title: Intravenous neuromyelitis optica autoantibody in mice targets aquaporin-4 in peripheral organs and area postrema.
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 t(½) ∼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.
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Julien
authors.initials: J
authors.lastname: Ratelade
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051401:Aquaporin 4 / Q000502:physiology*; D031608:Area Postrema / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D007275:Injections, Intravenous; D051379:Mice; D018345:Mice, Knockout; D009471:Neuromyelitis Optica / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G
references.citation: Biochem Biophys Res Commun. 2010 Mar 26;394(1):205-10
references.pmid: 20188706
references.citation: Brain. 2008 Nov;131(Pt 11):3072-80
references.pmid: 18945724
references.citation: Ann Neurol. 2009 Nov;66(5):617-29
references.pmid: 19938104
references.citation: FASEB J. 2011 May;25(5):1556-66
references.pmid: 21257712
references.citation: Acta Pharmacol Sin. 2011 Jun;32(6):702-10
references.pmid: 21552296
references.citation: Brain. 2007 May;130(Pt 5):1224-34
references.pmid: 17405762
references.citation: Lancet Neurol. 2007 Sep;6(9):805-15
references.pmid: 17706564
references.citation: J Immunol. 2008 Oct 15;181(8):5730-7
references.pmid: 18832732
references.citation: Neuroscience. 2010 Jul 28;168(4):1009-18
references.pmid: 19699271
references.citation: Neuroscience. 2010 Jul 28;168(4):892-902
references.pmid: 19699275
references.citation: J Clin Invest. 1997 Sep 1;100(5):957-62
references.pmid: 9276712
references.citation: J Biol Chem. 2009 Dec 18;284(51):35850-60
references.pmid: 19843522
references.citation: Neurology. 2011 Apr 5;76(14):1229-37
references.pmid: 21368286
references.citation: J Neuroimmunol. 1999 Feb 1;94(1-2):204-11
references.pmid: 10376954
references.citation: Clin Exp Pharmacol Physiol. 2000 May-Jun;27(5-6):422-7
references.pmid: 10831247
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 Aug;279(2):G448-53
references.pmid: 10915655
references.citation: Neurobiol Dis. 2009 Sep;35(3):368-75
references.pmid: 19520164
references.citation: FASEB J. 2008 Mar;22(3):870-9
references.pmid: 17965267
references.citation: Brain. 2010 Feb;133(Pt 2):349-61
references.pmid: 20047900
references.citation: Brain. 2007 May;130(Pt 5):1235-43
references.pmid: 17449477
references.citation: Glia. 2009 Oct;57(13):1363-73
references.pmid: 19229993
references.citation: J Biol Chem. 1995 Sep 29;270(39):22907-13
references.pmid: 7559426
references.citation: J Cell Sci. 1995 Sep;108 ( Pt 9):2993-3002
references.pmid: 8537439
references.citation: Brain. 2007 May;130(Pt 5):1194-205
references.pmid: 17282996
references.citation: Am J Physiol Cell Physiol. 2000 Jun;278(6):C1108-15
references.pmid: 10837338
references.citation: Biochem Biophys Res Commun. 2009 Sep 4;386(4):623-7
references.pmid: 19545538
references.citation: J Exp Med. 2008 Oct 27;205(11):2473-81
references.pmid: 18838545
references.citation: Lancet. 2004 Dec 11-17;364(9451):2106-12
references.pmid: 15589308
references.citation: Mult Scler. 2009 Apr;15(4):487-92
references.pmid: 19324982
references.citation: J Biol Chem. 2011 May 6;286(18):16516-24
references.pmid: 21454592
references.citation: J Exp Med. 2005 Aug 15;202(4):473-7
references.pmid: 16087714
references.citation: Nat Rev Neurol. 2010 Jul;6(7):383-92
references.pmid: 20639914
references.citation: Immunity. 2004 Aug;21(2):179-88
references.pmid: 15308099
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4328-31
references.pmid: 7538665
references.citation: J Neuroinflammation. 2010 Sep 07;7:50
references.pmid: 20822515
references.citation: J Immunol. 1997 Jul 1;159(1):497-507
references.pmid: 9200491
references.citation: J Neurosci. 1997 Jan 1;17(1):171-80
references.pmid: 8987746
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10908-12
references.pmid: 8855281
references.citation: J Cell Sci. 2011 Jul 1;124(Pt 13):2107-12
references.pmid: 21670197
references.citation: Ann Neurol. 2009 Nov;66(5):630-43
references.pmid: 19937948
references.citation: J Immunol. 2002 Nov 1;169(9):5171-80
references.pmid: 12391234