Immunity and Inflammation in Epilepsy

Abstract

This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.

Figure 1.

Pathophysiological consequences of glia activation in epilepsy. Epileptogenic injuries and recurrent seizures activate glial cells (microglia and astrocytes), which release inflammatory molecules with proictogenic properties, such as interleukin (IL)-1β and high-mobility group box 1 (HMGB1), therefore triggering neuroinflammation. This event leads to changes in brain physiology because cytokines provoke neuronal hyperexcitability, blood–brain barrier (BBB) dysfunction, and contribute to neuronal cell loss. These pathologic sequelae (panels in bottom row), in turn, perpetuate neuroinflammation, thereby leading to chronic lowering of seizure threshold, and thus promoting epileptogenesis and seizure generation. Panels (top and middle rows) depict confocal microscope pictures from the forebrain tissue of epileptic rats, showing IL-1β and HMGB1 expressed both in activated glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive microglia. No IL-1β staining in glia is detectable in physiological conditions (not shown). IL-1β-positive astrocytes are observed in epilepsy tissue, also in close apposition to brain vessels (white arrow). HMGB1 is bound to nuclei in brain physiology (not shown), while it translocates to cytoplasm in epilepsy tissue as depicted in the related panels by cytoplasmatic and perinuclear staining in activated CD11b-positive microglia and GFAP-positive astrocytes, respectively. Toll-like receptor 4 (TLR4) mediates the proconvulsive effects of HMGB1; their activation in astrocytes (second row, bottom panel) promotes neuroinflammation, whereas their activation in neurons (not shown) mediates hyperexcitability (see Maroso et al. 2010).

Figure 2.

Inflammation in the brain of patients with refractory focal epilepsy. Schematic drawing summarizing neuropathological observations that indicate the activation of inflammatory processes, and the concomitant synthesis and release of inflammatory molecules (with neuromodulatory properties) in a variety of focal epilepsies, such as hippocampal sclerosis (HS), focal malformations of cortical development (MCD) (focal cortical dysplasia [FCD] type II, and cortical tubers in tuberous sclerosis complex [TSC]) and glioneuronal tumors (GNTs). Neuropathological examination of surgical specimens from patients with HS provides evidence of a sustained activation of the innate immune response, which involves both astrocytes and microglial cells. Neuropathological examination of surgical specimens from patients with FCD, TSC, and GNT provides evidence of activation of both innate and the adaptive immune response (with the presence of T lymphocytes within the lesion). The identification of proinflammatory pathways, such as the interleukin (IL)-1R/toll-like receptor (TLR)–signaling pathway, involved in ictogenesis in experimental models may create the basis to develop effective therapeutic strategies to control pharmacoresistant seizures.