A new gateway between the immune system and the brain?

Last week, a study published in the prestigious journal Nature made waves in the scientific community with the discovery of a direct connection between the lymphatic system and the central nervous system (CNS). This finding was ground-breaking in that it provided concrete evidence that toppled the classically-held belief that the brain and spinal cord (together comprising the CNS) lacked lymphatic drainage and a direct link to the immune system, and unveiled a new avenue for exploring the disease-causing mechanisms of multiple sclerosis.

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What is the lymphatic system, exactly? The lymphatic system is a network of vessels and organs in the body involved in both draining and filtering interstitial fluid (the fluid that bathes the cells of our tissues) back into the blood. In addition, the lymphatic system transports lymphocytes (a type of white blood cell) and antigen-presenting cells (APCs), which are both integral components of the immune system. During an infection, invading microbes are detected by APCs, which engulf the microbe and display pieces of them (called antigens) on their surface. The APCs travel to the lymph nodes (lymph organs distributed throughout the body) where they interact with lymphocytes that “recognize” the microbial antigen, causing the lymphocyte to activate and mount an immune response in order to fight the infection.

To date, the brain has been among a small handful of organs considered to be “immune privileged”; that is, antigens present in the brain were thought unlikely to trigger an inflammatory immune response, presumably due to the absence of lymphatic drainage. Although it has been increasingly evident that there is in fact much more interaction between the immune system and the CNS than we once thought, the mechanisms underlying this interaction have been poorly understood making it difficult to understand just how MS begins.

This new study, conducted by a group of neuroimmunology researchers at the University of Virginia, have discovered the presence of functional lymphatic vessels lining the dural sinuses (compartments in the brain filled with cerebrospinal fluid that bathes and protects the tissues of the brain) in both mouse and human brain tissues. These vessels drain into the deep cervical lymph nodes in the neck, thus providing the first direct link between the CNS and the lymphatic system and a means for the movement of immune cells between these two systems.

So what does this mean for MS? Although it’s too early to say for sure, these findings could open up new opportunities for studying the disease mechanisms by which the body’s immune system turns against its own tissues in MS. It’s been known for some time that myelin antigens displayed by APCs have turned up in lymph nodes throughout the body (where they interact with lymphocytes and prime them to become reactive against myelin) in people living with MS. This in turn leads to the cascade of immune events called epitope spreading whereby inflammatory destruction of tissue in the CNS releases new antigens that are presented to lymphocytes in the lymph nodes and primes immune responses against them. However, how these myelin antigens leak out of the CNS has been something of a mystery.

The newly discovered lymphatic drainage system from the CNS complements other demonstrated pathways by which immune cells move freely between the CNS and the periphery, notably the disruption of the blood-brain barrier that has been the subject of intensive study (for instance, in this recent MS Society-funded study by Dr. Alexandre Prat and colleagues). Whether this discovery will translate into a new therapeutic target for suppressing or preventing the autoimmune response in people with MS remains to be seen; in the meantime, we’ll be keeping an eye on these developments and keeping you informed.

Reference
Louveau A et al. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature. doi: 10.1038/nature14432

Image credits: National Institutes of Health

12 thoughts on “A new gateway between the immune system and the brain?

  1. Wendy Newell

    I’m tuned in
    Please send information
    When readily available
    Thank you so much
    Extremely interested

    Reply
  2. Frances Meehan

    Found this article so very interesting relating to the lymphatic system as have m.s. What interests me is that my right foot & ankle swell sometimes for weeks, & then will be normal for a bit. When I saw a vascular doctor he told me that he sees many m.s. patients with this problem. It is the right side of my body which is affected by m.s.

    Reply
    1. drkarenlee Post author

      Hi Frances,

      MS is one of those unpredictable disorders in that it can strike nearly anywhere in the central nervous system; sometimes, the lesions in the brain and/or spinal cord will cause symptoms that are unilateral (that is, on one side), such as weakness in one of your extremities or loss of vision in one eye. How this relates specifically to the lymphatic system is still unknown and hopefully new research will uncover some more answers in the near future. Thank you for sharing your story with us.

      Dr. K

      Reply
      1. Martin Matko

        Chronic Cerebrospinal Venous Insufficiency (CCSVI) is a treatable congenital recognized medical condition, scientifically established to have a role/play part in 42 neurological afflictions and Multiple Sclerosis !

        Reply
    1. drkarenlee Post author

      Hi Yavor,

      Thank you for sharing your story. You’re absolutely right in that there is likely a strong connection. Several studies (this one, and this one) have shown compelling evidence that a previous history of infectious mononucleosis (mono) – which is caused by infection with Epstein Barr virus – leads to a higher risk of developing MS, regardless of age, sex, and time since mono or severity of infection.

