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An immunohistochemical study of lymphatic elements in the human brain
Journal article   Open access   Peer reviewed

An immunohistochemical study of lymphatic elements in the human brain

Éva Mezey, Ildikó Szalayova, Christopher T Hogden, Alexandra Brady, Ágnes Dósa, Péter Sótonyi and Miklós Palkovits
Proceedings of the National Academy of Sciences - PNAS, Vol.118(3), e2002574118
01/19/2021
DOI: 10.1073/PNAS.2002574118
PMCID: PMC7826383
PMID: 33446503
url
https://doi.org/10.1073/PNAS.2002574118View
Published (Version of record) Open Access

Abstract

Almost 150 papers about brain lymphatics have been published in the last 150 years. Recently, the information in these papers has been synthesized into a picture of central nervous system (CNS) "glymphatics," but the fine structure of lymphatic elements in the human brain based on imaging specific markers of lymphatic endothelium has not been described. We used LYVE1 and PDPN antibodies to visualize lymphatic marker-positive cells (LMPCs) in postmortem human brain samples, meninges, cavernous sinus (cavum trigeminale), and cranial nerves and bolstered our findings with a VEGFR3 antibody. LMPCs were present in the perivascular space, the walls of small and large arteries and veins, the media of large vessels along smooth muscle cell membranes, and the vascular adventitia. Lymphatic marker staining was detected in the pia mater, in the arachnoid, in venous sinuses, and among the layers of the dura mater. There were many LMPCs in the perineurium and endoneurium of cranial nerves. Soluble waste may move from the brain parenchyma via perivascular and paravascular routes to the closest subarachnoid space and then travel along the dura mater and/or cranial nerves. Particulate waste products travel along the laminae of the dura mater toward the jugular fossa, lamina cribrosa, and perineurium of the cranial nerves to enter the cervical lymphatics. CD3-positive T cells appear to be in close proximity to LMPCs in perivascular/perineural spaces throughout the brain. Both immunostaining and qPCR confirmed the presence of adhesion molecules in the CNS known to be involved in T cell migration.
 Aged Aged, 80 and over Antibodies - immunology Antibodies - isolation & purification Autopsy Brain - diagnostic imaging Brain - metabolism Cell Movement - genetics Central Nervous System - immunology Central Nervous System - metabolism Dura Mater - diagnostic imaging Dura Mater - metabolism Endothelium, Lymphatic - diagnostic imaging Endothelium, Lymphatic - metabolism Female Glymphatic System - metabolism Humans Immunohistochemistry - methods Lymphatic System - diagnostic imaging Lymphatic System - metabolism Lymphatic Vessels - diagnostic imaging Lymphatic Vessels - metabolism Male Membrane Glycoproteins - isolation & purification Membrane Glycoproteins - metabolism Subarachnoid Space - diagnostic imaging Subarachnoid Space - metabolism T-Lymphocytes - immunology Vascular Endothelial Growth Factor Receptor-3 - genetics Vesicular Transport Proteins - isolation & purification Vesicular Transport Proteins - metabolism

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