title: Immune activation during the implantation phase causes preeclampsia-like symptoms via the CD40-CD40 ligand pathway in pregnant mice.
abstract: The CD40 ligand (CD40L) is expressed by T cells and has a critical role in immune system regulation. Interventions targeting CD40L interactions following embryo implantation represent an approach to preventing preeclampsia (PE). To better understand the role of CD40L in PE, we developed a PE mouse model in which we examined how CD40L-induced immune activation affects embryo implantation. Blastocysts were incubated with CD40L-expressing adenovirus and then were transferred into the uterine horns of pseudopregnant ICR mice. Histology, biochemistry and flow cytometry experiments were performed to examine the characteristics of the mouse model. In early pregnancy, decidualization and spiral artery remodeling were reduced in CD40L-transfected mice (CD40L mice) compared with control mice. Hematoxylin-eosin (HE) staining revealed hemorrhaging and excess fibrin deposition at the labyrinth layer-junctional zone interface of the placenta, and PAS staining demonstrated prominent focal and segmental sclerosis with collapsed glomerular capillaries in the kidneys of the CD40L mice. Flow cytometry data showed that interferon-γ production derived from CD4(+) T cells was elevated in the splenic cells of CD40L mice. Blood pressure (measured by the tail-cuff method) and urine albumin concentrations were significantly increased in CD40L mice compared with control mice. Furthermore, the plasma concentrations of soluble Flt-1 and soluble endoglin were increased in CD40L mice, as occurs in human patients with PE. Thus, CD40L-induced T-helper cell type 1 differentiation during embryo implantation may have a critical role in the pathogenesis of a PE-like presentation in a novel mouse model of PE.
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Uchikura
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hamada
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Fujioka
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Obstetrics and Gynecology, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D010920:Placenta / Q000276:immunology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand