1. CCR7 signaling in pediatric opsoclonus-myoclonus: upregulated serum CCL21 expression is steroid-responsive.
- Author
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Pranzatelli MR, Tate ED, McGee NR, and Ransohoff RM
- Subjects
- Adolescent, Adrenal Cortex Hormones therapeutic use, Adrenocorticotropic Hormone therapeutic use, Antibodies, Monoclonal, Murine-Derived pharmacology, B-Cell Activating Factor cerebrospinal fluid, Biomarkers blood, Case-Control Studies, Chemokine CCL19 cerebrospinal fluid, Chemokine CCL21 metabolism, Chemokine CCL22 blood, Chemokine CXCL13 blood, Child, Child, Preschool, Cross-Sectional Studies, Cyclophosphamide pharmacology, Down-Regulation, Female, Humans, Immunoglobulins, Intravenous pharmacology, Immunologic Factors pharmacology, Immunosuppressive Agents pharmacology, Immunotherapy, Infant, Inflammation, Male, Opsoclonus-Myoclonus Syndrome blood, Opsoclonus-Myoclonus Syndrome drug therapy, Prospective Studies, Receptors, CCR7 blood, Rituximab, Young Adult, Adrenal Cortex Hormones metabolism, Adrenocorticotropic Hormone metabolism, Chemokine CCL21 blood, Opsoclonus-Myoclonus Syndrome metabolism, Receptors, CCR7 metabolism
- Abstract
Identifying and blocking chemokine inflammatory mediators in pediatric opsoclonus-myoclonus syndrome (OMS) is critical to the treatment of this autoimmune, paraneoplastic, neurological disorder. In a prospective, case-control, clinico-scientific study of children with OMS compared to non-inflammatory neurological controls and other inflammatory neurological disorders, CCL19 (n=369) and CCL21 (n=312) were quantified in CSF and serum, respectively, by ELISA. Both cross-sectional and longitudinal effects of OMS and various immunotherapies were evaluated. Significant upregulation of CCL21 concentration (mean ± SD) (+32%) was found in serum of untreated OMS (630 ± 133 pg/mL), compared to controls (478 ± 168 pg/mL), (p<0.0001). Both corticosteroids and ACTH (corticotropin) significantly lowered CCL21 to control levels, as they did in combination with IVIg, rituximab, cyclophosphamide or other treatments, without additional reduction attributable to the other agents. In a pilot longitudinal study of ACTH-based triple therapy, the mean serum CCL21 concentration fell 59% from elevated to less than 1 SD below controls 1 week after high-dose ACTH, gradually returning to the control mean with ACTH tapering by 3 weeks and out to 12 weeks (p<0.0001). In contrast, CCL19, detectable in CSF, was not significantly altered by OMS or various immunotherapies. In the "high" CCL21 subgroup, higher serum concentrations of CCL22 (+57%) and CXCL13 (+40%), as well as the CSF concentration of BAFF (+64%), also were found. Elevated serum CCL21, not CSF CCL19, correlates with OMS severity and duration in pediatric OMS. Corticosteroids and ACTH were the only immunotherapies evaluated that down-regulated CCL21 production. Validation studies are needed to assess treatment biomarker status., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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