      Dr. K

      Reply
  3. A Fisher

    As the work of Prof Prineas indicates that myelin is ALREADY damaged when the immune system kicks in to clear up the dead myelin cells and given that the lymphatic system drains into the veins of the brain which then drain into the internal jugular veins perhaps it is now time for neurologists to consider the actual underlying venous pathology of MS and the actual anatomy involved rather than continuing to claim some unproven autoimmune reaction in MS… This blog contains links to important research and information which neurologists cannot surely keep ignoring if patients are to access the care we actually need in our generation

    http://ccsviinms.blogspot.co.uk

    Reply
  4. A Fisher

    one further thing – please read this letter to Dr Cedric Raine from Dr Franz Schelling:

    In his 2010 book Dr Raine expresses some concerns that MS research is only addressing reactive and reparative changes; Dr Schelling notes Dr Raine’s comments on venous aspects of MS and asks him to consider, based on pathological evidence, whether retrograde pressure waves are causing the havoc that we see affecting and exceeding from veins in the ventricular walls or parts of the cortex that covers the brain.

    OPEN LETTER TO Dr Cedric S Raine – from Dr Franz Schelling

    Re: Multiple sclerosis – THE process of demyelination?

    Raine CS. Demyelinating diseases. In Davis PL, Robertson DM. Textbook of neuropathology. William & Wilkins, Baltimore, MD 1990; 627-714;

    Raine CS. The neuropathology of MS. In Raine CS, McFarland HF, Tourtellotte WW. MS: Clinical and pathogenic basis. Chapman & Hall, London 1997, pp. 151-171

    Dear Dr. Raine,

    Your dedication to furthering insight into the nature of MS, multiple sclerosis, is admirable. No less your noticing sore points in MS research. Who mastered an as candid as dry owning up to its problems as found, e.g. in your autobiographical notes (Raine CS. Erratum. J Neuroimmunol 2010; 225:2-4; Raine CS. Autobiography. J Neuropath Exp Neurol 2014; 73: 270-81)?

    In reviewing the history of MS you opened a treasure trove of precious observations, the content and meaning of which seems worth the effort of being deeply sounded out.

    Some of your assertions call for corrections, a few relevant findings may in addition be pointed out.

    (1) “The pathological anatomy of disseminated sclerosis bears no analogy to any other known pathological process” (Dawson 1916) – A well-worn cliché?

    Your Dawson quote actually proceeds to specify MS by relative neuronal persistence in areas marked out by their enormous interstitial tissue increase.

    Said to be unique on account of its anatomical pathology, MS thus emerges a histological entity. But instead of the said demyelination, something quite different came to be spoken of.

    Providential references to Charcot pinpoint the source of the quandary.

    December 3rd 1868. In presenting colored specimens of a clinically diagnosed MS, Charcot declares: “Indefinite, so to speak, persistence of some axons amidst the most advanced fibrillary tissue transformation is – mark this well – a characteristic which appears to be proper to MS” (Charcot JM. Histologie de la sclérose en plaques. Gaz Hop (Paris) 1868; 41: 557, right column, 2nd paragraph).

    Charcot’s statement parallels Dawson’s in again not speaking of a demyelinating disease.

    Charcot even stresses that the myelin decay seen in MS looks no different from that seen in the periphery of a cut nerve, the axons persisting also here distinctly longer than the myelin sheaths (Charcot JM. Histologie de la sclérose en plaques. Gaz Hôp (Paris) 1868; 41:557-8).

    March 14th, 1868: Having shown fresh autopsy specimens of the same case, Charcot concludes: What initiates MS is a neoformation, a proliferation of connective tissue that “suffocates the nerve fibers’ myelin” (Charcot JM. Séance du 14 mars. CR Soc Biol (Paris) 1868; 20: 13-14).

    Charcot’s case presentation closes in an emphatic pointing out that it is a hyperplasy of the interstitial fibrous feltwork, preceded by a multiplication of its nuclei, that forms the initial, fundamental, and necessary antecedent of the lesion formation.

    The atrophy of the nerve elements is explicitly said to be secondary, a consecutive event (Charcot JM. Histologie de la sclérose en plaques. Gaz Hôp (Paris) 1868; 41:566).

    (2) Misled into postulating a sclerosing process?

    Charcot set great store by Frommann’s pertinent documentation, presented the year before. Frommann’s findings are actually the key to getting insight into Charcot’s understanding of MS.

    The illustrations of an – apparently spontaneous and aggressive – excessive sprawling of interstitial connective tissue structures in a case of spinal MS are without par in precision and clarity.

    Frommann’s work also left no doubt that, at least in MS of the spinal cord, myelin sheath and axons tend to disappear side by side (Fig. E of http://www.ms-info.net/evo/msmanu/1030.htm, http://www.ms-info.net/evo/msmanu/1015.htm).

    In the wake of Frommann’s work, MS was accordingly no longer referred to as a form of ‘grey degeneration’, but instead highlighted the fibrous scarring or sclerosis of its lesion domains.

    Charcot spoke of ‘sclérose en plaques (îles, taches)’, German pathologists of ‘multiple Sklerose’, British ones chose ‘insular’ or ‘disseminated sclerosis’ instead.

    But now Charcot, as stressed by himself, made haste to leave the post mortem study to show symptoms by which MS can be recognized.

    (3) Clinically definite MS, the solid ground of MS research?

