicine.disease, Survival Analysis, chemistry, Immunoglobulin G, [ SHS.ANTHRO-BIO ] Humanities and Social Sciences/Biological anthropology, Neurology (clinical), business, Cotinine, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Published
2015

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