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Comparative Study
.2014 Dec 9;83(24):2219-26.
doi: 10.1212/WNL.0000000000001066. Epub 2014 Nov 7.

Epitope spreading as an early pathogenic event in pediatric multiple sclerosis

Affiliations
Comparative Study

Epitope spreading as an early pathogenic event in pediatric multiple sclerosis

Francisco J Quintana et al. Neurology..

Abstract

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.

© 2014 American Academy of Neurology.

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Figures

Figure 1
Figure 1. IgG antibody reactivities in ADS-mono and ADS-MS serum samples
(A) Heatmap in which each column represents the mean IgG antibody reactivities in the ADS-mono or the ADS-MS group, and each row shows the antibody reactivity to an antigen according to the colorimetric scale depicted on the left. Represented are samples taken at the time of an acute demyelinating attack (attack). The antibody reactivities included in this heatmap are listed in table e-4. (B) The total number of antigens to which antibodies are detected in ADS-mono and ADS-MS serum samples. These antigens are designated as CNS antigens (CNS), and non-CNS antigens (other). (C) The total number of CNS antigens to which antibodies are detected in ADS-mono and ADS-MS serum samples. These CNS antigens are designated into antigens previously linked to MS in adult cohorts (MS), as well as CNS antigens not previously linked to MS (other CNS). (D) Heatmap of the mean IgG antibody reactivities in the ADS-mono or the ADS-MS group, 3 months after the attack (follow-up). The antibody reactivities included in this heatmap are listed in table e-6. (E) Heatmap depicting the mean IgG antibody reactivities against MBP, PLP, and CNPase in ADS-MS serum samples. ADS = acquired CNS demyelinating syndrome; IgG = immunoglobulin G; MBP = myelin basic protein; MOG = myelin oligodendrocyte glycoprotein; mono = monophasic; MS = multiple sclerosis; PLP = proteolipid protein.
Figure 2
Figure 2. Performance of IgG antigen array reactivity classifiers in discriminating ADS-mono from ADS-MS at the time of an acute demyelinating attack
Receiver operating characteristic curves were obtained with classifiers constructed based on IgG reactivities and evaluated on (A) training set samples, and (B) test set samples (all obtained at the time of an acute demyelinating attack). ADS = acquired CNS demyelinating syndrome; AUC = area under the curve; IgG = immunoglobulin G; mono = monophasic; MS = multiple sclerosis.
Figure 3
Figure 3. Performance of IgG antigen array reactivity classifiers in discriminating ADS-mono from ADS-MS 3 months after an acute demyelinating attack, and stability in later follow-up
Receiver operating characteristic curves were obtained with classifiers constructed based on IgG reactivities and evaluated on (A) training set samples, (B) test set samples (all obtained 3 months after an acute demyelinating attack), as well as (C) stability set samples, obtained in later follow-up (12 months after ADS presentations). ADS = acquired CNS demyelinating syndrome; AUC = area under the curve; IgG = immunoglobulin G; mono = monophasic; MS = multiple sclerosis.
Figure 4
Figure 4. Changes in MRI T2 lesion volumes in children with ADS-mono or ADS-MS
The change in average brain T2 lesion volumes (mL) in the ADS-mono and ADS-MS cohorts, calculated as the difference in volumes between the time of follow-up and the time of ADS presentation. ADS = acquired CNS demyelinating syndrome; mono = monophasic; MS = multiple sclerosis.
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References

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