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Neuromyelitis Optica Igg Causes Placental Inflammation and Fetal Death Samira Saadoun, Patrick Waters, M

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Neuromyelitis Optica Igg Causes Placental Inflammation and Fetal Death Samira Saadoun, Patrick Waters, M Neuromyelitis Optica IgG Causes Placental Inflammation and Fetal Death Samira Saadoun, Patrick Waters, M. Isabel Leite, Jeffrey L. Bennett, Angela Vincent and Marios C. Papadopoulos This information is current as of October 1, 2021. J Immunol 2013; 191:2999-3005; Prepublished online 9 August 2013; doi: 10.4049/jimmunol.1301483 http://www.jimmunol.org/content/191/6/2999 Downloaded from References This article cites 40 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/191/6/2999.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Neuromyelitis Optica IgG Causes Placental Inflammation and Fetal Death Samira Saadoun,* Patrick Waters,† M. Isabel Leite,† Jeffrey L. Bennett,‡,x Angela Vincent,† and Marios C. Papadopoulos* Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS and affects women of childbearing age. Most patients with NMO have circulating Abs, termed NMO-IgG, against the astrocytic water channel protein aquaporin-4. In the CNS, NMO-IgG causes complement-mediated astrocyte damage, inflammatory cell infiltration, and myelin loss. In this study, we show that aquaporin-4 is expressed in the syncytiotrophoblast of human and mouse placenta. Placental aquaporin-4 expression is high during mid-gestation and progressively decreases with advancing pregnancy. Intraperitoneally injected NMO-IgG binds mouse placental aquaporin-4, activates coinjected human complement, and causes inflammatory cell infiltration into the placenta and placental necrosis. There was no damage to maternal organs that express aquaporin-4, including the brain, spinal cord, kidneys, Downloaded from and skeletal muscle. In control experiments, no placentitis was found in mice injected with NMO-IgG without complement, non– NMO-IgG with human complement, or in aquaporin-4 null mice injected with NMO-IgG and human complement. The infiltrating cells were primarily neutrophils with a few scattered eosinophils and macrophages. NMO-IgG and human complement–induced placentitis caused fetal death, but some fetuses were born normal when lower amounts of NMO-IgG and human complement were injected. Sivelestat, a neutrophil elastase inhibitor, and aquaporumab, a nonpathogenic IgG that competes with NMO-IgG for aquaporin-4 binding, significantly reduced NMO-IgG and human complement induced placentitis and fetal death. Our data http://www.jimmunol.org/ suggest that NMO-IgG can cause miscarriage, thus challenging the concept that NMO affects only the CNS. These findings have implications for the management of NMO during pregnancy. The Journal of Immunology, 2013, 191: 2999–3005. euromyelitis optica (NMO) is an inflammatory, demye- binding to AQP4, NMO-IgG activates the classical complement linating disease of the CNS, with predilection for the pathway, causing deposition of membrane attack complexes (C5b- N optic nerve and spinal cord (1, 2); 68–91% of patients 9) in astrocyte plasma membranes. Astrocytes become damaged, with NMO have circulating IgG1 Abs against extracellular con- which leads to loss of AQP4 and loss of glial fibrillary acidic protein formational epitopes of aquaporin-4 (AQP4), termed NMO-IgG (GFAP) expression. Inflammatory cells (initially neutrophils with (3–5). AQP4, the main water channel protein in the CNS, is ex- eosinophils and later macrophages) then infiltrate into the lesion, by guest on October 1, 2021 pressed in the plasma membrane of astrocytes, primarily the peri- causing oligodendrocyte damage and myelin loss (1). vascular foot processes and the glia-limiting membrane (6). Female:male ratios range between 3:1 and 10:1, with a mean age The pathophysiology of NMO CNS lesions has been studied at onset 34–43 y (1, 2). Therefore, many patients with NMO are extensively in humans (7–9), rodent models (10–13), mouse spinal women of childbearing age. The effect of pregnancy on NMO has cord slices (14), and cultured cells (15, 16). These studies revealed been studied recently: the risk of acute NMO attacks is elevated that NMO-IgG has a key role in NMO lesion formation. After in the first trimester postpartum (17, 18). However, the effect of NMO on the placenta and fetus is unclear. In a retrospectively ascertained cohort of patients from the National NMO Service + *Academic Neurosurgery Unit, St. George’s, University of London, London SW17 (Oxford, U.K.), 13% of the pregnancies in NMO-IgG women 0RE, United Kingdom; †Nuffield Department of Clinical Neurosciences, University ended in miscarriage. This number rises to 33% if