title: Increased interleukin-6 correlates with myelin oligodendrocyte glycoprotein antibodies in pediatric monophasic demyelinating diseases and multiple sclerosis.
abstract: Acquired demyelinating syndromes (ADS) in children evolve either as a monophasic disease diagnosed as acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM) or optic neuritis (ON), or a multiphasic one with several relapses most often leading to the diagnosis of multiple sclerosis (MS) or neuromyelitis optica (NMO). These neuroinflammatory disorders are increasingly associated with autoantibodies against proteins such as aquaporin-4 in rare instances, and more frequently against myelin oligodendrocyte glycoprotein (MOG). Recently, in adult NMO patients, C5a levels were shown to be elevated in cerebrospinal fluid (CSF) during acute exacerbation. We investigated the CSF levels of anaphylatoxins and pro-inflammatory cytokines, and plasma MOG antibodies in onset samples from children with ADS. Thirty four children presenting with a first episode of ADS, 17 with monophasic ADS (9 with ADEM, 4 with TM and 4 with ON) and 17 with MS, who had paired blood and CSF samples at onset were included and compared to 12 patients with other non-inflammatory neurological disorders (OND). Cytokines and anaphylatoxins in CSF were measured by Cytometric Bead Array immunoassay. MOG antibody titers in plasma were tested by flow cytometry using a stable cell line expressing full-length human MOG. We found a significant increase in C5a levels in the CSF of patients with monophasic ADS (n=17) compared to OND (n=12, p=0.0036) and to MS (n=17, p=0.0371). The C5a levels in MS were higher than in OND without reaching significance (p=0.2). CSF IL-6 levels were significantly increased in monophasic ADS compared to OND (p=0.0027) and to MS (p=0.0046). MOG antibody plasma levels were significantly higher in monophasic ADS (p<0.0001) and, to a lesser extent, in MS compared to OND (p=0.0023). Plasma MOG antibodies and CSF IL-6 levels were significantly correlated (r=0.51, p=0.018). CSF C5a and IL-6 levels are increased in monophasic ADS but not in MS when compared to OND, suggesting that these markers may help to predict monophasic or relapsing fate of ADS at onset. MOG antibody titers, which were higher in monophasic ADS than in MS, correlated with IL-6 levels, but not with C5a, suggesting an association between MOG antibodies and neuroinflammation in pediatric ADS.
authors.affiliation: Inserm, U 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud 11, CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Faculté de médecine - 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France. Electronic address: philippe.horellou@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Horellou
authors.affiliation: Inserm, U 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud 11, CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Faculté de médecine - 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Inserm, U 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud 11, CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Faculté de médecine - 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France.
authors.forename: Vixra
authors.initials: V
authors.lastname: Keo
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Immunology Department, Le Kremlin-Bicêtre, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Chrétien
authors.affiliation: CRC MIRCen, INSERM/CEA, Fontenay-aux-Roses, France.
authors.forename: Ché
authors.initials: C
authors.lastname: Serguera
authors.affiliation: Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Waters
authors.affiliation: Inserm, U 1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Université Paris-Sud 11, CEA, DSV/iMETI, Division of Immuno-Virology, IDMIT, Faculté de médecine - 63, rue Gabriel Péri, 94276 Le Kremlin-Bicêtre Cedex, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Pediatric Neurology department, National Referral Center for Neuro-Inflammatory Diseases in Children, Le Kremlin-Bicêtre, France.
authors.forename: Kumaran
authors.initials: K
authors.lastname: Deiva
mesh_terms: D000293:Adolescent; D000706:Anaphylatoxins / Q000134:cerebrospinal fluid / Q000276:immunology / Q000378:metabolism; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003711:Demyelinating Diseases / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D012189:Retrospective Studies
chemical_list: D000706:Anaphylatoxins; D016207:Cytokines; D007074:Immunoglobulin G; D015850:Interleukin-6; D063308:Myelin-Oligodendrocyte Glycoprotein
keywords: Acute demyelinating encephalomyelitis; Complement; Interleukin-6; Multiple sclerosis; Myelin oligodendrocyte glycoprotein; Optic neuritis; Transverse myelitis