Quintana FJ et al. Epitope spreading as an early pathogenic event in paediatric multiple sclerosis. Neurology December, 2014 vol. 83 2219-2226
Objectives: For most adults with initial clinical presentation of multiple sclerosis (MS), biological disease was likely initiated many years prior. Paediatric-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 paediatric 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 paediatric-onset CNS demyelinating diseases point to an active process of epitope spreading during early stages of MS, not seen in monophasic CNS inflammatory conditions.
Heat map (red meaning high IgG antibody reactivity) of antigens to which antibodies are detected in monophasic inflammatory attack (MONO) and MS at baseline and at follow up
Comparing monophasic inflammatory episode seen in children to those who go onto develop MS (or relapsing-remitting disease) can hold the clue to discovering what in fact leads to MS; irrespective of whether it is childhood or adult MS. A looking glass into early MS is the key here, unhampered by the dilution of factors which have occurred by the time a person becomes an adult.
The authors looked specifically at the immunologic/immune system which takes place between the monophasic presentation and the established MS. They looked at two time points, first presentation of the event and at three month follow up. What they found, was an expansion of the initial antibody response to CNS antigens; a concept called epitope spreading in the scientific communities. In their heat map (see diagram) they also address possible culprits, and the usual suspects are there (PLP, MOG, MBP) and some interesting ones (Helicobacter pylori, CNPase, ssDNA,).
What you may ask is the utility of this research?
This is very simple, develop treatments targeted at boosting immunoregulatory mechanisms (targets the entire autoantibody response) or control the effector T cells at an antigen-specific level (e.g. targeting MOG, PLP, MBP, H. pylori, CNPase, ssDNA) using vaccines. And there you have it, the cure for MS - or is it...
Labels: Autoantibodies, autoimmunity, epitope spreading, heat map, immune response, immune senescence. T-reg, Immune tolerance