Anti-MOG autoantibodies pathogenicity in children and macaques demyelinating diseases
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Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species.
The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared.
Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG−. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG− children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration.
Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.
KeywordsAnti-MOG IgG Cytokines Complement Demyelination Brain inflammation CSF
Acute demyelinating encephalomyelitis
- ADS MOG+
ADS with anti-MOG-Abs
Acquired demyelinating syndromes
Experimental autoimmune encephalomyelitis
Incomplete Freund’s adjuvant
Myelin oligodendrocyte glycoprotein
Magnetic resonance imaging
Neuromyelitis optica spectrum disorder
- RADS MOG+
Relapsing ADS with anti-MOG-Abs
Recombinant human MOG
More than 50% of acquired demyelinating syndromes (ADS) in children are associated to myelin oligodendrocyte glycoprotein antibodies (anti-MOG-Abs). Anti-MOG-Abs are frequent in optic neuritis (ON), transverse myelitis (TM), acute demyelinating encephalomyelitis (ADEM), or neuromyelitis optica spectrum disorder (NMOSD), but are rare in multiple sclerosis (MS) . About 40% of ADS associated to anti-MOG-Abs (MOG+) evolve as a non-MS relapsing disease reluctant to conventional treatments, with cognitive disabilities in 20% of these children .
MOG is a CNS protein located at the outermost lamellae of myelin, and the extracellular domain of MOG or MOG peptides are efficiently used to induce brain restricted inflammatory demyelinating experimental autoimmune encephalomyelitis (EAE) in animals, the reference model of ADS .
Mouse EAE helps to understand the genetic and immune processes of autoimmunity , while non-human primates (NHP) models recapitulate the complex interplay between environment and the immune response. Moreover, macaques are phylogenetically closer to humans, which makes them uniquely suitable to test new therapies with antibodies or cytokines retaining functional and structural features restricted to primates.
Cynomolgus macaques immunized with recombinant human MOG (rhMOG) in incomplete Freund’s adjuvant (IFA) develop an acute encephalomyelitis, with brain magnetic resonance imaging (MRI) and demyelinating lesions reminiscent to that described in ADS .
To assess relatedness between anti-MOG-Abs-associated encephalomyelitis in macaques and children, we performed a comparative analysis between species with emphasis on cytokine production at disease onset and IgG and complement deposition in lesions. We report similar inflammatory processes in either species related to the presence of anti-MOG-Abs. This work contributes to our understanding of immunopathology of ADS associated with anti-MOG-Abs and substantiates the value of NHP for the setting of prospective therapies for ADS with anti-MOG-Abs (ADS MOG+).
Materials and methods
To assess the pathogenic role of anti-MOG-Abs in humans and macaques in the course of encephalomyelitis, we compared radiological, immune, and histologic parameters of nine animals with EAE and 27 humans with ADS of which 12 with anti-MOG-Abs. We used samples available in our respective collections consisting of three main groups of nine macaques with EAE, 15 children with ADS without anti-MOG-Abs, and 12 children with ADS with anti-MOG-Abs. As for comparisons between these groups, no previous data allowed to calculate sample size effect, we evaluated sample size through the resource equation method, which states that an acceptable degree of freedom (DF) for estimation of error with ANOVA ranges between 10 and 20. DF is calculated through the formula DF = (n (number of subjects) × k (number of groups)) − k. For each group, the DF was equal to 24 (EAE), 42 (ADS MOG+), and 33 (ADS MOG−), all above 20 indicating in each case an adequate size to assess statistical differences between groups .
