title: Complement-independent retinal pathology produced by intravitreal injection of neuromyelitis optica immunoglobulin G.
abstract: Neuromyelitis optica (NMO), an autoimmune inflammatory disease of the central nervous system, is often associated with retinal abnormalities including thinning of the retinal nerve fiber layer and microcystic changes. Here, we demonstrate that passive transfer of an anti-aquaporin-4 autoantibody (AQP4-IgG) produces primary retinal pathology.
  
  
  
  AQP4-IgG was delivered to adult rat retinas by intravitreal injection. Rat retinas and retinal explant cultures were assessed by immunofluorescence.
  
  
  
  Immunofluorescence showed AQP4-IgG deposition on retinal Müller cells, with greatly reduced AQP4 expression and increased glial fibrillary acidic protein by 5 days. There was mild retinal inflammation with microglial activation but little leukocyte infiltration and loss of retinal ganglion cells by 30 days with thinning of the ganglion cell complex. Interestingly, the loss of AQP4 was complement independent as seen in cobra venom factor-treated rats and in normal rats administered a mutated AQP4-IgG lacking complement effector function. Exposure of ex vivo retinal cultures to AQP4-IgG produced a marked reduction in AQP4 expression by 24 h, which was largely prevented by inhibitors of endocytosis or lysosomal acidification.
  
  
  
  Passive transfer of AQP4-IgG results in primary, complement-independent retinal pathology, which might contribute to retinal abnormalities seen in NMO patients.
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.|Departments of Medicine and Physiology, University of California, San Francisco, 1246 Health Sciences East Tower, San Francisco, CA, 94143-0521, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Felix
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA.|Department of Ophthalmology, The Palo Alto Medical Foundation, Palo Alto, CA, USA.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Levin
authors.affiliation: Departments of Medicine and Physiology, University of California, San Francisco, 1246 Health Sciences East Tower, San Francisco, CA, 94143-0521, USA. Alan.Verkman@ucsf.edu.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000633:toxicity*; D058449:Intravitreal Injections; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009471:Neuromyelitis Optica / Q000209:etiology / Q000276:immunology / Q000473:pathology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C100745:Aif1 protein, rat; D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D008840:Microfilament Proteins; D003165:Complement System Proteins
keywords: Aquaporin-4; Autoimmunity; Complement; Müller cells; NMO; Retina