Functional deficiency in endogenous interleukin‐1 receptor antagonist in patients with febrile infection‐related epilepsy syndrome

Abstract

Objective We recently reported successful treatment of a child with febrile infection‐related epilepsy syndrome (FIRES), a subtype of new onset refractory status epilepticus, with the recombinant interleukin‐1 (IL1) receptor antagonist (IL1RA) anakinra. On this basis, we tested whether endogenous IL1RA production or function is deficient in FIRES patients. Methods Levels of IL1β and IL1RA were measured in serum and cerebrospinal fluid (CSF). The inhibitory activity of endogenous IL1RA was assessed using a cell‐based reporter assay. IL1RN gene variants were identified by sequencing. Expression levels for the secreted and intracellular isoforms of IL1RA were measured in patient and control cells by real‐time polymerase chain reaction. Results Levels of endogenous IL1RA and IL1β were elevated in the serum and CSF of patients with FIRES (n = 7) relative to healthy controls (n = 10). Serum from FIRES patients drove IL1R signaling activity and potentiated IL1R signaling in response to exogenous IL1β in a cell‐based reporter assay. Functional assessment of endogenous IL1RA activity in 3 FIRES patients revealed attenuated inhibition of IL1R signaling. Sequencing of IL1RN in our index patient revealed multiple variants. This was accompanied by reduced expression of intracellular but not secreted isoforms of IL1RA in the patient's peripheral blood mononuclear cells. Interpretation Our findings suggest that FIRES is associated with reduced expression of intracellular IL1RA isoforms and a functional deficiency in IL1RA inhibitory activity. These observations may provide insight into disease pathogenesis for FIRES and other inflammatory seizure disorders and may provide a valuable biomarker for therapeutic decision‐making. Ann Neurol 2019;85:526–537

Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection‐related epilepsy syndrome and febrile status epilepticus

“…Clarkson et al reported elevation of CSF IL‐1ra and IL1‐β in patients with FIRES, reduced expression of intracellular IL‐1ra isoforms, and a functional deficiency in IL‐1ra inhibitory activity. Although IL‐1β has been shown to play a critical role in epileptogenesis, CSF IL‐1β was low in our study.…”

“…9,17,26,27,37 Previous studies have reported that seizures can perpetuate inflammation, thus activating a vicious cycle that in turn fosters aberrant hyperexcitability contributing to seizure recurrence and severity. 38 Clarkson et al 39 reported elevation of CSF IL-1ra and IL1-β in patients with FIRES, reduced expression of intracellular IL-1ra isoforms, and a functional deficiency in IL-1ra inhib itory activity. Although IL-1β has been shown to play a crit ical role in epileptogenesis, CSF IL-1β was low in our study.…”

A pericyte‐glia scarring develops at the leaky capillaries in the hippocampus during seizure activity

“…An important driver of fibrosis at the vasculature is the transforming growth factor beta (TGFβ), specifically involved in the epileptogenesis process and BBB dysfunction . A number of reports suggest a plethora of neurovascular therapeutic entry points, including anakinra, rapamycin, and losartan, supporting a venue for novel therapeutic, anti‐inflammatory or cerebrovascular repairing, approaches to the epileptic pathophysiology …”

“…50 A number of reports suggest a plethora of neurovascular therapeutic entry points, including anakinra, rapamycin, and losartan, supporting a venue for novel therapeutic, anti-inflammatory or cerebrovascular repairing, approaches to the epileptic pathophysiology. [50][51][52][53]…”

Extinguishing Febrile Infection-Related Epilepsy Syndrome: Pipe Dream or Reality?

“…15 Compelling evidence exists that implicates IL cytokine system imbalance in FIRES patients. 9 Such imbalance caused by an intrinsic functional deficiency in endogenous IL1-RA activity will lead to an unopposed pathological inflammatory state, "a spark to the blaze," 5 driven by overactive IL-1β, a master cytokine of local and systemic inflammation and innate immunity. 16 The role of IL-1RA/ IL-1β pathway endowing genetic predisposition also comes from candidate gene analysis in children with FIRES.…”