Patients and ethics
Twenty-seven children followed for a first episode of ADS in the national referral center for neuroinflammatory disease in children, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, from 2006/01/01 to 2014/31/12, and who had blood and/or CSF sample at onset, were included. An acute episode of demyelinating disease was defined as described . Ten patients samples (five MS, three ADEM, two ON had been already involved in a previous study) . Three patients, one from the 27 children group and two new patients lacking blood and CSF samples, were added to this study for histological analysis as they had a brain biopsy following an atypical pseudo-tumoral presentation. Patient 1 was a 7-year-old girl at the time of the biopsy (3 months after ON at onset, when she relapsed as severe ataxia with a pseudo-tumoral right peduncular lesion) and was later diagnosed as relapsing ADS with anti-MOG-Abs (RADS MOG+). Patient 2, a 2-year-old boy, presented an acute hemiplegia and alteration of consciousness with a pseudo-tumoral lesion on the right hemisphere. He had a brain biopsy at onset and was later diagnosed with monophasic ADEM with anti-MOG-Abs (ADS MOG+). Patient 3, a 4-year-old boy, presented an ADEM at onset which relapsed 1 month later. The third attack (gait difficulties) occurred 9 months later without encephalopathy and MRI evolved as an extensive leukodystrophy and a brain biopsy was performed at month 19. Extensive metabolic and genetic workup remained negative; there were no criteria for pediatric onset MS and the patient was diagnosed as non-MOG relapsing ADS (RADS MOG−). The brain biopsy was performed in this child at distance from steroids (> 30 days of steroids); he had no other immunomodulatory treatment in between). All human studies have been reviewed by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki. The national cohort of first demyelinating episode “Kidbiosep 2004” (N° 910506) was authorized by the Commission National de l’Information et des Libertés and an informed consent form was obtained for all included children.
Animals and ethics
Samples from the MIRCen collection including plasma, CSF, and brain tissue as well as MRI images and clinical data from nine adult cynomolgus macaques (Macaca fascicularis) immunized with rhMOG/IFA were included in this study. Immunization protocols, clinical observations, CSF, and blood collection methods were described previously . Seven to 9-year-old cynomolgus macaques were purpose-bred animals imported from a licensed primate-breeding center in Mauritius (Cynologics Ltd, Port Louis, Mauritius). Following European directive 2010/63/UE and French regulations, the project was performed in an agreed user establishment (agreement number C 92-032-02), with an institutional permission obtained from the French Ministry of Agriculture after evaluation by an ethical committee (2015081710528804vl). All procedures were performed in compliance with CEA’s animal welfare structure under veterinary care at all times. Macaques were observed double-blinded daily from immunization until the end of the experiment; they were scored daily for EAE outcome directly by the experimenter or through webcam surveillance, using a semi-quantitative functional scale grading disease severity form grade 0 (healthy), grade 0.5 (loss of appetite, vomiting), grade 1 (apathy), grade 2 (ataxia, sensory loss and/or visual problems), grade 2.5 (hemiparesis or paraparesis), grade 3 (hemiplegia or paraplegia), grade 4 (quadriplegia), to grade 5 (protraction), all signs corresponding to classical neurological nosology conducing to ADS diagnosis (Additional file 1: Table S1 and S2). Ethical endpoints of EAE are based on evaluation of disease gravity, with increased severity shortening time of the experiment ultimately ending with animal euthanasia . One animal (EAE_c, Additional file 1: Table S2) was treated with 140 mg/kg per day of corticoids (Solumedrol ®) intravenous for 3 days starting at the very onset of disease, grade 0.5 with tremor of lower limbs confirmed with MRI.
Treatment of cerebrospinal fluid and plasma
In children, CSF samples were obtained by lumbar puncture before treatment at onset of encephalomyelitis and processed by the laboratory hospital. For our study, we used 0.5 ml of CSF, centrifuged and stored at − 80 °C. Plasma was collected from 10 ml of blood in heparinized tubes and stored at − 80 °C.
In macaques, CSF was sampled before immunization, as well as at EAE onset, for up to 500 μl per puncture. A 150 μl aliquot was used for analysis and the remaining was centrifuged and stored at − 80 °C free of cells. Venous blood samples were collected every week, starting before the first immunization with rhMOG/IFA and until the end of experimentation, as well as at EAE onset and before euthanasia, with a maximum volume of up to 15% of the total blood volume per animal per month. Blood was centrifuged and plasma was stored at − 80 °C.
