Expression of CXCR3 and its ligands CXCL9, -10 and -11 in paediatric opsoclonus-myoclonus syndrome.

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.

B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes.

BACKGROUND: Although many lines of evidence suggest an autoimmune etiology, the pathophysiology of opsoclonus-myoclonus syndrome (OMS) remains poorly understood and no immunologic abnormalities have correlated with neurologic severity. Conventional immunotherapies often do not prevent relapse or permanent sequelae. OBJECTIVE: To test the cellular immune hypothesis of OMS in a cross-sectional study and determine if CSF lymphocyte subset analysis provides biomarkers of disease activity. METHODS: The expression of lymphocyte surface antigens was investigated in CSF and blood of 36 children with OMS and 18 control subjects, using a comprehensive panel of monoclonal antibodies to adhesion and activation proteins in combination with anti-CD3 and anti-CD45 antibodies in four-color fluorescence-activated cell sorting. RESULTS: Although most children with OMS had normal CSF cell counts, they exhibited expansion of CD19+ B-cell (up to 29%) and gammadelta T-cell (up to 26%) subsets and a lower percentage of CD4+ T-cells and CD4/CD8 ratio, which persisted even years after disease onset and conventional treatments. The percentage of activated CSF T-cells was also higher. Abnormalities correlated with neurologic severity, as scored blinded from videotapes using a 12-item motor scale, and disease duration. No significant differences were found between tumor and no-tumor groups. In children with neuroblastoma, tumor resection or cancer chemotherapy did not alter immunologic abnormalities. CONCLUSIONS: CSF B- and T-cell recruitment is linked to neurologic signs in pediatric OMS, which may relate to relapses and disease progression.

Evidence for an interferon-related inflammatory reaction in the trisomy 16 mouse brain leading to caspase-1-mediated neuronal apoptosis.

The trisomy of human chromosome 21 (Down syndrome) is the leading genetic cause of learning difficulties in children, and predisposes this population to the early onset of the neurodegeneration of Alzheimer's disease. Down syndrome is associated with increased interferon (IFN) sensitivity resulting in unexpectedly high levels of IFN inducible gene products including Fas, complement factor C3, and neuronal HLA I which could result in a damaging inflammatory reaction in the brain. Consistent with this possibility, we report here that the trisomy 16 mouse fetus has significantly increased whole brain IFN-gamma and Fas receptor immunoreactivity and that cultured whole brain trisomy 16 mouse neurons have increased basal levels of caspase 1 activity and altered homeostasis of intracellular calcium and pH. The trisomic neurons also showed a heightened sensitivity to the increase in both Fas receptor levels and caspase 1 activity we observed when IFN-gamma was added to the neuron culture media. Because of the autoregulatory nature of IFN activity, and the IFN inducing capability of caspase-1-activated cytokine activity, our data argue in favor of the possibility of an interferon-mediated, self-perpetuating, inflammatory response in the trisomy brain that could subserve the loss of neuron viability seen in this trisomy 16 mouse model for Down syndrome.