the pregnancies ‡ of Oxford, Oxford OX3 9DU, United Kingdom; Department of Neurology, Univer- occurring more than 1 y before disease onset are excluded (Leite sity of Colorado School of Medicine, Aurora, CO 80045; and xDepartment of Oph- thalmology, University of Colorado Denver, Aurora, CO 80045 et al., manuscript in preparation). A case report showed sponta- Received for publication June 5, 2013. Accepted for publication July 11, 2013. neous miscarriage associated with placental inflammation in a patient with NMO-IgG+ (19), but others reported normal preg- This work was supported by a research grant from the Guthy Jackson Charitable + Foundation (to M.C.P.); the National Institute for Health Research Oxford Biomedical nancies in NMO-IgG women receiving treatment (20). Our aim Research Centre (to P.W. and A.V.); the National Health Service Specialised Services was to determine whether NMO-IgG damages the fetoplacental for Neuromyelitis Optica (to P.W., A.V., and M.I.L.); and Guthy-Jackson Charitable Foundation and the National Institutes of Health Grant EY022936 (to J.L.B.). unit. Address correspondence and reprint requests to Dr. Marios C. Papadopoulos, Aca- demic Neurosurgery Unit, Room 1.122 Jenner Wing, St. George’s, University of Materials and Methods London, London SW17 0RE, U.K. E-mail address: [email protected] Mice Abbreviations used in this article: AQP4, aquaporin-4; C5b-9, complement mem- We used CD1 wild type (WT) and AQP4-null (KO) mice (21) that were brane attack complex; Chu, human complement; CON-IgG2B4, measles virus–specific recombinant IgG1; CON-IgG2B4[Cy3], Cy3 labeled CON-IgG2B4; E, embryonic day; 8–12 wk old. Protocols were approved by the British Home Office. IgGCON, serum IgG fraction from healthy volunteers; IgGNMO, serum IgG fraction Investigators analyzing the data were unaware of mouse genotype and type from NMO-IgG+ patients; KO, AQP4 null; NMO, neuromyelitis optica; NMO- of IgG injected. IgG53, rAb-53 monoclonal recombinant anti-AQP4 IgG1;NMO-IgG58,rAb-58 monoclonal recombinant anti-AQP4 IgG1; NMO-IgG53[Cy3], Cy3-labeled NMO- Mouse tissue IgG53; WT, wild type. Anesthetized mice were perfused-fixed through the left cardiac ventricle Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 with 0.9% saline followed by 4% formaldehyde. Tissues were removed and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301483 3000 NMO-IgG CAUSES PLACENTAL INFLAMMATION postfixed in 4% formaldehyde, dehydrated, and processed into paraffin. We Placental AQP4 expression after i.p. injection. AQP4 expression was de- also purchased ready-to-use CD1 mouse embryonic day (E) 10 to E18 termined to be normal if the grade was ++ or +++. Investigators were placenta tissue sections (AMS Biotechnology, Abingdon, U.K.). Sections unaware of the experimental conditions when examining samples. were stained with H&E or immunostained as described. NMO-IgG and control IgG Human tissue Sera from two patients with NMO (with strong AQP4 autoantibody serum We used normal human tissue (formalin fixed, paraffin embedded) including positivity), and two healthy subjects were processed to obtain the IgG fetal brain and spinal cord (20 and 40 wk old; Abcam, Cambridge, U.K.), fractions, termed IgGNMO and IgGCON, respectively. IgG concentration was placenta (15–20 wk; AmsBio, Abingdon, U.K.; GeneTex/TebuBio, Peter- 6–38 mg/ml. Chu was collected from healthy volunteers. Details are given borough, U.K.; Insight Biotechnology, Wembley, U.K.), ovaries, uterus, elsewhere (12). Purified human monoclonal recombinant NMO-IgGs (rAb- and cervix (Insight Biotechnology, Wembley, U.K.). Normal 40-wk-old 53 and rAb-58) were generated as described, and a measles virus-specific placentas were obtained from the Department of Pathology at St. George’s rAb (2B4) was used as isotype-matched control (10). We termed these Abs Hospital. Tissue sections were stained with H&E or immunostained for NMO-IgG53, NMO-IgG58, and CON-IgG2B4. Labeling of NMO-IgG58 and AQP4. CON-IgG2B4 with the red fluorophore Cy3 (NMO-IgG53[Cy3], CON- IgG2B4[Cy3]) was done using the Amersham Cy3 Ab Labeling Kit (GE Quantification of staining Healthcare, Buckinghamshire, U.K.). We examined four sections for each human placenta and two sections for Mouse i.p. IgG and Chu injections each mouse placenta. Baseline placental AQP4 immunoreactivity. We quantified syncytiotropho- To determine placental inflammation and fetal death, we injected pregnant mice with 0.8 ml polyclonal Ab (IgG )or25mg recombinant mAb blast AQP4 expression as the percentage of 10 high-power fields that were NMO immunopositive: 0, for 0–25%; +, for 25–50%; ++, for 50–75%; +++, for (NMO-IgG53, NMO-IgG58, CON-IgG2B4) plus 0.8 ml Chu. Pregnant mice 75–100%.
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