A Narrative Review of Emerging Immune Targets in Neuroinflammation-Driven Epileptogenesis: From Complement Pathways to Immune Checkpoints

Epileptogenesis, the process by which a normal brain becomes epileptic, has long been attributed to excitotoxicity and neuronal hyperexcitability. Advances in neuroimmunology now indicate that neuroinflammation contributes materially to seizure initiation, propagation, and chronicity, opening avenues for therapies that aim to modify disease biology rather than merely suppress symptoms. To maintain a clear scope, this review focuses on three interconnected pathways with the strongest mechanistic and translational support: 1) the complement cascade-particularly C1q, C3/C3aR, and C5aR1, as mediators of maladaptive synaptic pruning and glia-neuron crosstalk; 2) cytokine signaling centered on interleukin (IL)-1β (and IL-6 where relevant) as convergent drivers of excitability and gliosis; and 3) programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint signaling within neurons and glia as an intrinsic brake on excitability and inflammation. Other mediators (e.g., tumor necrosis factor-α, cytotoxic T-lymphocyte antigen 4, T cell immunoreceptor with Ig and ITIM domains, lymphocyte activation gene 3, and the NLRP3 inflammasome) are discussed in brief to contextualize the landscape but are not primary foci unless data bear directly on clinical translation. Regarding causality, the evidence supports a contributory and, in defined contexts, causal role for inflammatory pathways in epileptogenesis. In autoimmune encephalitides (e.g., anti-N-methyl-D-aspartate receptor, anti-leucine-rich glioma-inactivated 1), seizure control frequently follows immunotherapy rather than ASMs alone, consistent with a causal immune mechanism in at least a subset of cases. In experimental systems, manipulating inflammatory nodes, blocking IL-1 signaling or toll-like receptor 4, inhibiting C5aR1, or attenuating BBB-driven transforming growth factor-beta signaling reduces epileptiform activity and epileptogenesis, strengthening biological plausibility. Nevertheless, causality is disease- and time-dependent; in many acquired epilepsies, neuroinflammation likely functions as a disease amplifier that sustains and worsens an epileptic network established by an initial insult rather than serving as the sole initiator. Within this framed scope, we synthesize recent experimental, translational, and clinical data on immune dysregulation in epilepsy. We emphasize mechanisms by which complement-mediated synaptic pruning, glial activation, and checkpoint dysfunction contribute to neuronal damage, circuit remodeling, and chronic seizure activity. We appraise current and investigational agents according to mechanism, efficacy signals, and clinical applicability (e.g., C5aR1 antagonism, IL-1 pathway blockade, and approaches that locally augment PD-1/PD-L1 signaling). We also review emerging biomarkers, including cerebrospinal fluid IL-1β, serum glial fibrillary acidic protein, and translocator protein positron-emission tomography, as promising but still developmental tools for stratifying patients and guiding immunotherapy, noting that validation for routine clinical selection is ongoing. Finally, we discuss combination strategies that pair innate and adaptive targets (e.g., NLRP3 inhibition with PD-L1 agonism) as exploratory avenues that may yield synergy while requiring careful infectious-risk mitigation and biomarker-guided deployment.