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The Central Nervous System

The Brain Is Actually Connected to the Lymphatic System

Here’s a surprise: there are lymphatic vessels going into the brain. That’s reported in this paper in Nature. (Here’s a pretty breathless press release from the University of Virginia, where the work was done). I’m no immunologist, but the work (done mostly in mice, and extended to human samples) looks pretty solid to me.
We were just having a discussion around this site about the immune system and the brain, and this discovery is going to set off a lot of research on that topic. Here’s how the authors finish off the paper:

The presence of a functional and classical lymphatic system in the central nervous system suggests that current dogmas regarding brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neurological disorders in which altered immunity is a fundamental player such as multiple sclerosis, Alzheimer’s disease, and some forms of primary lymphoedema that are associated with neurological disorders.

That seems like a bit of a leap, but not a crazy one. The state of this part of the lymphatic system in various diseases is now officially a big topic, I’d say. The authors already seem to have both demonstrated its existence and some real differences between it and the more well-known lymphatic vessels, and there will surely be more to come. Who knew?

46 comments on “The Brain Is Actually Connected to the Lymphatic System”

  1. steve says:

    You can easily imaging Alzheimer’s being the result of impaired clearance of amyloid through these lymphatics. This may be why a variety of therapies aimed at reducing amyloid don’t work; the clearance mechanism is blocked.

  2. Anonymous says:

    Why on earth has this not been nvestigated before???

  3. PPedroso says:

    @2 exactly.
    This seems like discovering in 2015 that we have a micro heart in our feet that pumps blood into our tiny toes.

  4. darwin says:

    Interesting. PDD-NOS (autism spectrum) also could be looked at for possible links. Some associations (weak) to hypersensitivities/mast cells, particularly in gut.

  5. Wile E. Coyote, Genius says:

    “Here’s a surprise: there are lymphatic vessels going into the brain.” Yes, that is a surprise. I would’ve bet anything that they are _coming out_ of the brain. So, since these vessels are going into the brain, where does all that lymph go?

  6. Biotech Capitalist says:

    @2 @3, quite surprising. You would think people like Aristotle and Da Vinci would have found this a long bit before the post genomic era.
    It serves as a humbling reminder of what amount of human biology we really understand.

  7. Lane Simonian says:

    #1 But supposedly for Biogen’s aducanumab there was a significant clearance of amyloid. At six months there was no difference in decline between placebo and any dose of the drug group. At one year, there was a significant difference especially in the high dose group and the placebo group but primarily because one third of the Apoe4 carriers had dropped out in the high dose drug group due to severe adverse reactions such as headaches and brain swelling and their last observed results were carried forward.
    It does not matter how much amyloid is produced or is cleared as many people have substantial amounts of amyloid in their brain and don’t have the disease.
    To relate this somewhat to immune function, oxidants initially increase the immune response and then decrease immune response in Alzheimer’s disease.
    Once the transition is made from Alzheimer’s disease as an amyloid/tau driven disease to an oxidative stress disease driven disease then the means for effective treatment become wide open. Maybe a page can be stolen from the canine cognitive dysfunction playbook:
    Decline in cognitive functions that accompany aging in dogs may have a biological basis, and many of the disorders associated with aging in canines may be mitigated through dietary modifications that incorporate specific nutraceuticals. Based on previous research and the results of both laboratory and clinical studies – antioxidants may be one class of nutraceutical that provides benefits to aged dogs. Brains of aged dogs accumulate oxidative damage to proteins and lipids, which may lead to dysfunction of neuronal cells. The production of free radicals and lack of increase in compensatory antioxidant enzymes may lead to detrimental modifications to important macromolecules within neurons. Reducing oxidative damage through food ingredients rich in a broad spectrum of antioxidants significantly improves, or slows the decline of, learning and memory in aged dogs. However, determining all effective compounds and combinations, dosage ranges, as well as when to initiate intervention and long term effects constitute gaps in our current knowledge.

