Julien Ratelade1, Jeffrey L. Bennett2, A. S. Verkman1*
1 Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California, United States of America, 2 Departments of Neurology and Ophthalmology, University of Colorado Denver, Aurora, Colorado, United States of America
Abstract?Top
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.
Citation: Ratelade J, Bennett JL, Verkman AS (2011) Intravenous Neuromyelitis Optica Autoantibody in Mice Targets Aquaporin-4 in Peripheral Organs and Area Postrema. PLoS ONE 6(11): e27412. doi:10.1371/journal.pone.0027412
Editor: Sookja Chung, The University of Hong Kong, Hong Kong
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Received: June 21, 2011; Accepted: October 17, 2011; Published: November 4, 2011
Copyright: ? 2011 Ratelade et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.