This doctrine would be obliterated in the seventeenth century by the discovery of systemic circulation and of the drainage of chyle through a thoracic duct to the subclavian veins. Keywords: Galen; Lymphatic system; discovery; history of medicine; seventeenth century. Abstract The early history of lymphatic anatomy from Hippocrates ca. Publication types Historical Article. They orchestrate immune surveillance of various bodily tissues so that specific immune responses can unfold in the body parts that need them.
Lymphatics are similar to blood vessels, but they carry immune cells in a fluid called lymph. Like tiny streams converging, this fluid collects and is channeled into the network of lymphatic vessels, passes through lymph nodes, and makes its way back to the bloodstream. When a tissue is infected by a pathogen, like a virus, bacteria, or parasite, bits and pieces of the offending pathogen end up in the lymph.
These pieces, along with immune cells from the infected tissue, reach the lymph node, and the cells in the lymph node then react to coordinate a specific immune response to the pathogen.
Thus, the system not only allows for recirculation of bodily fluid, but it also provides a means for the immune system to sift through material from around the body in order to scan for infection. Without lymphatics, fluid would build up in body tissues, and there would be no way to alert the adaptive immune system to invading pathogens. The result is that normal immune reactions within the brain are rare. Immune privilege likely exists because an overzealous immune response can act as a double-edged sword.
The immune system is important for maintaining healthy tissues, fighting off bugs, and cleaning up after injury, but too much activation can be severely damaging. T cells are a common subset of immune cells that are particularly important when it comes to offing viruses or bacteria. They are constantly on the lookout for invaders, and they can be cytotoxic cell-killing , so they find and eliminate infected cells. Autoimmune diseases like type I diabetes T1D or rheumatoid arthritis RA are examples of conditions caused by problematic immune responses, wherein the immune system mistakes a bit of self for a bit of invader and wreaks havoc on the tissue where that bit is found—the pancreas in T1D, and joints in RA.
Attacking an invading bug often comes at the cost of collateral damage to surrounding tissue, which must later be repaired. Thus, restricting immune system access to our most important tissue sites is a mode of self-preservation, especially for those sites that cannot easily repair after hosting a battle.
For a long time, scientists thought that the brain had a totally autonomous system of immune defense[1] based on brain-compatible immune cells called microglia, which live inside the parenchyma and never come and go the way a normal immune cell would. Some other types of immune cells—ones that are great at capturing and exposing elements of pathogens—survey the brain for infections not by going into the brain, but by monitoring it from the outside.
These cells sample material from the brain that gets into the cerebrospinal fluid or CSF, the fluid that surrounds the brain and spinal cord. They show what they find to T cells, which circulate around the outside of the brain looking for signs of trouble, but typically stay within the CSF.
If there is no sign of infection, the T cells continue on their way. If they see evidence of a problem, they can be triggered to enter the parenchyma[2] Figure 2. It was believed that CSF could play the part of the lymphatic system in the brain [2].
Even so, conceptions of how CSF allowed information to be passed from the brain to the lymph nodes had been fuzzy at best. However, the discovery of brain lymphatics points to a far simpler route. This past year, researchers at the University of Virginia UVA led by Jonathan Kipnis and Antoine Louveau were analyzing the brains of healthy mice, and happened upon what looked like well-organized immune cells—specifically T cells—throughout brain tissue [1].
Independently, a group of researchers in Switzerland, led by Kari Alitalo and Aleksanteri Aspelund, made the same discovery [5], making it highly unlikely that the finding is a fluke.
The sophisticated imaging technology the researchers used had never before been applied to this task. Their study involved looking at large, intact brain samples from mice, as well as monitoring live mouse brains.
For example, T cells might be tagged with red fluorescence, blood vessels with green, and so on. This strategy allowed them to visualize these lymphatic systems by fluorescent microscopy [4].
Discovering a new body part in the 21 st century is in itself remarkable, and the scientific significance of this finding is equally extraordinary. They could be passing along information about what is going on in the peripheral immune system.
Additionally, recent studies suggest that the incoming messages could somehow influence cognitive functions [6]. A hint at a role for immune cells in neurological health comes from the observation that cognitive functions can be sharp or dull depending on the status of the immune system—whether it is fully competent or compromised. This relationship has been explored by researchers examining cognitive function in healthy versus immunocompromised mice.
The healthy mice can easily fight off typical infections, and they behave like any normal mouse would in cognitive tests involving mazes and other stimuli. Researchers uncovered evidence that the immune systems of the mice may be directly responsible for these behavioral differences. They demonstrated this by using bone marrow transfers to swap the immune systems of the two types of mice. The findings were striking: the typical cognitive defects seen in immunocompromised mice were remedied by receiving healthy marrow.
Conversely, the healthy mice receiving immunocompromised bone marrow started to behave more poorly in the tests [6]. How could the immune system be affecting cognition? Among many possible explanations, some scientists speculate that T cells and brain-resident microglia are responsible for these cognitive effects—that T cells just outside the brain could be communicating with brain-resident microglia and orchestrating their behavior, and that microglia could in turn affect neuronal signaling.
This is plausible because microglia are not only in charge of fighting pathogens in the brain, but also play a role in brain homeostasis, meaning they keep everything in line day-to-day.
They also help refine connections between neurons in the brain, keeping signals sharp and specific. The theory is that T cells outside the brain signal to the microglia to perform these duties. Without the T cells, microglia might be dysfunctional, leading to a build-up of debris or connections that go haywire, ultimately disrupting proper cognitive function.
Another possibility is that systemic or local levels of chemicals produced by a normal immune system, but not by a weakened one, influence the chemical context of the brain.
This could affect the cognitive functions of mice by influencing any of the diverse cells in the brain, even the neurons themselves. Whether the lymphatic-bound T cells, like the ones observed by the researchers at UVA, are actively promoting the cognitive wellbeing of mice or humans remains to be proven.
However, the immune system is clearly involved. It is not yet clear whether lymphatics and cognition are part of the same neuroimmunology story, but these two examples demonstrate that communication between the brain and the immune system is a two-way street, and powerful in ways that the scientists of yesterday might have never anticipated.
Science, 18 December Vol. The anatomical and cellular basis of immune surveillance in the central nervous system. National Institute of Neurological Disorders and Stroke.
In the rest of the body, the lymphatic system collects and drains the fluid that bathes our cells, in the process exporting their waste. It also serves as a conduit for immune cells, which go out into the body looking for adversaries and learning how to distinguish self from other, and then travel back to lymph nodes and organs through lymphatic vessels.
Senior investigator Daniel Reich trained as both a neurologist and radiologist, and his expertise is in inflammatory brain disease. The connection between the immune system and the brain is at the core of what he says he spends most of his time thinking about: multiple sclerosis. The immune system appears to modulate or even underlie many neurologic diseases, and the cells of the central nervous system produce waste that needs to be washed away just like other metabolically active cells.
This discovery should make it possible to study how the brain does that, how it circulates white blood cells, and how these processes may go awry in diseases or play a role in aging. Reich started his search in , after a major study in Nature reported a similar conduit for lymph in mice. Reich reasoned that since this fluid exists in human brains, and the conduits exist in mice, the conduits likely exist in humans, too.
There are occasional references to the idea of a lymphatic system in the brain in historic literature. Two centuries ago, the anatomist Paolo Mascagni made full-body models of the lymphatic system that included the brain, though this was dismissed as an error.
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