title: Expression of CXCR3 and its ligands CXCL9, -10 and -11 in paediatric opsoclonus-myoclonus syndrome.
abstract: Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder associated with remote cancer. To understand more clearly the role of inflammatory mediators, the concentration of CXCR3 ligands CXCL10, CXCL9 and CXCL11 was measured in 245 children with OMS and 81 paediatric controls using enzyme-linked immunosorbent assay (ELISA), and CXCR3 expression on CD4(+) T cells was measured by flow cytometry. Mean cerebrospinal fluid (CSF) CXCL10 was 2·7-fold higher in untreated OMS than controls. Intrathecal production was demonstrated by significantly different CXCL10 CSF : serum ratios. The dichotomized 'high' CSF CXCL10 group had higher CSF leucocyte count (P = 0·0007) and B cell activating factor (BAFF) and CXCL13 concentrations (P < 0·0001). CSF CXCL10 did not correlate with clinical severity or relapse using grouped data, although it did in some patients. Among seven types of immunotherapy, including rituximab or chemotherapy, only adrenocorticotrophic hormone (ACTH) monotherapy showed reduced CSF CXCL10, but prospective longitudinal studies of ACTH combination therapies indicated no reduction in CXCL10 despite clinical improvement (P < 0·0001). CXCL10 concentrations were 11-fold higher in CSF and twofold higher in serum by multiplexed fluorescent bead-based immunoassay than enzyme-linked immunosorbent assay, but the two correlated (r = 0·7 and 0·83). In serum, no group differences for CXCL9 or CXCL11 were found. CXCR3 expression on CD4(+) T cells was fivefold higher in those from CSF than blood, but was not increased in OMS or altered by conventional immunotherapy. These data suggest alternative roles for CXCL10 in OMS. Over-expression of CXCL10 was not reduced by clinical immunotherapies as a whole, indicating the need for better therapeutic approaches.
authors.affiliation: Department of Neurology, National Pediatric Myoclonus Center and Neuroimmunology Research Laboratory, Springfield, IL, USA. mpranzatelli@siumed.edu
authors.forename: M R
authors.initials: MR
authors.lastname: Pranzatelli
authors.forename: E D
authors.initials: ED
authors.lastname: Tate
authors.forename: N R
authors.initials: NR
authors.lastname: McGee
authors.forename: A L
authors.initials: AL
authors.lastname: Travelstead
authors.forename: S J
authors.initials: SJ
authors.lastname: Verhulst
authors.forename: R M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage; D053264:B-Cell Activating Factor / Q000134:cerebrospinal fluid; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000097:blood / Q000134:cerebrospinal fluid*; D054371:Chemokine CXCL11 / Q000097:blood*; D054382:Chemokine CXCL13 / Q000134:cerebrospinal fluid; D054370:Chemokine CXCL9 / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007118:Immunoassay; D007167:Immunotherapy; D007223:Infant; D018836:Inflammation Mediators / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D053578:Opsoclonus-Myoclonus Syndrome / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000628:therapy; D054367:Receptors, CXCR3 / Q000097:blood / Q000378:metabolism*; D013256:Steroids / Q000008:administration & dosage
chemical_list: D053264:B-Cell Activating Factor; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C110663:CXCL13 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054382:Chemokine CXCL13; D054370:Chemokine CXCL9; D018836:Inflammation Mediators; D054367:Receptors, CXCR3; D013256:Steroids; C505719:TNFSF13B protein, human; D000324:Adrenocorticotropic Hormone