title: IgG leakage may contribute to neuronal dysfunction in drug-refractory epilepsies with blood-brain barrier disruption.
abstract: Focal epilepsies are often associated with blood-brain barrier disruption. In 4 entorhinal cortex tissue samples and 13 hippocampal samples from patients with pharmacoresistent temporal lobe epilepsy, we observed immunoglobulin G (IgG) leakage in the parenchyma and IgG-positive neurons that had evidence of neurodegeneration, such as shrinkage and eosinophilia. These findings were not present in samples from 12 nonepileptic control subjects. To complement these findings, we used a rat in vivo model that mimics the development of limbic epilepsy with blood-brain barrier disruption. During epileptogenesis, IgG leakage and neuronal IgG uptake increased concomitantly with the occurrence of seizures. Immunoglobulin G accumulation in neurons was selective, particularly for interneurons and pyramidal neurons. Immunohistochemistry and electron microscopy showed that IgG uptake in the rat neurons was associated with eosinophilia, shrinkage, and ultrastructural degenerative changes. Moreover, IgG-positive neurons lost their NeuN immunohistochemical staining. Together, these observations suggest that IgG leakage is related to neuronal impairment and may be a pathogenic mechanism in epileptogenesis and chronic epilepsy.
authors.affiliation: From the CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Michalak
authors.forename: Aurore
authors.initials: A
authors.lastname: Lebrun
authors.forename: Mathieu
authors.initials: M
authors.lastname: Di Miceli
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Rousset
authors.forename: Arielle
authors.initials: A
authors.lastname: Crespel
authors.forename: Philippe
authors.initials: P
authors.lastname: Coubes
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
authors.forename: Mireille
authors.initials: M
authors.lastname: Lerner-Natoli
authors.forename: Valérie
authors.initials: V
authors.lastname: Rigau
mesh_terms: D000328:Adult; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology* / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000139:chemically induced / Q000150:complications* / Q000473:pathology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D018021:Lithium Chloride / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D010750:Phosphoproteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053668:Syndecan-1 / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult; D062826:Zonula Occludens-1 Protein
chemical_list: D007074:Immunoglobulin G; D008565:Membrane Proteins; D010750:Phosphoproteins; D053668:Syndecan-1; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; D010751:Phosphopyruvate Hydratase; D018021:Lithium Chloride