title: Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy.
abstract: Clinical and experimental evidence indicates that inflammatory processes contribute to the pathophysiology of epilepsy, but underlying mechanisms remain mostly unknown. Using immunohistochemistry for CD45 (common leukocyte antigen) and CD3 (T-lymphocytes), we show here microglial activation and infiltration of leukocytes in sclerotic tissue from patients with mesial temporal lobe epilepsy (TLE), as well as in a model of TLE (intrahippocampal kainic acid injection), characterized by spontaneous, nonconvulsive focal seizures. Using specific markers of lymphocytes, microglia, macrophages, and neutrophils in kainate-treated mice, we investigated with pharmacological and genetic approaches the contribution of innate and adaptive immunity to kainate-induced inflammation and neurodegeneration. Furthermore, we used EEG analysis in mutant mice lacking specific subsets of lymphocytes to explore the significance of inflammatory processes for epileptogenesis. Blood-brain barrier disruption and neurodegeneration in the kainate-lesioned hippocampus were accompanied by sustained ICAM-1 upregulation, microglial cell activation, and infiltration of CD3(+) T-cells. Moreover, macrophage infiltration was observed, selectively in the dentate gyrus where prominent granule cell dispersion was evident. Unexpectedly, depletion of peripheral macrophages by systemic clodronate liposome administration affected granule cell survival. Neurodegeneration was aggravated in kainate-lesioned mice lacking T- and B-cells (RAG1-knock-out), because of delayed invasion by Gr-1(+) neutrophils. Most strikingly, these mutant mice exhibited early onset of spontaneous recurrent seizures, suggesting a strong impact of immune-mediated responses on network excitability. Together, the concerted action of adaptive and innate immunity triggered locally by intrahippocampal kainate injection contributes seizure-suppressant and neuroprotective effects, shedding new light on neuroimmune interactions in temporal lobe epilepsy.
authors.affiliation: Institute of Pharmacology and Toxicology and Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Michela
authors.initials: M
authors.lastname: Zattoni
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Mura
authors.forename: Francine
authors.initials: F
authors.lastname: Deprez
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Karl
authors.initials: K
authors.lastname: Frei
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Fritschy
mesh_terms: D056704:Adaptive Immunity; D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007608:Kainic Acid; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007958:Leukocyte Count; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012598:Sclerosis / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D018799:Intercellular Adhesion Molecule-1; D017493:Leukocyte Common Antigens; D007608:Kainic Acid