A dual role for fibroblast growth factor 9 in multiple sclerosis: Inhibition of (re)myelination and induction of pro-inflammatory environment

Abstract

Inflammatory basal ganglia disorders are infectious and autoimmune conditions presenting with movement disorders and psychiatric symptoms. Autoimmune basal ganglia disorders (ABGA) include Sydenham's chorea and recently described basal ganglia encephalitis associated with autoantibody against dopamine D2 receptor. Although autoantibodies are implicated in the pathogenesis of ABGA, the presence of seronegative cases suggests their etiological diversity. To elucidate the immune mechanisms of pediatric ABGA, we retrospectively analyzed clinical and neuroradiological data of patients with acute-onset inflammatory basal ganglia disorders and studied immunological markers in sera and CSF. Fourteen patients (11 males) aged between 8 months to 13 years were enrolled. Initial presentation was preceded by streptococcal infection in 5 cases. Clinical manifestations included chorea (n = 7), dystonia (n = 6), oral dyskinesia (n = 5), psychiatric symptoms (n = 7), and seizures (n = 9). Eleven showed magnetic resonance image signal abnormalities in basal ganglia. Moderate cerebrospinal fluid (CSF) pleocytosis (more than 50 cells per microliter) was found in 4 patients. Cytokines (interferon gamma, interleukin (IL)-6, IL-10, IL-12p70, tumor necrosis factor alpha) and chemokines (CCL2, CCL4, CXCL8, CXCL9, CXCL10) were measured in sera and CSF obtained from 9 patients. They were divided into two groups according to the presence of CSF pleocytosis: pleocytosis-positive (P group, n = 4) and -negative (N group, n = 5). Serum CCL4 level was significantly higher in N group than in P group (P b 0.05) and CSF IL-6 was significantly higher in P group than in N group (P b 0.05). CSF to serum ratio of CXCL9 and CXCL10 were significantly higher in P group than in N group (P b 0.05). Antineuronal antibodies tested by immunocytochemistry using rat primary neuronal culture detected antibodies against dendrite (n = 5), soma (n = 3), and nuclei (n = 5), with similar frequency between two groups. These results suggest that intracerebral inflammation generates chemokine gradient to recruit leukocytes into the brain in P group, whereas inflammation predominantly occurs systemically in N group.