Breaching the Barrier and Inflaming Epilepsy Research

The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood. 1‐3 Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P‐selectin glycoprotein ligand‐1 (PSGL‐1, encoded by Selplg ) and leukocyte integrins α 4 β 1 and α L β 2 . Inhibition of leukocyte‐vascular interactions, either with blocking antibodies or by genetically interfering with PSGL‐1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood‐brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte‐vascular adhesion, suggesting a pathogenetic link between leukocyte‐vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte‐endothelial interaction as a potential target for the prevention and treatment of epilepsy. Lymphocytic choriomeningitis virus 1 infection of the mouse central nervous system (CNS) elicits fatal immunopathology through blood–brain barrier breakdown 2 and convulsive seizures 3 . Although lymphocytic‐choriomeningitis‐virus‐specific cytotoxic T lymphocytes (CTLs) are essential for disease 4 , their mechanism of action is not known. To gain insights into disease pathogenesis, we observed the dynamics of immune cells in the meninges by two‐photon microscopy. Here we report visualization of motile CTLs and massive secondary recruitment of pathogenic monocytes and neutrophils that were required for vascular leakage and acute lethality. CTLs expressed multiple chemoattractants capable of recruiting myelomonocytic cells. We conclude that a CD8 + T‐cell‐dependent disorder can proceed in the absence of direct T‐cell effector mechanisms and rely instead on CTL‐recruited myelomonocytic cells.