    Charcot was the first to teach how MS is to be diagnosed in life. The claim that this was possible if the patient’s paralysis was attended by intentional tremor and a scanning speech appeared even verified at post mortem (Charcot JM. Séance du 14 mars. CR Soc Biol (Paris) 1868; 20: 13-14).

    But as might have been expected, Charcot’s attempts at defining MS by symptoms and signs didn’t stand the test of time.

    If they show up separate in time and in space, symptomatic CNS lesions of all (indeterminate) sorts are now taken as evidence for MS, provided they manifest at and for defined times.

    The fact that symptoms which persist for 24 hours suffice for a clinical diagnosis of MS clashes with their interpretation as demyelinating events: Irreparably damaged myelin sheaths take a matter of days to weeks to clear up, their replacement months.

    An MS defined by symptomatic CNS lesions having neither a concrete nature nor cause excludes the elaboration of a diagnostic test. Neurologists make do with diagnostic red flags and checklists of potential MS misdiagnoses that are never complete.

    (4) Why not go back along Ariadne’s red thread?

    In sketching brain and spinal cord of Mme Leruth at her post mortem in June 1866, Charcot offered a first synopsis of the features that mark MS in anatomical pathological respects (Schelling F. CCSVI in MS. Abstract book, 2nd scientific ISNVD meeting, Orlando 2012, 1-4, http://www.isnvd.org/files/ISNVD%20Abstract%20Book.pdf).

    The findings parallel Carswell’s ‘peculiar diseased state’ and two of Cruveilhier’s instances of ‘grey degeneration’ in these respects:

    (a) There are scarred wedges that invade the spinal cord’s sides. In Carswell’s and Cruveilhier’s cases they do so in bits and pieces, in Charcot’s all along the line of insertion of the dent(icul)ate ligament. The changes end where the ligament ends.

    (b) There are pons lesions which differ in both form and distribution.

    (c) Charcot’s specimen showed in addition an involvement of the cerebral hemispheres by lesions that embed veins in the lateral ventricle’s roof.

    As for point (c), your disputed essays offer additional, quite revealing lesion specifications.

    We read, “The [MS]plaques are desposited in relation to the distribution of veins and to the walls of the ventricles” (Bruce 1911, quoted by Dawson). And you specify:

    The damage involves and flanks veins spread on the wall of the lateral ventricle(Figure 9.7, p.156).

    The area along the outer margin of the lateral ventricle, Steiner’s ‘Wetterwinkelzone’ or ‘storm center’, is commonly involved (a statement made thrice besides being impressively illustrated).

    The deepest, oldest part of the largest lesions lies immediately underneath the ependyma in the wall of the lateral ventricle, affecting its lining as well (granular ependymitis).

    Here many blood vessels [veins] show severely fibrotic, hyaline walls, testifying to some vascular insult. The degenerative venous changes yet appear not to have been injurious in themselves.

    Dawson’s fingers radiate from Wetterwinkel plaques into the cerebral hemispheres.

    Their heaviest concentration is again almost invariably paraventricular and they relate to subependymal vessels [veins]. A few lesions emerge just from one side of a certain length of their vessel[vein] of origin (Figure 14.11, p. 639). Others expand all through the white matter.

    Shadow plaques, felt to be unique to MS, tend to present as satellitic areas of cup-shaped lesions punched out over the angles of the lateral ventricles. They look like single-hit lesions.

    In the spinal cord, the typical lesions go down from the surface forming sort of wedges. Here and in the optic nerve, fibrillary, fibrous [and eventually trabecular] astroglial reactions prevail.

    Together with that last point, your observations of hypertrophic astroglial changes that precede and outreach the tissue destruction (Figure 14.18 – p.644 – A against B), lead straight back to Frommann’s, in part even to Charcot’s, Cruveilhier’s, and Carswell’s discoveries.

    (5) An MS not autoimmune but venous in origin. Something not even to be thought of?

    What constitutes the initial event in lesion formation is still open to question.

    What, however, if – as you revered Dr. Raine seem to suspect – MS research is just dealing with reactive and reparative changes, because even preparative artifacts and cracks in the myelin sheaths that came about before death cannot be reliably told apart?

    What averts suspicion that retrograde pressure waves are causing the havoc that we see affecting and exceeding from veins in the ventricular walls or parts of the cortex that covers the brain?

    Nobody has determined how fast and high the pressure inside the involved veins can rise above the pressure in their surroundings; this neither in accidents nor during the activities of daily life. The same applies to the large venous plexuses in the spinal canal.

    Good enough reasons for rethinking, even choosing new ways in MS research?

    What a relief, if you might honestly ponder or even alleviate these concerns!

    Yours sincerely,

    Franz Schelling, M.D.

    Reply
  5. Carol

    I have bilateral lymphodema in my lower extremities from a very serious fall in 2002. I do self massage every day and I use compression boot system for one hour each day. I also wear compression hose. I had swelling in 2002, after the fall, but was not diagnosed with MS until 2005. Interesting. Please keep me posted.

    Reply
    1. drkarenlee Post author

      Hi Carol,

      Thank you for sharing your story with us. I will continue to monitor progress related to this research and other studies related to MS and post them here.

      Dr. K

      Reply

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