title: Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.
abstract: Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions.
authors.affiliation: St George's, University of London, London SW17 0RE, UK.
authors.forename: Samira
authors.initials: S
authors.lastname: Saadoun
authors.forename: Patrick
authors.initials: P
authors.lastname: Waters
authors.forename: B Anthony
authors.initials: BA
authors.lastname: Bell
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Marios C
authors.initials: MC
authors.lastname: Papadopoulos
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D016466:CHO Cells; D003165:Complement System Proteins / Q000008:administration & dosage / Q000009:adverse effects*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000009:adverse effects*; D007276:Injections, Intraventricular; D051379:Mice; D018345:Mice, Knockout; D009471:Neuromyelitis Optica / Q000276:immunology* / Q000473:pathology*
chemical_list: D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G; D003165:Complement System Proteins