Measurement of anti-MOG-Abs levels
Plasma was tested by cell-based assay (CBA) for titration of antibodies to cell surface MOG epitopes as described . Briefly, 1.5 × 105 HEK293A cells transfected with the pIRES2-DsRed2-human MOG were incubated with patient or macaque plasma at dilutions ranging from 1:10 to 1:160 for 1 h at 4 °C. Cells were incubated with FITC conjugated anti-IgG H + L Fab'2 secondary antibody (Kallestad FITC conjugate, Bio-Rad, Marnes la Coquette, France) for 15 min at 4 °C and fixed. A total of 5 × 104 events per sample were recorded on a FACS Canto II instrument and analyzed with Flow Jo software (Ashland, OR, USA). Binding was expressed as mean fluorescence intensity (MFI). Levels of specific antibody binding in transfected cells were expressed as ΔMFI determined by the subtraction of MFI obtained with HEK293A control cells from that obtained with HEK293MOG+ cells. When a positive signal was found with transfected cells incubated with patients plasma diluted at 1:160, the sample was considered MOG-Abs positive (MOG+) .
Cerebrospinal fluid analysis
For children, CSF aliquots were sent for routine CSF analysis: cell count, oligoclonal band, glucose, lactate, total protein, and viral diagnosis. For macaques, the presence of cells in the CSF was evaluated and quantified in 100 μl after Cytospin™ 4 Cytocentrifuge (ThermoFisher Scientific, Villebon sur Yvette, France) centrifugation. Slides were stained with routine May-Grünwald Giemsa (MGG) special stain. Overall cell density and cell type were recorded.
Fifteen cytokines, for which kit cross-reaction with macaques’ epitopes had been previously assessed at IDMIT, were measured in plasma and CSF with multiplex technology, MILLIPLEX MAP human Cytokine Magnetic Bead Panel–Customized Premixed 13 Plex (Bulk) Packaging (IL-1β, GM-CSF, G-CSF, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-17A, TNFα, IFNγ), and MILLIPLEX MAP TGFß Magnetic Bead 3 Plex Kit–Immunology Multiplex Assay (TGFβ 1, TGFβ 2, and TGFβ 3), as two separate dosages, following supplier (Merckmillipore, Burlington, MA, USA) guidelines using a Bioplex 200 (BioRad, Hercules, CA, USA). The quantification of all samples was performed all together at the end of study samplings.
In children, brain MRI at onset was done during the first week and reviewed by a trained pediatric neurologist and a radiologist. The other items added were as follows: (1) for distribution, multiple lobe lesions: lesions present in more than one lobe (frontal, temporal, parietal, and occipital); bilateral lesion: lesions in both hemispheres; symmetric lesions: symmetric distribution of lesions; (2) signal intensity was evaluated in Spin Echo T2-weighted images, fluid-attenuated inversion recovery (FLAIR) Spin Echo, or T1-weighted images sequences; (3) for appearance of the lesion, fuzzy lesions: lesions lacking clear limits/borders. Similar sequences and images were compared to MRI from cynomolgus macaques at EAE onset for comparative analysis.
For macaques, magnetic resonance imaging (MRI) acquisitions were performed on a horizontal 7T Agilent scanner (Palo Alto, CA, USA), using a surface coil for transmission and reception (RAPID Biomedical GmbH, Rimpar, Germany). T2-weighted images were acquired using a high-resolution 2D fast spin-echo sequence. Lesion segmentation was performed on the T2-weighted images. During scanning, animals were anesthetized and maintained in a dedicated stereotaxic frame. The respiratory rate was monitored (SA Instruments Inc., Stony Brook, NY, USA) and body temperature was maintained at 37 °C using heated waterbed.
Human brain biopsies and 4% PFA-perfused macaque brains were processed to paraffin blocks, cut and stained with hematoxylin eosin stain (HE). Brain lesions were scored according to their overall severity, number, size, morphological characteristics, as well as according to the intralesional myelin loss.
Immunohistochemistry was used to investigate intracerebral IgG and IgM distribution. Briefly, paraffin wax-embedded tissues from humans or macaques were dewaxed in xylene and hydrated through graded alcohols. Endogenous peroxidase activity was suppressed by 3% H2O2 in PBS. Subsequently, sections were incubated with goat anti-IgG (anti-human IgG (gamma chain), 1/100, SAB3701291, Sigma-Aldrich, Saint-Louis, MI, USA), with rabbit anti-IgM (anti-human IgM, mu chain, 1/250, A0425), with polyclonal rabbit anti-Human C1q (1/100, A0136, Dako, Les Ulis, France), with anti-MBP (1/100, SMI94R BioLegend, San Diego, CA, USA), with rabbit anti-IBA1 (1/100, ab178846, Abcam, Cambridge, UK), or with mouse anti-CD68 (1/150, ab 955, KP1, Abcam). Tissues were then incubated with secondary antibodies coupled to fluorochromes Alexa 488 or Alexa 594 (ThermoFisher, Villebon-sur-Yvette, France). Alternatively, biotinylated rabbit-anti-goat, rabbit-anti-mouse, or goat-anti-rabbit antibodies were used as secondary antibodies, for 30 min at room temperature, followed by the avidin-biotin-peroxidase complex (Vectastain Elite ABC Kit, Vector Laboratories, PK 6100; Burlingame, CA, USA). Positive antigen-antibody reactions were visualized by incubation with 3,3-diaminobenzidine-tetrahydrochloride (DAB)–H2O2 in 0.1 M imidazole, pH 7.1 for 5 min, followed by slight counterstaining with hematoxylin.
Statistical analyses and graphical representations were obtained using Prism 5 (GraphPad Software, Inc). Student’s t test was used to compare two groups of values. The two-sided one-way ANOVA test with Tukey’s multiple comparison test was used to compare three groups or more values. Heatmaps were generated using R software (R Foundation for Statistical Computing, Vienna, Austria). A chi-squared test was performed to compare frequencies of lesions detected with MRI per brain regions. Hierarchical clustering represented by dendrograms were generated based on the Euclidian distance and using the complete linkage method.
Data availability statement
All data files enclosing values or images corresponding to clinical characteristic of patients or monkeys including routine biological measurements, MRI, as well as dosages of anti-MOG-Abs and cytokines are available upon request. Tissue sections from patient or animal lesions and samples of plasma or CSF can be shared upon request depending on availability and purpose.
Diseases characteristics in humans and macaques
In this study, with the purpose to compare the characteristics of encephalomyelitis among two species of primates, we analyzed nine macaques with EAE together with 27 patients with ADS. All macaques immunized with rhMOG/IFA declared EAE between 11 and 211 days post immunization (dpi) and disease manifested through signs of neurological dysfunction mimicking major clinical and radiological features of human ADS (Additional file 1: Table S1,), of variable severity that was diagnosed and graded at each round of observation  (Additional file 1: Table S2).
Children involved in this study. Characteristics of included children at last follow-up (FU)
ADS n = 27
MS n = 10
ADEM n = 5
ADS MOG+ n = 6
Others n = 6
Age years, mean, SD
11.1 ± 4.1
12.8 ± 1.9
7.9 ± 5.5
8.9 ± 4.3
13.1 ± 2.6
EDSS mean, SD
0.7 ± 1.2
1.4 ± 1.6
0 ± 0
0.7 ± 0.8
0 ± 0
Cell > 10 mm3
Prot > 0.5 g/dL
OCB (n = 22)
FU years, mean, SD
3.0 ± 1.6
3.5 ± 1.2
3.2 ± 0.9
3.8 ± 2.3
1.3 ± 0.7
Anti-MOG IgG levels in humans and macaques
Cytokine assessments in macaques and humans with EAE and ADS
Histopathology of lesions in EAE and ADS
Depending on diseases, the anatomical sites of lesions and their respective dissemination within the CNS varies , which usually determines the nature and magnitude of the neurological deficits. Main aspects of active lesions of cynomolgus macaques are well characterized . However, although the main histopathological hallmark is similar in EAE and ADS, and consists in perivenular inflammation and demyelination, the precise content in immune effectors varies among diseases (Additional file 1: Table S1).
In three macaque brains, prephagocytic lesions could be observed at relative proximity from active lesions, similar to that described in type II MS brain. These were characterized by myelin vacuolization but without leukocyte infiltrate (Fig. 5d). They contained diffuse IgG and C1q deposits surrounding white matter (Fig. 5e, f). These “early” lesions also contained IBA1+ activated microglia uniformly distributed in tissue or gathered at perivascular location (Fig. 5g), but a complete absence of astrogliosis (Fig. 5h), while GFAP expression is always observed in active lesions of macaques . This points at an early role of IgG and complement in triggering inflammation and myelin destruction in macaque EAE.