  8. Anonymous says:

    Is this the same?
    If so, it has been known for a while…
    I think there was a talk about this at last year’s ACNP meeting.
    Neurochem Res. 2015 May 7. [Epub ahead of print]
    The Glymphatic System: A Beginner’s Guide.
    Jessen NA, Munk AS, Lundgaard I, Nedergaard M.
    The glymphatic system is a recently discovered macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the central nervous system. Besides waste elimination, the glymphatic system also facilitates brain-wide distribution of several compounds, including glucose, lipids, amino acids, growth factors, and neuromodulators. Intriguingly, the glymphatic system function mainly during sleep and is largely disengaged during wakefulness. The biological need for sleep across all species may therefore reflect that the brain must enter a state of activity that enables elimination of potentially neurotoxic waste products, including β-amyloid. Since the concept of the glymphatic system is relatively new, we will here review its basic structural elements, organization, regulation, and functions. We will also discuss recent studies indicating that glymphatic function is suppressed in various diseases and that failure of glymphatic function in turn might contribute to pathology in neurodegenerative disorders, traumatic brain injury and stroke.

  9. PharmaHeretic says:

    Another form of medical tourism? And will it start affecting the prices of drugs for treating Hep C?
    Patients Get Extreme to Obtain Hepatitis Drug That’s 1% the Cost Outside U.S.
    “This is how far one Express Scripts Holding Co. executive was willing to go to secure inexpensive versions of Gilead Sciences Inc.’s hepatitis C drug Sovaldi, unavailable to U.S. consumers under federal drug import and patent laws. His plan: Dock a cruise ship flying an Indian flag off the coast of Miami. Stock the ship with versions of Sovaldi sold in India for $83,000 less than the U.S. retail price for 12 weeks of treatment. Ferry U.S. patients to the boat and send them home with the potentially life-saving medicines at a huge discount.”
    “Greg Jefferys, a 61-year-old historian from Australia, is one of those who has already made the trip. Jefferys’ doctor told him the government wouldn’t subsidize the cost of Sovaldi for him because his disease wasn’t advanced enough. He’d have to wait until the virus further scarred his liver or pay the retail price of nearly $90,000. It was money he didn’t have and he didn’t want to get any sicker so when a friend mentioned to him that the drug was being sold for much less in India, he immediately booked a trip there.”

  10. Anon says:

    Is it only me who thinks drug delivery.?

  11. Chris says:

    Sorry for the stupid questions, I really don’t have a solid understanding of human biology.
    The discovery is that the cerebral fluid is directly connected to the lymphatic system (i.e. same fluid in the end)? While previously it was thought that the two were separated and that there is a barrier and that the interaction of the immune system with the brain was highly regulated?
    Does this mean that any antibodies swimming around in the lymphatic system can just enter the brain? If so, why is it such a big deal? Did we think there were strict selection criteria before?

  12. Anonymous says:

    could this relate to concussions and brain injuries as well?

  13. Roger Goddell says:

    another stupid question: could this relate to concussions and brain injuries as well?

  14. Anonymous says:

    I admit I tend to tune out anytime I read or hear anything about the lymphatic system – it usually comes up in connection with The Food Babe or some other huckster promising that their miracle cure will clear toxins out of my body.

  15. NJBiologist says:

    @2 Anonymous: “Why on earth has this not been nvestigated before???”
    To an extent, it has. Helen Cserr (Brown Univ., physiology department) did a lot of research on CSF production and drainage; IIRC, some of that indicated that proteins delivered to the CNS–adjuvant-free–triggered substantial immune responses. I think she left the anatomical route as a question mark, but showed the function. Kind of a shame that she didn’t live to see this.
    @11 Chris, my paraphrase [what’s the discovery here]
    We knew that CSF got out of the CNS by leakage around the nerve roots, but not that there were specialized lymphatic vessels. It’s still possible that the leakage route accounts for a larger fraction of the total flow. A blockage of CSF flow in the cervical region–say, an obstruction just below the skull–leads to hydrocephalus, a dangerous accumulation of CSF in the head. That tells me that whatever the capacity of this route is, it can’t accommodate total CSF production.
    @11 [does the flow go both ways] Classic lymphatic vessels have check valves, so if these are plumbed like the rest of the body’s lymphatics, it will be unidirectional.

