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Refers to: https://news.virginia.edu/illimitable/discovery/theyll-have-rewrite-textbooks

The subject of this news story is the 2015 publication of lymphatics in the brain itself, i.e., finally physical connection between the brain and the immune system. However, beyond the mechanics, an overarching brain-immune system connection is well-known and indeed has been so for decades. After all, though somewhat removed from mainstream immunology, Psychoneuroimmunology does study interactions between the nervous and immune systems.

What held up the discovery of brain lymphatics is the thrall of Immune privilege. Back in the 1940s and 50s, led by the Nobel Prize-winner Peter Medawar, immunologists Leslie Brent and Rupert E. Billingham performed an extremely influential series of animal model tissue graft studies. Contrary to expectations based on rapid rejection of mismatched transplants in other sites such as skin, they found such grafts survived for extended periods of time in places like the eyes, testes, the hamster’s cheek pouch. Oblivious to the possibility that his idea might be constrained by the type of immune response he was studying, Medawar contrived the concept of immune privilege to explain why tissue graft survival rates varied widely in different parts of the body. Medawar interpreted such data to imply these tissues were immunologically ‘ignored’ because he considered such sites incapable of handling the fallout of inflammation. Per this line of thinking, the brain being encased by the bony skull rendered it even less suitable to handle inflammation since it involves local swelling due to blood vessel dilation followed by influx of fluid and leukocytes. Thus, Medawar’s notion of immune privilege has prevailed since the 1950s. As well, the Blood–brain barrier, i.e., a physical barrier limiting influx of cells into the brain, rendered the Medawar-driven notion of immune privilege even more impregnable, at least in the minds of rank and file immunologists.

However, we need to keep in mind that back in the 1950s, methods of assessing immune responses were quite crude. Physical rejection of tissue grafts, i.e., an unrepresentative albeit extremely powerful immune response, was state of the art. Yet what’s more shockingly untenable about immune privilege is its dissociation from evolutionary biology. Isn’t a tissue or organ not protectable by the immune system open sesame for a pathogen to capitalize? Yet, barring a few voices in the wilderness (1), the notion of immune privilege, i.e., immune ignorance, not only prevailed for decades but continues to exist even today though it may have lost some of its hegemony. After all, we now understand far better that there are many types of inflammation, that the type of tissue rejection observed by Billingham, Brent and Medawar is but one in a panoply of immune responses, and that a graft can survive not just due to absence of immune response, i.e., immune tolerance, but rather because a non-rejecting type of immune response prevails in certain tissues, i.e., immune regulation (2).

Conceptual blinders aside, the journey towards the discovery of brain lymphatics is incomplete without the story of a remarkably prescient neuroimmunologist, Helen F. Cserr, who, decades before this recent study was published, already uncovered that rather than ignoring the brain, the immune system was physically well-enmeshed with it, with traffic channels going both in and out of it. Studying brain-lymphatic connections mainly in mouse and rat models, this groundbreaking scientist consistently swam upstream in her effort to get her data published in a forbiddingly unreceptive era dominated by the notion of immune privilege. Alas tragically enough, her story’s one of what ifs since she died prematurely of cancer much before her life’s work was complete (3). In my estimation, if not for this unforeseeable tragedy, her published work (see figure below from 4 for a representative example) suggests that already back in the 1990s she’d have uncovered the final physical link between the brain and the immune system, i.e., lymphatics in the brain itself.

A much more detailed answer on brain and lymphatics here (warning: a long answer so not for the faint-hearted): Tirumalai Kamala’s answer to Why aren’t there lymph nodes in the brain?

Bibliography

1. Stein-Streilein, Joan, and J. Wayne Streilein. “Anterior chamber associated immune deviation (ACAID): regulation, biological relevance, and implications for therapy.” International reviews of immunology 21.2-3 (2002): 123-152.

2. Matzinger, Polly, and Tirumalai Kamala. “Tissue-based class control: the other side of tolerance.” Nature Reviews Immunology 11.3 (2011): 221-230. http://nevillab.org/images/pdf/p…

3. The New York Times, August 18, 1994. Helen F. Cserr; Physiology Professor, 57

4. Cserr, Helen F., Christine J. Harling‐Berg, and Paul M. Knopf. “Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance.” Brain pathology 2.4 (1992): 269-276.

https://www.quora.com/Why-did-it-take-so-long-to-discover-that-the-brain-is-connected-to-the-immune-system/answer/Tirumalai-Kamala

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