title: GluR3 autoantibodies destroy neural cells in a complement-dependent manner modulated by complement regulatory proteins.
abstract: GluR3 autoantibodies have been implicated in the development of Rasmussen's encephalitis, a rare neurodegenerative disease of humans characterized by epilepsy and degeneration of a single cerebral hemisphere. GluR3 autoantibodies are found in some Rasmussen's encephalitis patients, and GluR3 antibodies raised in rabbits destroy cultured cortical cells in a complement-dependent manner. In this study, the cellular targets of anti-GluR3 antisera-mediated cytotoxicity were examined in mixed primary neuronal-glial cultures of rat cortex. Unexpectedly, astrocytes were the principal target of the cytotoxic effects as assessed by immunohistochemistry and lactate dehydrogenase activity; neurons were destroyed to a lesser extent. Astrocyte vulnerability was rescued by transfection with complement regulatory proteins, and neuronal resistance was defeated by impairing complement regulatory protein function. Astrocyte death may occur in Rasmussen's encephalitis, and destruction of this cell type may play a critical role in the progression of this disorder. The present findings suggest complement regulatory protein expression may in part determine the nature and severity of Rasmussen's encephalitis and other complement-dependent nervous system diseases and thus underscore the need for a systematic investigation of the expression of all known complement regulatory proteins in healthy and diseased nervous system tissues.
authors.affiliation: Epilepsy Research Laboratory, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Whitney
authors.forename: J O
authors.initials: JO
authors.lastname: McNamara
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism* / Q000633:toxicity; D018957:CD59 Antigens / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015938:Complement Membrane Attack Complex / Q000276:immunology / Q000378:metabolism / Q000633:toxicity; D003165:Complement System Proteins / Q000378:metabolism* / Q000494:pharmacology; D019610:Cytoprotection / Q000276:immunology; D004660:Encephalitis / Q000209:etiology / Q000276:immunology*; D007106:Immune Sera / Q000276:immunology / Q000633:toxicity; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D007106:Immune Sera; D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3; D003165:Complement System Proteins; D007770:L-Lactate Dehydrogenase; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase