Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment.
Autoantibody neuromyelitis optica-IgG (NMO-IgG) recognizing aquaporin-4 (AQP4) is implicated as playing a central role in the physiopathology of NMO. The aim of this in vitro-based study was to characterize functional consequences of interaction between NMO-IgG and cells of the neurovascular unit (astrocytes and brain endothelium) that would provide insight into recognized features of NMO, namely altered blood-brain barrier (BBB) permeability and granulocyte recruitment. We used sera from NMO and longitudinally extensive transverse myelitis cases shown to bind in a characteristic perivascular pattern to primate cerebellar slices. Using flow cytometry, we found that sera from NMO-IgG-positive patients reacted with CNS-derived human fetal astrocytes, whereas sera from multiple sclerosis patients did not. We demonstrated that NMO-IgG binding to astrocytes alters aquaporin-4 polarized expression and increases permeability of a human BBB endothelium/astrocyte barrier. We further demonstrated that NMO-IgG binding to human fetal astrocytes can result in NK cell degranulation, astrocyte killing by Ab-dependent cellular cytotoxicity and complement-dependent granulocyte attraction through the BBB model. Our study highlights important functional roles for NMO-IgG that could account for pathological lesions and BBB dysfunction observed in NMO.
Vincent
Thierry
T
Laboratoire d'Immunologie, Hôpital Saint-Eloi-CHU Montpellier, Montpellier, France.
Saikali
Philippe
P
Cayrol
Romain
R
Roth
Alejandro D
AD
Bar-Or
Amit
A
Prat
Alexandre
A
Antel
Jack P
JP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology*; D001253:Astrocytes / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000473:pathology; D015550:Cell Degranulation / Q000276:immunology; D002531:Cerebellum / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D003165:Complement System Proteins / Q000276:immunology; D005260:Female; D005333:Fetus / Q000276:immunology / Q000473:pathology; D006098:Granulocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology / Q000473:pathology; D009471:Neuromyelitis Optica / Q000097:blood / Q000276:immunology* / Q000473:pathology; D010539:Permeability; D011323:Primates
C496030:AQP4 protein, human; D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G; D003165:Complement System Proteins