Epitope spreading as an early pathogenic event in pediatric multiple sclerosis.
OBJECTIVE
For most adults with initial clinical presentation of multiple sclerosis (MS), biological disease was likely initiated many years prior. Pediatric-onset MS provides an opportunity to study early disease processes.


METHODS
Using antigen microarrays, including CNS-related proteins, lipids, and other autoantigens, we studied early immunologic events involved in clinical onset of pediatric MS. Serum samples were collected at the time of incident acquired CNS demyelinating syndromes (ADS) in children who, in subsequent prospective follow-up, were ascertained to have either pediatric MS (ADS-MS) or a monophasic illness (ADS-mono). Samples were obtained both at the time of ADS presentation and 3 months into follow-up. We used an initial training set of samples to implicate antibody signatures associated with each group, and then a test set. An additional set of follow-up samples (stability set) was used as a form of internal validation.


RESULTS
Children with ADS-MS tended to have distinguishable serum antibody patterns both at the time of ADS presentation and 3 months into follow-up. At the time of ADS, serum samples from patients with ADS-MS or ADS-mono reacted against similar numbers of CNS antigens, although CNS antigens implicated in adult MS were more often targeted in children with ADS-MS. The follow-up ADS-MS samples reacted against a broader panel of CNS antigens, while corresponding ADS-mono samples exhibited a contraction of the initial antibody response.


CONCLUSIONS
Our findings in this prospective cohort of pediatric-onset CNS demyelinating diseases point to an active process of epitope spreading during early stages of MS, not seen in monophasic CNS inflammatory conditions.
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Francisco J
FJ
Quintana
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Bonny
B
Patel
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Ada
A
Yeste
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Mukanthu
M
Nyirenda
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Jessica
J
Kenison
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Roya
R
Rahbari
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Dumitru
D
Fetco
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Mohammad
M
Hussain
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Julia
J
O'Mahony
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Sandra
S
Magalhaes
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Melissa
M
McGowan
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Trina
T
Johnson
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Sathy
S
Rajasekharan
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Sridar
S
Narayanan
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Douglas L
DL
Arnold
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Howard L
HL
Weiner
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA.
Brenda
B
Banwell
From the Center for Neurologic Diseases (F.J.Q., B.P., A.Y., J.K., R.R., M.H., H.L.W.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Neuroimmunology Unit (M.N., S.M., A.B.-O.) and the McConnell Brain Imaging Centre (D.F., S.N., D.L.A.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Hospital for Sick Children (J.O., M.M., B.B.) and the Institute of Health Policy, Management, and Evaluation (J.O.), University of Toronto; Experimental Therapeutics Program (T.J., S.R., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; and The Children's Hospital of Philadelphia (B.B.), PA. amit.bar-or@mcgill.ca fquintana@rics.bwh.harvard.edu.
Amit
A
Bar-Or
D000293:Adolescent; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D001921:Brain / Q000473:pathology; D002493:Central Nervous System Diseases / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D002648:Child; D003711:Demyelinating Diseases / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D046228:Microarray Analysis; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology; D011446:Prospective Studies; D012372:ROC Curve
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D007074:Immunoglobulin G