Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice

• Published in: Brain (London, England : 1878) Vol. 133; no. 2; pp. 349 - 361
• Main Authors: Saadoun, Samira, Waters, Patrick, Bell, B. Anthony, Vincent, Angela, Verkman, A. S., Papadopoulos, Marios C.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-02-2010
• Subjects: Animals; Aquaporin 4 - immunology; Autoantibodies - biosynthesis; autoantibody; Biological and medical sciences; CHO Cells; Complement System Proteins - administration & dosage; Complement System Proteins - adverse effects; Cricetinae; Cricetulus; Devic’s syndrome; Disease Models, Animal; Humans; immunoglobulin; Immunoglobulin G - administration & dosage; Immunoglobulin G - adverse effects; Injections, Intraventricular; Medical sciences; Mice; Mice, Knockout; mouse model; Neurology; Neuromyelitis Optica - immunology; Neuromyelitis Optica - pathology; Original; Vascular diseases and vascular malformations of the nervous system; water channel; autoantibody; immunoglobulin; mouse model; Devic's syndrome; water channel; Autoimmunity; Animal model; Central nervous system; Neurooptic myelitis; Complement; Encephalon; Visual pathway; Human; Immunoglobulins; Nervous system diseases; Optic nerve; Rodentia; Autoantibody; Eye disease; Vertebrata; Mammalia; Cranial nerve disease; Mouse; Animal; Central nervous system disease; Spinal cord disease
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awp309

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.