  16. steve says:

    The reason it hasn’t been seen before is that the lymphatics run along a central artery that’s difficult to image. They did whole mounts that allowed them to see rather delicate lymphatics that don’t show up in normal histological sections.

  17. steve says:

    @8, the newly found lymphatic system serves the meninges and may act as a connection from the meninges to the glymphatic system.

  18. MoMo says:

    Chris-No apologies needed. Even brain neurologists and biologists don’t understand the brain.
    We are still in the dark ages here.

  19. luysii says:

    Well one thing this might explain is why autoimmune attack on the brain (particularly MS) has lesions around veins (perivenous) since the veins drain directly into the dural venous sinuses.
    Another example of finding something under our nose for years (CRISPR, protein inclusions in ALS etc. etc.)_

  20. academic111 says:

    Does this add/change the way we do preclinical assays on CNS targeting compounds vis-a-vis assessing their potential to cross blood-brain barrier?

  21. clarice says:

    come on. do we actually believe this? It is in Nature after all…

  22. Wile E. Coyote, Genius says:

    @20 academic111,
    I don’t think it does. The flow of lymph in the lymphatics would be anticipated to be one way (out) as previously indicated. In addition, I would fully anticipate any lymphatics that might be in the brain parenchyma (not sure that this paper indicates that they are anywhere but in the meninges – behind a pay wall for me) would also be surrounded by astrocyte foot processes, just as capillaries are, which are the primary structural/functional unit of the blood-brain barrier. The meninges consist of the dura (outermost), arachnoid (middle), and pia mater. The pia mater is tightly adhered to the brain surface and also has podocyte foot processes up against it such that the cells of the pia and the podocytes also form a blood-brain type barrier. Therefore, the lymphatics in the meninges observed in this paper were likely external to the BBB as it is. Again, I haven’t paid for the paper since it is behind a pay wall. However, the implication is that there is drainage of some sort from the brain into these lymphatic vessels, suggesting that there is a possible nexus there of some sort. I would wonder if the lymphatic drainage is only meningeal drainage (dura and arachnoid) and not of the brain proper.

  23. Wile E. Coyote, Genius says:

    Also, note that the abstract indicates that the vessels were identified in the dural sinus, ergo external to the pia. That also puts the vessels they identified outside of the BBB.

  24. Jonathan says:

    Now last week’s news about that anti-IL-17 psoriasis trial being stopped early for suicidal ideation makes a a lot more sense.

  25. Matt says:

    This is the stuff of massive debates – it’s amazing at the Barriers of the CNS meetings (CHSL, Gordon) to watch people slanging each other over which way CSF flows, how immune cells translocate the BBB, etc.
    This is interesting work, and there have been other anatomy/physiology discoveries in the past 20 years. It’s amazing what we don’t know.

  26. Slicer says:

    You can say “wow, it’s amazing what we don’t know” all you like, but HOW THE HELL ARE WE STILL ARGUING OVER THIS BASIC ANATOMICAL S–T??
    Arguing over structures? Seriously?! CHOP UP A CADAVER AND FIND OUT!

  27. Jeff says:

    @25 Yes, let the slanging begin…
    As pointed out above (@5,22,23) it looks like the direction of fluid flow here is outward (higher-pressure CSF toward lymph), suggesting a lymph ‘drainage’ system rather than an entry route. Perhaps a way for the immune system to sample the CSF?
    It will be interesting to see a cellular/molecular characterization of the pore structures involved here. According to the study they are at least large enough to allow the brain-to-lymph escape of Alexa488-labeled antibodies injected into the CSF.
    Amazing as the work is, I wouldn’t really consider these vessels to be ‘in’ the brain (i.e. embedded in neural/glial tissue). They are in the dura (first layer of fibroblasts/collagen under the skull), and thus outside the BBB.

  28. tangent says:

    @NJBiologist or other anatomists, could you help me understand what connectivity these are adding? What I read sounds like this is a lymphatic ‘bypass’ around part of the venous system, all outside the brain’s compartment. Is the point that the lymphatic system gets a first-pass look at contents of the CSF, before they otherwise make the long ride out to capillaries and into the lymphatic that way?
    ‘Bypass’ because the paper says these vessels line the dural sinuses. Sooo I looked dural sinuses up on Wikipedia, and it says they are channels that receive venous blood and CSF, and feed into the jugular. Right near where the lymph path will enter the subclavian, so we can take this trip via vein or via lymph.

  29. Anonymous says:

    BREAKING NEWS: The hip bone’s connected to the … thigh bone; the thigh bone’s connected to the … knee bone; the knee bone’s connected to the … well we’ll figure that one out in 20 years.

  30. Chest Rockwell says:

    This finding also likely explains how bacteria from the bloodstream find their way into the CSF to cause meningitis . . it’s always been sort of a “black box” to explain how they get across the BBB.

  31. NJBiologist says:

    @28 tangent: I’m not an anatomist–I’m a pharmacologist with an interest in the CNS.
    Standard dogma is that lymphatics drain into venous circulation, so it isn’t a total bypass. However, I’ve heard that sub-dural tracers can light up the cervical lymph nodes, so there would be a first-pass look happening.

  32. NJBiologist says:

    @30 Chest Rockwell–I suspect stress-related increases in blood-brain barrier permeability are a more likely explanation (even if we find out that these lymphatics are valve-less, this doesn’t seem like a large-volume pathway).

  33. In Vivo Veritas says:

    #26, Slicer…. lemme guess… chemist….. molecular biologist…… or pharma VP? 🙂

  34. Matthew K says:

    @8, no, the glymphatic system is a separate entity. It describes astrocytes clearing the extracellular space and draining to the perivascular space around vessels in the brain parenchyma. This new article finds actual lymphatic vessels in the dura alongside the dural sinuses, complete with the requisite markers expressed by lymphatic vessels in the rest of the body. Furthermore they show them draining into the cervical nodes, and along the way seem to disprove an older myth about pathogens from the CNS reaching the lymphatics by means of the space around the olfactory bulbs. It’s genuinely startling.

  35. Matthew K says:

    @28 Tangent, this is a path where the extracellular fluid would travel (probably via astrocytes) to the CSF (although in a slight mod to my statement above, the drainage of the glymphatic system to the perivascular space may also provide a path to the CSF space) which then leaks molecules, cells etc into the lymph vessel, independent of the venous return. This happens in tissues throughout the body of course, there is an arteriovenous circulation and 4% of the extravasated fluid travels back via lymph vessels to the thoracic duct.
    The big deal is that lymph nodes along the way are sampling stations, and basically a school for B cells to make antibodies etc. So yes, it’s a first pass look at the ECF of the brain, in a zone where the system is primed to recognise pathogens etc.

  36. Anonymous says:

    @29: brain bone?

  37. Anonymous says:

    @NJBiologist: Yeah you’re right about the lymph going venous at some point, but in this case it’s the csf going through the lymphatics straight to the deep (and later superficial) cervical lymph nodes. After they get filtered through those lymph nodes the lymph will go through efferent lymphatic vessels and drain back into the jugular and subclavian veins.
    *With this model there is still the question of how the glymphatic system and the arachnoid granulations/villi will play into this.

