An immunohistochemical study of lymphatic elements in the human brain

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-01, Vol.118 (3), p.1-12
• Main Authors: Mezey, Éva, Szalayova, Ildikó, Hogden, Christopher T., Brady, Alexandra, Dósa, Ágnes, Sótonyi, Péter, Palkovits, Miklós
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Antibodies - immunology; Antibodies - isolation & purification; Autopsy; Biological Sciences; 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
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/PNAS.2002574118

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.