OBJECTIVE: In neuromyelitis optica (NMO), the destruction of the blood-brain barrier (BBB) has been considered to be the first step of the disease process. It is unclear whether sera from patients with NMO can open the BBB, and which component of patient sera is most important for this disruption. METHODS: The effects of sera from antiaquaporin4 (AQP4) antibody positive NMO patients, multiple sclerosis patients and control subjects were evaluated for expression of tight junction proteins and for transendothelial electrical resistance (TEER) of human brain microvascular endothelial cells (BMECs). Whether antibodies against human BMECs as well as anti-AQP4 antibodies exist in NMO sera was also examined using western blot analysis. RESULTS: Expression of tight junction proteins and TEER in BMECs was significantly decreased after exposure to NMO sera. However, this effect was reversed after application of an antivascular endothelial growth factor (VEGF) neutralising antibody. Antibodies against BMECs other than anti-AQP4 antibodies were found in the sera of NMO patients whereas no specific bands were detected in the sera of healthy and neurological controls. These antibodies apparently disrupt the BBB by increasing the autocrine secretion of VEGF by BMECs themselves. Absorption of the anti-AQP4 antibody by AQP4 transfected astrocytes reduced AQP4 antibody titres but was not associated with a reduction in BBB disruption. CONCLUSIONS: Sera from NMO patients reduce expression of tight junction proteins and disrupt the BBB. Autoantibodies against BMECs other than anti-AQP4 antibodies may disrupt the BBB through upregulation of VEGF in BMECs.
OBJECTIVE: In neuromyelitis optica (NMO), the destruction of the blood-brain barrier (BBB) has been considered to be the first step of the disease process. It is unclear whether sera from patients with NMO can open the BBB, and which component of patient sera is most important for this disruption. METHODS: The effects of sera from antiaquaporin4 (AQP4) antibody positive NMO patients, multiple sclerosispatients and control subjects were evaluated for expression of tight junction proteins and for transendothelial electrical resistance (TEER) of human brain microvascular endothelial cells (BMECs). Whether antibodies against human BMECs as well as anti-AQP4 antibodies exist in NMO sera was also examined using western blot analysis. RESULTS: Expression of tight junction proteins and TEER in BMECs was significantly decreased after exposure to NMO sera. However, this effect was reversed after application of an antivascular endothelial growth factor (VEGF) neutralising antibody. Antibodies against BMECs other than anti-AQP4 antibodies were found in the sera of NMO patients whereas no specific bands were detected in the sera of healthy and neurological controls. These antibodies apparently disrupt the BBB by increasing the autocrine secretion of VEGF by BMECs themselves. Absorption of the anti-AQP4 antibody by AQP4 transfected astrocytes reduced AQP4 antibody titres but was not associated with a reduction in BBB disruption. CONCLUSIONS: Sera from NMO patients reduce expression of tight junction proteins and disrupt the BBB. Autoantibodies against BMECs other than anti-AQP4 antibodies may disrupt the BBB through upregulation of VEGF in BMECs.
Authors: Candice Chapouly; Azeb Tadesse Argaw; Sam Horng; Kamilah Castro; Jingya Zhang; Linnea Asp; Hannah Loo; Benjamin M Laitman; John N Mariani; Rebecca Straus Farber; Elena Zaslavsky; German Nudelman; Cedric S Raine; Gareth R John Journal: Brain Date: 2015-03-23 Impact factor: 13.501
Authors: Christian Lange; Erik Storkebaum; Carmen Ruiz de Almodóvar; Mieke Dewerchin; Peter Carmeliet Journal: Nat Rev Neurol Date: 2016-07-01 Impact factor: 42.937
Authors: Claire M Rice; David Rossiter; Janev Fehmi; James C Stevens; Shelley A Renowden; Nicki Cohen; Clare Bailey; Neil J Scolding Journal: BMJ Case Rep Date: 2015-12-16
Authors: Fumitaka Shimizu; Kristin L Schaller; Gregory P Owens; Anne C Cotleur; Debra Kellner; Yukio Takeshita; Birgit Obermeier; Thomas J Kryzer; Yasuteru Sano; Takashi Kanda; Vanda A Lennon; Richard M Ransohoff; Jeffrey L Bennett Journal: Sci Transl Med Date: 2017-07-05 Impact factor: 17.956