  38. Slicer says:

    @33: None of those things, sorry. Just a supremely confused layman.
    Recently, MIT discovered that brain cells break their own DNA, and that’s how you learn things. That’s the kind of stuff I expect to be researched in 2015. Not stuff you could discover with a close physical look, and particularly not “We discovered entirely new anatomical structures that we didn’t know existed before”! Why wasn’t this extensively cataloged by someone, anyone, back in the late 20th century in the course of Alzheimer’s research? Are there any other anatomical structures in there that we don’t know about? (I’m sure they’ll be discovered shortly now that the pump’s primed.)

  39. Lane Simonian says:

    Slicer, I just read this study, so I am going to go off topic again.
    I am not able to post links over the weekend on this site but I will try to stick with titles and a short abstract.
    DNA breakage underlies both learning, age-related damage
    Process that allows brains to learn and remember also leads to degeneration with age.
    This dovetails well with a recent study that the genes which led to greater human intelligence also made us one of the few animals prone to Alzheimer’s disease.
    Alzheimer’s origins tied to rise of human intelligence
    Factors that drove evolution of intellectual capacity also implicated in memory disorder.
    Most of the genes found in the above study are linked to NMDA receptor activation. This activation via the phosphatidyinositol-3 kinase/Akt pathway results in synpatic plasticiy and neurogenesis but it also leads to DNA damage which can be repaired by PARP. However, under oxidative and nitrostative stress, the neuroprotective phosphatiylinositol-3 kinase/Akt pathway is cut off and PARP is cleaved by caspases. The result is unrepairable DNA damage, mitochondrial dysfunction, and neuronal cell death all of which can happen in the absence of neurofibrillary tau tangles, amyloid oligomers, and amyloid plaques.
    Population-based studies have shown that approximately 20% of the ageing population (aged 65 years and over) with dementia have little or no classical Alzheimer-type neuropathology. Cumulative DNA damage and a reduced capacity of DNA repair may result in neuronal dysfunction and contribute to cognitive impairment independent of Alzheimer-type pathology in the ageing brain.

  40. Anonymous BMS Researcher says:

    “watch people slanging each other over which way CSF flows, how immune cells translocate the BBB, etc”
    At Virology meetings, there is argument about whether the CNS represents an HIV reservoir or not (and therefore whether treatments aimed at clearing HIV from the reservoirs would have to get past the blood brain barrier).

  41. Lane Simonian says:

    At least this study may be tangentially related to the subject.
    Lymphocytes of Patients with Alzheimer’s Disease Display Different DNA Damage Repair Kinetics and Expression Profiles of DNA Repair and Stress Response Genes

  42. Steve says:

    Mice are not people.

  43. Pinky says:

    @36: Brainstem! Brainstem!
    Brain: Neo-cortex, frontal lobe
    Pinky: Brainstem! Brainstem!
    Brain: Hippocampus, neural node. Right hemisphere
    Brain: Pons and cortex visual
    Pinky: Brainstem! Brainstem!
    Brain: Sylvian fissure, pineal, left hemisphere
    Brain: Cerebellum left! Cerebellum right! Synapse, hypothalamus, striatum, dendrite
    Brain: Axon fibers, matter gray
    Pinky: Brainstem! Brainstem!
    Brain: Central tegmental pathway, temporal lobe
    Brain: White core matter, forebrain, skull
    Pinky: Brainstem! Brainstem!
    Brain: Central fissure, cord spinal, parietal
    Brain: Pia mater! Menengeal vein! Medulla oblongata and lobe limbic, micro-electrodes
    The Brain!

  44. kdawg says:

    My mom and her brother had frontotemporal lobe degeneration (one a behavioral variant 18 year course and the other a motor variant 3 year course ) Their mom had early onset dementia and a brother had diabetes with another multiple myeloma sibling – all protein/immune problems?? Any theories?? They all had yellow fatty plaque like growths on camera as well…

  45. sepisp says:

    Funny though the same finding was reported at the same time by another research group: doi: 10.1084/jem.20142290

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