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Epitope spreading as an early pathogenic event in pediatric multiple sclerosis
Francisco J Quintana1, Bonny Patel1, Ada Yeste1
1From 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.
Objectives:
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.
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