Being immune privileged does not mean the immune system can’t see you!

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The lymphatic system is part of the circulatory system, similar to the cardiovascular system, but instead of blood that carries nutrients and oxygen, the lymphatic system circulates lymph, the extracellular fluid from within tissues containing cellular waste and excess water (called interstial fluid or ISF). The immune system uses the wide network of lymphatic vessels and lymph nodes to check ISF for pathogens and as pathways for immune cells to spread the message of a possible threat.

Up to now it was believed that the brain does not contain any lymphatic structures – raising the question how the brain gets rid of excess water and waste molecules? While blood vessels are present in the brain, the so-called blood-brain-barrier blocks the exchange of cells or bigger molecules between the brain and blood to protect the brain from infections occurring in the periphery. Nonetheless immune cells still need to surveil the brain for infections within. But how is this possible if both blood and lymph cannot get in contact with the brain?

Two studies published in June 2015 in Nature and JEM now describe lymphatic vessels in the brain. Both studies demonstrate the presence of the vessels using immunohistochemistry, a commonly used technique in science and immunology using antibodies to identify different cells within one given tissue.

            Immunohistochemistry

In this technique, tissue samples either from human biopsies or mouse organs are fixed to conserve the tissue 3D structure using crosslinking chemicals such as paraformaldehyde. Afterwards the pieces of tissues need to be embedded in a material which supports the sectioning of the tissue in 5-20μm sections. The fine sections are then placed on glass slides (and may smile back at you like these gut sections below) and used for staining with antibodies. As each cell types produces a unique set of proteins, antibodies against those proteins can be used to identify different cell types within the tissue.

smiling gut

B cells produce antibodies and normally they recognise molecules (antigens) on pathogens allowing us to fight them. However, nowadays antibodies can be made against any antigen you like – in fact you can simply order them from companies making them a crucial tool for immunology!! But how can antibodies be made against self-antigens, which B cells should not normally recognise at all? They can be engineered since we know the genetic information that encodes for antibodies, but more commonly the protein of interest will be injected, similar to a vaccination, into a different species (mouse antigen into rabbit for example). As the protein is from a different species it’s recognised as foreign and an immune response is mounted in the “vaccinated” host. Host cells are then used to create hybridoma cell lines, which produce the antibody of interest.

 

The scientists used the knowledge that lymph vessels express the molecules Lyve-1, Vegfr3 and Prox1 while the surrounding cells in the tissue such as neurons do not express these markers to produces striking images showing us the existence of lymphatic system within the brain.

whole brain pic
Staining whole meninges. Lyve-1 in green shows lymphatic vessels and DAPI in blue shows all cell nuclei. Picture from Louveau et al. Nature 2015.

The lymph vessels were found in the dura mater, one of three meningeal layers covering the brain. The vessels run along blood vessels and sinuses, initiating at the eyes and existing at the base of the skull (as shown in the picture above). Using fluorescent tracers injected into the brain both studies showed that the interstial as well as the cerebrospinal fluid is drained by the newly discovered lymphatic vessels and transported into the deep cervical lymph nodes, located at the neck. In addition to the fluid, immune cells can be found in these vessels demonstrating a new way for the immune system to patrol the brain.

It’s a little surprising that these vessels have not been found earlier, right? In fact, they have been described before: in 1816 by an Italian anatomist called Paolo Mascagni, but nobody could reproduce his data till now. In one of the publications the authors argue that the vessels are hard to find due to their unique location and small size. The lymphatic network in the brain is much smaller compared to other organs, where the vessel are far more wide spread and branched. Nonetheless I think this finding underlines that there are still things we do not know about the human body.

So what does that mean for us? First of all, while one paper shows some data on human dura mater, the data is mainly based on mouse and needs to be confirmed in humans. Nonetheless the data suggests a new way how the immune system can surveil the brain. Draining the fluids in the brain into the lymph system any infection within the brain can be detected. Furthermore, one experiment in the Aspelund et al paper demonstrates that the lymphatic system may be important for the removal of waste molecules in the brain, which may have implications for neurodegenerative diseases such as Alzheimer’s diseases, in which protein accumulation leads to neuronal death. Injecting a protein called OVA into the brains of genetically modified mice lacking the lymphatic system within the brain, the scientists found an accumulation of OVA in the brain, as it can no longer be drained into the lymph node like it happens in normal mice. This raises the question, if a defect of lymphatic drainage may influence Alzheimer patients?

Any questions about these exciting findings? Let us know!

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