Spinal interleukin-6 contributes to central sensitisation and persistent pain hypersensitivity in a model of juvenile idiopathic arthritis

Pain is the most debilitating symptom in juvenile idiopathic arthritis. As pain correlates poorly to the extent of joint pathology, therapies that control joint inflammation are often inadequate as analgesics. We test the hypothesis that juvenile joint inflammation leads to sensitisation of nociceptive circuits in the central nervous system, which is maintained by cytokine expression in the spinal cord. Here, transient joint inflammation was induced in postnatal day (P)21 and P40 male Sprague-Dawley rats with a single intra-articular ankle injection of complete Freund's adjuvant. Hindpaw mechanical pain sensitivity was assessed using von Frey hair and weight bearing tests. Spinal neuron activity was measured using in vivo extracellular recording and immunohistochemistry. Joint and spinal dorsal horn TNFα, IL1β and IL6 protein expression was quantified using western blotting. We observed greater mechanical hyperalgesia following joint inflammation in P21 compared to P40 rats, despite comparable duration of swelling and joint inflammatory cytokine levels. This is mirrored by spinal neuron hypersensitivity, which also outlasted the duration of active joint inflammation. The cytokine profile in the spinal cord differed at the two ages: prolonged upregulation of spinal IL6 was observed in P21, but not P40 rats. Finally, spinal application of anti-IL-6 antibody (30 ng) reduced the mechanical hyperalgesia and neuronal activation. Our results indicate that persistent upregulation of pro-inflammatory cytokines in the spinal dorsal horn is associated with neuronal sensitisation and mechanical hyperalgesia in juvenile rats, beyond the progress of joint pathology. In addition, we provide proof of concept that spinal IL6 is a key target for treating persistent pain in JIA

Rare variants and de novo variants in mesial temporal lobe epilepsy with hippocampal sclerosis

Objective: We investigated the role of rare genetic variants and of de novo variants in the pathogenesis of mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). Methods: Whole-exome sequencing (WES) was performed in patients with MTLE-HS and their unaffected parents (trios). Genes or gene sets that were enriched with predicted damaging rare variants in the patients as compared to population controls were identified. Patients and their parents were compared to identify whether the variants were de novo or inherited. Results: After quality control, WES data from 47 patients (26 female), including 23 complete trios, were available for analysis. Compared with population controls, significant enrichment of rare variants was observed in SEC24B. Integration of gene set data describing neuronal functions and psychiatric disorders showed enrichment signal on fragile X mental retardation protein (FMRP) targets. Twenty-one de novo variants were identified, with many known to cause neuropsychiatric disorders. The FMRP-targeted genes also carried more de novo variants. Inherited compound heterozygous and homozygous variants were identified. Conclusions: The genetic architecture underlying MTHE-HS is complex. Multiple genes carrying de novo variants and rare variants among FMRP targets were identified, suggesting a pathogenic role. MTLE-HS and other neuropsychiatric disorders may have shared biology