The Discovery of Central Nervous System Lymphatic Vessels: The Missing Link That Closes the Circle of Brain Immunosurveillance

Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature 2015;523:337–341.

The seeming absence of lymphatic vessels in the brain was considered one hallmark feature of its immune privilege1 and thought to result in a reduced transport of antigenic material to peripheral lymphatic organs where an immune response could be mounted. It is now time to revisit this paradigm given that Louveau and colleagues made the pivotal discovery of central nervous system (CNS) lymphatic vessels.2

In their attempt to identify the routes of circulation of surveying meningeal immune cells, they developed a whole‐mount preparation of mouse brain meninges and stained it for endothelial cells, T cells, and cells expressing major histocompability complex II. It appeared that immune cells were highly concentrated in close proximity of the dural sinuses, namely in perisinusal vessels. This meningeal lymphatic network appeared to start from the eyeballs and track above the olfactory bulb before aligning adjacent to the sinuses. By injecting different dyes intravenously and intraventricularly in anesthetized mice, the investigators observed the filling of vessels through the thinned skull my multiphoton microscopy. The vessels drained cerebrospinal fluid (CSF) and would also allow cells to travel to draining lymph nodes. T cells, potentially antigen presenting cells, dendritic cells, and immature B cells, were immunohistochemically identified and further dye experiments proved drainage into the deep cervical lymph nodes.

Moreover, the CNS lymphatic vessels may be connected to the recently emerged “glymphatic pathway,” a perivascular pathway that facilitates CSF flow through the brain parenchyma and thereby the clearance of interstitial solutes, among which may figure the drivers or by‐products of neurodegeneration, like for example amyloid‐beta.3 So far, the work was carried out in rodents, but similar structures were identified in human dura samples and further work will probably verify the existence of lymphatic CNS vessels in humans.

Thus, the ties between the brain and the peripheral immune system seem much stronger than hitherto imagined. This discovery opens new perspectives upon how the brain may generate adapted immune responses. How may this become relevant for the field of movement disorders?

It may change our understanding of the pathophysiology of autoimmune CNS disease, or of protective or detrimental immune mechanisms in neurodegenerative disease. For example, presentation of neuronal antigens released e.g. by an infectious encephalitis, or by neurodegeneration itself, may incite or fuel an immune response in cervical lymph nodes. This seems to be the case in the choreatic relapses after herpes encephalitis in children, which turned out to be mediated by N‐methyl‐d‐aspartate receptor antibodies.4 Similarly, neuronal antibodies can occur in patients with Creutzfeld Jakob disease and may not only lead to diagnostic difficulties, but could possibly modify the disease course.5 The antibodies against IgLON5 in the newly described tauopathy are discussed in terms of potential protective properties and their use as biomarkers.6 If and how this new pathway relates to autoimmune movement disorders, such as, for example, stiff person syndrome, or ataxia in the context of coeliac disease, is more unclear. Potentially, it may perpetuate an immune response against CNS antigens that has initially started in the periphery.

In this regard, the new discovery will fuel new attempts to explore secondarily generated antibodies as markers for neurodegenerative disease, such as alpha‐synuclein antibodies.7 It may also spur new diagnostic approaches and our endeavour to find feasible biomarkers, for instance by detecting certain molecules in lymph nodes with biopsies.8

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

B.B.: 3A

M.S.: 3B

Disclosures

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: B.B. holds a research grant from the Gossweiler Foundation and received travel grants from the International and Parkinson Movement Disorder Society and the EFNS‐ENS. M.S. serves at the editorial board of Movement Disorders Journal and Frontiers in Movement Disorders; received travel and speaker honoraria from AbbVie; and received research support from the Michael J. Fox Foundation.