Immune mechanisms in epileptogenesis

Abstract

Epilepsy is a chronic brain disorder that affects 1% of the human population worldwide. Immune responses are implicated in seizure induction and the development of epilepsy. Pre-clinical and clinical evidence have accumulated to suggest a positive feedback cycle between brain inflammation and epileptogenesis. Prolonged or recurrent seizures and brain injuries lead to upregulation of proinflammatory cytokines and activated immune responses to further increase seizure susceptibility, promote neuronal excitability, and induce blood–brain barrier breakdown. This review focuses on the potential role of innate and adaptive immune responses in the pathogenesis of epilepsy. Both human studies and animal models that help delineate the contributions of brain inflammation in epileptogenesis will be discussed. We highlight the critical role of brain-resident immune mediators and emphasize the contribution of brain-infiltrating peripheral leukocytes. Additionally, we propose possible immune mechanisms that underlie epileptogenesis. Several proinflammatory pathways are discussed, including the interleukin-1 receptor/toll-like receptor signaling cascade, the pathways activated by damage-associated molecular patterns, and the cyclooxygenase-2/prostaglandin pathway. Finally, development of better therapies that target the key constituents and processes identified in these mechanisms are considered, for instance, engineering antagonizing agents that effectively block these pathways in an antigen-specific manner.

Epileptic Encephalopathy in Infants and Children

“…Neuroinflammation following seizures can both trigger brain dysfunction and serve as a potential target of therapy (24). Sookyong Koh described a positive feedback cycle between brain inflammation and epileptogenesis: seizures and brain injury increase inflammation, and those proinflammatory changes in turn heighten seizure susceptibility and neuronal excitability (25). Microglia are immune cells present in the brain that become activated rapidly with a brain injury such as seizure.…”

“…In animal models, specific inflammatory pathways are being targeted to attenuate seizure-induced increases in inflammation-related genes as well as to decrease the susceptibility of animals to subsequent seizures. These mechanisms may well play a role in preventing epileptogenesis in the developing brain (25). For example, dexamethasone, minocycline treatment, and environmental enrichment all prevent the priming effect of early-life seizures on subsequent seizure susceptibility by retarding the activation of microglia.…”

The Emerging Role of Gamma-Delta (γδ) T cells in Neurological Diseases and Rasmussen Encephalitis

“…Epilepsy is a chronic neurological disease based on recurring seizures and accompanied by cognitive deficits and mood disorders in common, affecting 1% of the human population worldwide [33]. There is a positive feedback cycle between brain inflammation and epileptogenesis due to recurrent seizures and brain injuries that leads to stimulation of proinflamatory cytokines [33].…”

“…There is a positive feedback cycle between brain inflammation and epileptogenesis due to recurrent seizures and brain injuries that leads to stimulation of proinflamatory cytokines [33]. Studies done so far have suggested that inflammation in the brain might advance epileptogenesis [33], however protective immune responses are also found in epilepsy besides other neurological diseases such as multiple sclerosis [33].…”

Neuronal mechanisms of epileptogenesis

“…Seizure activity elicits release of pro-inflammatory cytokines and activates immune responses. These phenomena have been widely related to an increased brain susceptibility to seizure, synaptic reorganization and neuronal death (Xu et al, 2013).…”