Abstract
The pathogenesis of neuromyelitis optica (NMO) involves binding of IgG autoantibodies (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system (CNS). We studied the in vivo processing in mice of a recombinant monoclonal human NMO-IgG that binds strongly to mouse AQP4. Following intravenous administration, serum [NMO-IgG] decreased with t1/2 ∼18 hours in wildtype mice and ∼41 hours in AQP4 knockout mice. NMO-IgG was localized to AQP4-expressing cell membranes in kidney (collecting duct), skeletal muscle, trachea (epithelial cells) and stomach (parietal cells). NMO-IgG was seen on astrocytes in the area postrema in brain, but not elsewhere in brain, spinal cord, optic nerve or retina. Intravenously administered NMO-IgG was also seen in brain following mechanical disruption of the blood-brain barrier. Selective cellular localization was not found for control (non-NMO) IgG, or for NMO-IgG in AQP4 knockout mice. NMO-IgG injected directly into brain parenchyma diffused over an area of ∼5 mm2 over 24 hours and targeted astrocyte foot-processes. Our data establish NMO-IgG pharmacokinetics and tissue distribution in mice. The rapid access of serum NMO-IgG to AQP4 in peripheral organs but not the CNS indicates that restricted antibody access cannot account for the absence of NMO pathology in peripheral organs.
Highlights
Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) associated with demyelinating lesions mainly in optic nerve and spinal cord, leading to blindness and paralysis [1,2]
The majority of NMO patients are seropositive for autoantibodies (NMO-IgG) against extracellular epitope(s) on aquaporin-4 (AQP4) [3,4,5], a plasma membrane water channel expressed in astrocytes throughout the CNS [6,7]
We found that recombinant antibody rAb-53, which strongly binds to human AQP4 [23], bound well to mouse AQP4 and caused NMO-like lesions following intracerebral administration
Summary
Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) associated with demyelinating lesions mainly in optic nerve and spinal cord, leading to blindness and paralysis [1,2]. The majority of NMO patients are seropositive for autoantibodies (NMO-IgG) against extracellular epitope(s) on aquaporin-4 (AQP4) [3,4,5], a plasma membrane water channel expressed in astrocytes throughout the CNS [6,7]. Mice deficient in AQP4 do not manifest significant baseline abnormalities in the CNS, but show, under appropriate stresses, impairment in brain and spinal cord water balance, neuroexcitation and glial scar formation [9]. AQP4-deficient mice do not manifest significant peripheral abnormalities, such as skeletal muscle dysfunction [10] or reduced gastric acid secretion [11], except for a very mild impairment in maximal urinary concentrating ability [12]. NMO-IgG binding to AQP4 in astrocytes is thought to initiate a cascade of inflammatory events, including antibody-dependent complement and cellmediated astrocyte damage, leukocyte recruitment, cytokine release and demyelination [1,21,22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
