Neuromyelitis Optica IgG Causes Placental Inflammation and Fetal Death

Abstract

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, 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 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.