title: Trafficking of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier.
abstract: The Blood-Brain Barrier (BBB) restricts access of large molecules to the brain. The low endocytic activity of brain endothelial cells (BECs) is believed to limit delivery of immunoglobulins (IgG) to the brain parenchyma. Here, we report that endogenous mouse IgG are localized within intracellular vesicles at steady state in BECs in vivo. Using high-resolution quantitative microscopy, we found a fraction of endocytosed IgG in lysosomes. We observed that loss of pericytes (key components of the BBB) in pdgf-b(ret/ret) mice affects the intracellular distribution of endogenous mouse IgG in BECs. In these mice, endogenous IgG was not detected within lysosomes but instead accumulate at the basement membrane and brain parenchyma. Such IgG accumulation could be due to reduced lysosomal clearance and increased sorting to the abluminal membrane of BECs. Our results suggest that, in addition to low uptake from circulation, IgG lysosomal degradation may be a downstream mechanism by which BECs further restrict IgG access to the brain.
authors.affiliation: Roche Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland.
authors.forename: Roberto
authors.initials: R
authors.lastname: Villaseñor
authors.affiliation: Roche Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale INSERM/UdS, Collège de France, BP 10142, Strasbourg, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.affiliation: Roche Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Grüninger
authors.affiliation: Roche Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Loetscher
authors.affiliation: Division of Neurosurgery, University Hospital Zürich, Zürich University, Frauenklinikstrasse 10, CH-8091 Zürich, Switzerland.
authors.forename: Annika
authors.initials: A
authors.lastname: Keller
authors.affiliation: Vascular Biology Program, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.|Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Roche Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland.
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Freskgård
authors.affiliation: Roche Pharma Research and Early Development (pRED), Neurodegeneration and Regeneration, Roche Innovation Center Basel, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Collin
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000648:ultrastructure; D042783:Endothelial Cells / Q000378:metabolism*; D007074:Immunoglobulin G; D007136:Immunoglobulins / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D020286:Pericytes / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D007074:Immunoglobulin G; D007136:Immunoglobulins; D016875:tau Proteins