These results establish that IgG and complement are associated to myelin in brain lesions of macaque EAE and in lesions of patients with ADS MOG+, which further point at a direct correlation between the presence of circulating anti-MOG IgG and a role for these IgG as a mediator of brain inflammation in both species. In addition, in a biopsy from a patient with ADS MOG−, the absence of IgG and complement depositions illustrate such an inflammatory lesion exempt of antibodies and complement, which possibly characterize part of all ADS MOG−.
We report that cynomolgus macaques immunized with rhMOG/IFA develop an acute encephalomyelitis with a characteristic neuro-inflammatory profile similar to that observed in children with ADS MOG+, but which is different from that seen in children with ADS MOG− including all cases of MS. This is evidenced through a matching cytokine profile in the CSF at onset of EAE and ADS MOG+. In addition, we also show analogous histologic depositions of IgG and complement in demyelinated brain lesions of EAE and ADS MOG+. This points to a similar pathogenic role of anti-MOG-IgG in macaque EAE and in children ADS MOG+ that trigger a complement-mediated immune response against myelin. The present comparison also establishes the value of this macaque model for translational studies related to anti-MOG associated disease.
Cytokines signature in the CSF of ADS MOG+ and EAE
Previous studies of pediatric and adult ADS indicate that MOG+ diseases rather respond to immunosuppression, B cell depletion, or intravenous IgG but not to MS-modifying treatments, putting humoral immunity at the center of the inflammatory response [2, 13]. In fact, during the acute phases of ADS MOG+ and ADS AQP4+ NMOSD, cytokines related to B-lymphocytes, Th17 CD4+ cells, and neutrophils have been recurrently found elevated in the CSF [8, 10, 13, 14, 15], while MS patients rather express Th1 cytokines and chemokines . In the present study, it is notorious that the cytokines IL6 and G-CSF are found increased in the CSF of children with ADS MOG+ and in EAE but not in ADS MOG−. This highlights the predominant role of Th17 lymphocytes triggering demyelination through humoral and innate immunity in children, as observed in adults with or anti-MOG IgG-associated disease [8, 10, 13] and in NMOSD with anti-AQP4 IgG [13, 14, 15]. The absence of cytokines elevation in blood at onset of EAE or ADS indicates that the inflammatory response is restricted to the CNS, once antibodies and leukocytes have crossed the blood-brain barrier.
Demyelinating lesions in children with ADS MOG+ and macaques with EAE
Histopathology analysis of brain biopsies of seven adults with ADS MOG+ have been previously reported, showing the concomitance of a perivascular inflammatory infiltrate with IgG and complement depositions on myelin sheets and within macrophages characterizing demyelinating plaques with preserved axons and tissue structure [16, 17, 18, 19, 20, 21]. Echoing these evidences, we show that IgG and complement are found coating myelinated axons or within macrophages in inflammatory lesions of two children with ADS or RADS MOG+. These lesions exhibit disparate severity with tissue structure found conserved in the monophasic form but destructed in the relapsing MOG+ diseases. This was correlated to respective transient or sustained levels of circulating anti-MOG IgG, suggesting a causal link between continuous antibodies production and relapses . It is noteworthy that macaque EAE is globally more severe than ADS MOG+ as it evolves to a lethal outcome more often than to a resolving or a relapsing disease . We speculate that such severe encephalomyelitis in EAE is conceivably associated to higher levels of circulating anti-MOG-Abs than that dosed in patients, explaining the more pronounced infiltration of lesions by phagocytic cells and the increased release of cytokines and chemokines, as compared to ADS MOG+. Such a strong response in the macaque model is conceivably due to immunization with massive amounts of antigen, efficiently breaking a precarious peripheral tolerance to MOG and inducing a more uniform and wider expansion of MOG-reactive CD4+ T cells and their priming into Th1 or Th17 phenotype than it may happen in post-infectious or otherwise idiopathic ADS MOG+. In fact, immunosuppression attenuates EAE in non-human primates, favoring milder forms of disease clinically more alike remitting-relapsing ADS .
In macaques, we observed prephagocytic lesions in the white matter characterized by vacuolized myelin associated to IgG and C1q and a complete absence of leukocyte infiltrate. These images are reminiscent of tissue changes described in the periphery of active MS plaques and they are interpreted as a nascent type II demyelinating lesions in MS  and EAE in marmoset . This observation suggests that the first myelin disturbance is induced by antibody opsonization and complement activation prior to the recruitment of myelomonocytic cells and gives further consistency to the view of anti-MOG IgG as being a central pathogenic element in ADS MOG+. The presence of prephagocytic lesions indicates that very few autoreactive T cells are sufficient to disrupt the blood brain barrier and permit subsequent antibody-mediated inflammatory events as demonstrated with combination of adoptive transfer of patients anti-MOG antibodies and autoreactive T cells in mouse models of EAE .
The main limitation of this study concerns the small size of each group, especially the subgroups of ADS MOG+, or particular clinical entities as ADEM, NMOSD, ON, TM, or CIS. Thus, nonetheless, we provide convergent observations with other studies, concerning main inflammatory processes in the brain in the presence of anti-MOG-Abs [8, 10, 13, 15, 16, 17, 20, 25], the small size of each subgroup precluded further comparisons between specific diseases. Another weakness of our work is the absence of dosage of additional cytokines or chemokines of potential interest for the classification of diseases as those more specifically related to B cells recruitment and differentiation. Clearly, larger cohorts and high-throughput measurements are required to assess in each case the causes for relapses and to identify markers specific to each disease.
ADS is a heterogeneous group of diseases presenting different clinical courses. In concert with previous observations made in adult patients, we describe a different cytokine profile in the CSF of children with ADS MOG+ compared to ADS MOG−. Local anti-MOG IgG deposits and complement activation in the perivenular white matter seem to play a central role in the pathogenesis of EAE and ADS MOG+, initiating and amplifying demyelination. Most importantly, the macaque EAE model recapitulates immune processes identified in ADS MOG+, including CSF cytokine signature and similar lesion appearance, establishing the medical value of such NHP model of ADS to study pathophysiological aspects of anti-MOG IgG-associated diseases. In addition, this monkey model is especially valuable to address the effectiveness of novel therapies, which due to phylogenetic distance cannot be completed in rodents .
Authors would like to thank Sophie Luccantoni, Kamelia Kara-Ali, and Benoit Gautier for technical help in setting histology experiments.
CS, CMF, LS, NT, RM, B’tH, PhHa, RLG, and KD contributed to the conception and design of the study as well as analysis and interpretation of data. CS, CMF, LS, PhHo, CL, AP, VC, NT, JM, JF, JD, PC, CA, and KD contributed to the acquisition and analysis of data; PC, PhHo, CL, and KD, patient diagnosis and samples collection; CMF, JM, JD, and LS, animals follow-up and sample collection; CS, VC, and PhHo, laboratory dosages; LS, CA, AP, and PC, tissues treatments and histology; CMF and JF, animals MRI; CS, LS, and NT, graphs and statistical analysis; and CS, CMF, LS, B’tH, RLG, and KD, manuscript drafting for main intellectual content. All authors gave final approval to the article.
This work was funded by INSERM, CEA and AP. T.N. was supported by a fellowship from the ANRS (France Recherche Nord&Sud Sida-HIV Hépatites).
Ethics approval and consent to participate
All human studies have been reviewed by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in an applicable version of the 1964 Declaration of Helsinki. The national cohort of first demyelinating episode “Kidbiosep 2004” (N°910506) was authorized by the Commission National de l’Information et des Libertés and an informed consent form was obtained for all included children. Animals were handled following European directive 2010/63/UE and French regulations the project was performed in an agreed user establishment (agreement number C 92-032-02), with an institutional permission obtained from the French Ministry of Agriculture after evaluation by an ethical committee (2015081710528804vl).
Consent for publication
An informed consent form for publication was obtained for all included children.
The authors declare that they have no competing interests.
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