Proinflammatory IL-17 pathways dominate the architecture of the immunome in pediatric refractory epilepsy

Abstract

Drug refractory epilepsy (RE) is a chronic neurological disease with varied etiology that represents a group of patients whose seizures do not respond to antiepileptic drugs. The immune system may have a role in seizure and epilepsy development, but the specific mechanisms of inflammation that lead to epileptogenesis and contribute to RE are unknown. Here, we used mass cytometry to comprehensively study the immune system of pediatric patients with RE and compared their immune profile and function with patients with age-matched autoimmune encephalitis (AIE) and healthy controls. Patients with RE and AIE displayed similar immune profiles overall, with changes in CD4 + and CD8 + T cell subsets and an unbalance toward proinflammatory IL-17 production. In addition, patients with RE uniquely showed an altered balance in NK cell subsets. A systems-level intercellular network analysis identified rewiring of the immune system, leading to loss of inhibitory/regulatory intercellular connections and emergence of proinflammatory pathogenic functions in neuroinflammatory immune cell networks in patients with AIE and RE. These data underscore the contribution of systemic inflammation to the pathogenesis of seizures and epileptogenesis and have direct translational implications in advancing diagnostics and therapeutics design.

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug‐resistant epilepsy

“…Accordingly, we found that the frequency of proinflammatory CD4 T cells expressing Th17/Th1‐related cytokines is higher in the peripheral blood of epilepsy and DRE patients, in line with previous reports in pediatric DRE 40,41 and in adult temporal lobe epilepsy 38 . Similar to a recent study in autoimmune epilepsy in children, we did not observe a concomitant increase in expression of Th17‐related surface markers CCR6 and CD161 42 . However, we did observe a higher frequency in epilepsy subjects of CD4 T cells expressing MCAM, a cell adhesion molecule associated with transmigration of proinflammatory Th17/Th1 cells toward the CNS compartment in multiple sclerosis 19 .…”

Cerebrospinal Fluid IL-17A Could Predict Acute Disease Severity in Non-NMDA-Receptor Autoimmune Encephalitis

“…In neurology, IL-17A has been found to be increased in MS and related disorders but also in NMDAR encephalitis and refractory epilepsy (RE) (15,27). Kumar et al reported a similar immune profile between children with RE and Rasmussen's encephalitis with expansion of CD4+ IL17+ T cells and expansion of CD25+ B cells suggesting that both Th17 and B cells are involved in the pathogenesis of RE and AE (27). However, epilepsy in patients with NIND does not result in a high level of CSF IL-17A or IL-6 as compared to immune-mediated epilepsy in the elderly (28).…”

Natural Medicines for the Treatment of Epilepsy: Bioactive Components, Pharmacology and Mechanism

“…A major portion of this process is the inflammatory response, and changes in the inflammatory factors to a certain extent indicate that the occurrence of epilepsy can also induce a certain inflammatory response. For instance, IL-1β, IL-6, IL-10, IL-2, IL-17 ( Kumar et al, 2019 ), IL-4, and TNF-α were abnormally expressed in patients, whose elevated levels can lead to neuronal degeneration and induce epilepsy ( Ravizza et al, 2006 ). Another mechanism by which IL-1 participates in epilepsy is through the upregulation of NMDA receptors on postsynaptic cells through the activation of GluN2B subunits of NMDA receptors ( Ravizza et al, 2006 ).…”