A Stunning Discovery

As stated in the press release for a study by Louveau and colleagues,¹ “In a stunning discovery that overturns decades of textbook teaching, researchers have determined that the brain is directly connected to the immune system by vessels previously thought not to exist.”

A hallmark characteristic of the central nervous system (CNS) is the absence of a classical lymphatic drainage system. Although the CNS is under constant immune surveillance within the meninges, the mechanisms governing the movement of immune cells in and out of the CNS are not well understood.

[[{"type":"media","view_mode":"media_crop","fid":"39474","attributes":{"alt":"brain-immune interactions","class":"media-image media-image-right","height":"221","id":"media_crop_1276322328012","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3979","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"©Lassedesignen/Shutterstock","typeof":"foaf:Image","width":"239"}}]]While searching for T-cell pathways in and out of the meninges, the researchers found functional lymphatic vessels lining the dural sinuses of dissected mouse brain meninges. The dural sinuses drain blood from both internal and external veins in the brain into the internal jugular veins. The identified structures expressed all of the molecular hallmarks of lymphatic endothelial cells (eg, expression of the main transcription factor of these cell types, Prox1), were able to carry both fluid (determined by injection of fluorescein and a fluorescent tracer dye) and immune cells (using immunohistochemistry) from the cerebrospinal fluid (CSF), and were connected to the deep cervical lymph nodes.

The authors also subsequently examined autopsy specimens of human dura, including the superior sagittal sinus. They identified a potentially similar lymphatic structure in human dura, but further studies are needed to assess and characterize the location and organization of meningeal lymphatics in the human CNS.

Drainage of the CSF into the peripheral blood has been an important area of investigation, and these meningeal lymphatic vessels represent a novel, and more conventional, path for CSF and immune cell drainage from the CNS.

The bottom line

The presence of a functional and classical lymphatic system in the CNS suggests that a reassessment of basic assumptions in neuroimmunology is needed. If the presence of these vessels is replicated/confirmed in humans, it may follow that dysfunction of meningeal lymphatic vessels contribute to the pathophysiology of a variety of CNS disorders associated with immune dysfunction, including multiple sclerosis, Alzheimer disease, schizophrenia, and mood disorders.

This paradigm-shifting finding holds the potential to alter how we perceive brain-immune interactions, and would enable a more mechanistic approach to the study of the neuroimmunology of these disorders.

References:

1. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015; DOI: 10.1038/nature14432. [Epub ahead of print]