CCR7 signaling in pediatric opsoclonus-myoclonus: upregulated serum CCL21 expression is steroid-responsive

Cytokine. 2013 Oct;64(1):331-6. doi: 10.1016/j.cyto.2013.05.020. Epub 2013 Jun 10.


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.

Keywords: ACTH; Corticosteroids; Neuroblastoma; Paraneoplastic syndrome; Pediatric neuroinflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Cortex Hormones / metabolism*
  • Adrenal Cortex Hormones / therapeutic use
  • Adrenocorticotropic Hormone / metabolism*
  • 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 / blood*
  • 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
  • Opsoclonus-Myoclonus Syndrome / metabolism*
  • Prospective Studies
  • Receptors, CCR7 / blood
  • Receptors, CCR7 / metabolism*
  • Rituximab
  • Young Adult


  • Adrenal Cortex Hormones
  • Antibodies, Monoclonal, Murine-Derived
  • B-Cell Activating Factor
  • Biomarkers
  • CCL19 protein, human
  • CCL21 protein, human
  • CCL22 protein, human
  • CCR7 protein, human
  • CXCL13 protein, human
  • Chemokine CCL19
  • Chemokine CCL21
  • Chemokine CCL22
  • Chemokine CXCL13
  • Immunoglobulins, Intravenous
  • Immunologic Factors
  • Immunosuppressive Agents
  • Receptors, CCR7
  • TNFSF13B protein, human
  • Rituximab
  • Cyclophosphamide
  • Adrenocorticotropic Hormone