Neuroimmunology: Finding their way out

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Wax model by sculptor Clemente Susini from the Specola museum; Susini was employed by Paolo Mascagni to model his anatomical discoveries

In the late 18th century, Emperor Joseph II commissioned the famous Italian anatomist Paolo Mascagni to develop a set of anatomical wax models – all the rage in that era – for what would later become the Josephinum collection of the Medical University in Vienna, Austria.

Mascagni’s passion lay on lymphatics, a network of vessels that clear waste from tissues and carry immune cells to lymph nodes, and so he ensured that these were present in his models, including the brain. Subsequent attempts to identify brain lymphatics, however, were unsuccessful, and researchers concluded that Mascagni was mistaken. “Mascagni was probably so impressed with the lymphatic system that he saw lymph vessels even where they did not exist — in the brain,” (comment Lucis et al.)

But science is full of surprises. Aleksanteri Aspelund, from Kari Alitalo’s laboratory at the University of Helsinki, Finland, was using the microscope in the animal facility one evening when he saw fluorescence in structures inside the skull. He had previously discovered that the eye, another organ thought to lack lymphatics, actually has a type of lymphatic vessel called the Schlemm’s canal, and wondered whether the same is true of the brain.

At the same time, in Jonathan Kipnis’ laboratory at the University of Virginia, USA, Antoine Louveau was trying to understand how immune cells enter and leave the meninges, a compartment that surrounds the brain and is full of immune cells under normal conditions. He saw that “some [immune cells] were stuck into a vascular structure that was not part of the cardiovascular structure.”

Published within two weeks of each other, Louveau and Aspelund’s work finally provided an answer to a question that has puzzled immunologists for decades: how do immune cells exit the brain? Although some remain hesitant, the findings change how we think about the brain–immune system relationship, with implications for neurological diseases with an immune component such as MS.

A problem of drainage

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A rat astrocyte grown in culture

Unlike other parts of the body, the brain is ‘immune privileged’: immune responses either develop slowly or not at all. However, it still requires a way to clear waste products in the cerebrospinal fluid (CSF), which bathes the brain and spine, and immune cells crossing the blood–brain barrier.

Many scientists have attempted to explain how this occurs in the absence of lymphatics. Roy Weller, from the University of Southampton, UK, described a system that allows the clearance of CSF from the brain to lymph nodes through the mucus membrane of the nose. A few years later, Maiken Nedergaard reported that CSF removes waste products through ‘the glymphatic system’ (video): a network of water channels around the outsides of brain blood vessels that are formed by star-shaped brain cells called astrocytes (see TedMed video).

These unconventional pathways, however, did not explain how immune cells exit the brain. As recalled by neuroimmunologist Michael Heneka, from the University Hospital in Bonn, Germany, T cells were assumed to patrol the brain and then “disappear someplace.”

This “someplace”, it seems, is a network of lymphatic vessels in the meninges that carries waste and immune cells to lymph nodes. According to Louveau, this acts as the second step of the glymphatic system. “With the glymphatic system, the brain removes its waste into the CSF, and with our system what is in the CSF is drained into the deep clavicle lymph nodes.”

A paradigm shift in disease?

Louveau is excited that their work could potentially explain some neurological diseases where the immune system is involved. Already, Aspelund’s paper has offered some clues: transgenic mice lacking the lymphatic system accumulated waste products in the brain. Although they are not likely to investigate this themselves, Alitalo believes that “there will a huge amount of work on immune cell trafficking”, in particular in the context of disease.

Heneka agrees. He thinks that “MS, ALS and Parkinson’s and Alzheimer’s [in that order] are likely to be influenced by that finding.”

Others are more sceptical. Neuropathologist Hugh Perry, from the University of Southampton, UK, argues that these hugely complex diseases, which are influenced by both genetics and the environment “are not going to be explained by unitary explanations like a change in our understanding of the lymphatics of the dura.”

One man’s waste is another man’s treasure

Regardless of the effect on disease, it is clear that the discovery of lymphatics substantially changes what we thought we knew about the immunology of the brain. So it seems surprising that such an integral part of the immune system has remained hidden until now. In the case of Louveau, what it took was to decide to not discard the meninges, as normally occurs with brain preparations.

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Paolo Mascagni

“Preparations of brain and meninges usually go the opposite way,” comments Heneka. This is because these are full of fibroblasts, which grow faster than neurons and can contaminate the culture.

“Like many aspects of neuroscience, advances in the brain depend upon the stain to paraphrase Bloom,” also notes Perry. The development of markers to help visualize the molecules lining lymphatic vessels, and of powerful microscopes that allow the visualization of tissues and live mice, were integral to this discovery.

And so, over 200 years later, and with major technical advances like microscopy, Mascagni has finally been vindicated. The lymphatics that he so carefully included in his wax models of the brain were not a figment of his imagination, but a legitimate system of transporting immune cells and waste to lymph nodes.

Rachel David is studying for an MSc in Science Communication

Images: Wax model by sculptor Clemente Susini from the Specola museum; Rat astrocyte; Paolo Mascagni (Wikimedia commons)

References:
1. Lukić, I.K et al. (2003) Virtual dissection: a lesson from the 18th century. Lancet. 362:2110–2113
2. Louveau, A. et al. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature doi:10.1038/nature14432
3. Aspelund, A. et al. (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. doi: 10.1084/jem.20142290

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