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I can't resist posting excerpts from a recent article announcing that researchers just found an entirely new lymph system ("lymphatic vessels") in the brain that transports fluid in the brain, and is probably "crucial to metabolic and inflammatory processes".  The image in this post shows the system in the brain. Amazing that it is only now "discovered" - apparently it was noticed by an anatomist 2 centuries ago, but this was pooh-poohed by modern day physicians. Until now. Excerpts from the Atlantic:

Scientists Somehow Just Discovered a New System of Vessels in Our Brains

You are now among the first people to see the brain’s lymphatic system. The vessels in the photo above transport fluid that is likely crucial to metabolic and inflammatory processes. Until now, no one knew for sure that they existed. Doctors practicing today have been taught that there are no lymphatic vessels inside the skull. Those deep-purple vessels were seen for the first time in images published this week by researchers at the U.S. 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.

Around the same time, researchers discovered fluid in the brains of mice and humans that would become known as the “glymphatic system.” It was described by a team at the University of Rochester in 2015 as not just the brain’s “waste-clearance system,” but as potentially helping fuel thebrain by transporting glucose, lipids, amino acids, and neurotransmitters.

Wouldn’t neurosurgeons, at some point in their meticulous down-to-the-millimeter dissecting of brains, have stopped and said, “Hey ... what’s this thing?”The lymph vessels probably escaped detection because they’re inside a thick membrane, the dura mater, which is the consistency of leather. They run alongside blood vessels that are much larger, and on MRI the signal that creates the images is dominated by the blood vessels.  

But this pathway appears crucial to life and health. A 2013 study in Science found that glymphatic flow seems to increase by almost double during sleep (in mice). Sleep disturbances are a common feature in Alzheimer’s and other neurologic disorders, and it’s possible that inadequate clearing of the brain’s waste products is related to exacerbating or even causing the disease.... 

The flow of glymphatic fluid can change based on a person’s intake of omega-3 fatty acids, a study showed earlier this year. Preliminary findings like these together suggest a pathway through which nutrition and sleep can be related to neurologic disorders. Optimizing this glymphatic flow could become a central theme for the future of neurologic health. “If all of this is true, there probably is a connection between these two systems, glymphatic and lymphatic,” Reich said. “And that would be one of the major functions of cerebrospinal fluid.”

From The Atlantic. Credit: Daniel Reich/ National Institute of Neurological Disorders and Stroke

 Some studies with humans suggest that cancer growth is slowed with exercise, better cancer prognosis with regular exercise, and lowered cancer recurrence (e.g., exercise after prostate cancer diagnosis), but this study looked at the issue more in depth. Yes, it was done in mice, but this way mice could be randomly assigned to different treatments (including various cancers - both fast and slow growing ones) and conditions in ways you can't with humans.

Why does exercise have these beneficial effects? Various suggestions include exercise causing changes in body composition, or sex hormone levels, or systemic inflammation, and changes in immune cell function. The researchers point out that cells of the immune system play dual roles in cancer: the immune system has a powerful capacity to combat cancer, but chronic inflammation has also been linked to formation of tumors (cancer). Thus, "mobilization" of cancer killing "immune cells during exercise might represent an indirect defense mechanism against cancer growth." Bottom line: research suggests that exercise or vigorous activity is beneficial in those with cancer diagnosis. From Science Daily:

Running helps mice slow cancer growth

Here's one more benefit of exercise: mice who spent their free time on a running wheel were better able to shrink tumors (a 50% reduction in tumor size) compared to their less active counterparts. Researchers found that the surge of adrenaline that comes with a high-intensity workout helped to move cancer-killing immune (NK) cells toward lung, liver, or skin tumors implanted into the mice. The study appears Feb. 16, 2016 in Cell Metabolism.

"It is known that infiltration of natural killer (NK) immune cells can control and regulate the size of tumors, but nobody had looked at how exercise regulates the system," says senior study author Pernille Hojman, at the University of Copenhagen. "In our experiments, we tried to inject our mice with adrenaline to mimic this increase you see during exercise, and when we do that we see that the NK cells are mobilized to the bloodstream, and if there's a tumor present then the NK cells will find the tumor and home to it."

Hojman and her colleagues next used mice depleted of NK cells to show that the increase in number of NK cells at the site of the tumor was directly contributing to the reduction in size. Even with exercise and a full suite of other immune cells, without the NK cells these mice experienced the normal rate of cancer growth. Blocking the function of adrenaline also blunted the cancer-killing benefits of the running wheel.

The research group also discovered that an immune signaling molecule called IL-6 was the link between adrenaline-dependent mobilization of NK cells and tumor infiltration. It's known that IL-6 is released from muscle tissue during exercise, but Hojman presents evidence that adrenaline specifically hails IL-6 sensitive NK cells and that the IL-6 molecules helped guide the immune cells to the tumors.

"As someone working in the field of exercise and oncology, one of the main questions that cancer patients always ask is: how should I exercise? Can we do anything?" she says. "While it has previously been difficult to advise people about the intensity at which they should exercise, our data suggest that it might be beneficial to exercise at a somewhat high intensity in order to provoke a good epinephrine surge and hence recruitment of NK cells." (http://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30003-1.pdf)

The key finding in this research (they studied mice, but this process would also happen in humans) is that: the presence of microbes specifically blocks the immune cells responsible for triggering allergies. Once again we see the importance of a healthy and diverse microbiota (the community of microbes within us), and the need to nurture it from birth. Studies have shown the importance of the first year of life in establishing a healthy microbiome and the development of the immune system. A number of studies have shown that the presence of pets or animals (e.g., living on a farm) reduces the incidence of allergies in children.From Science Daily:

Role of microbiota in preventing allergies

The human body is inhabited by billions of symbiotic bacteria, carrying a diversity that is unique to each individual. The microbiota is involved in many mechanisms, including digestion, vitamin synthesis and host defense. It is well established that a loss of bacterial symbionts promotes the development of allergies. Scientists at the Institut Pasteur have succeeded in explaining this phenomenon, and demonstrate how the microbiota acts on the balance of the immune system: the presence of microbes specifically blocks the immune cells responsible for triggering allergies. 

The hygiene hypothesis suggests a link between the decline in infectious diseases and the increase in allergic diseases in industrialized countries. Improvements in hygiene levels necessarily lead to reduced contact with microbes that is paralleled by an increased incidence in allergic and autoimmune diseases, such as type 1 diabetes.

Epidemiological studies have substantiated this hypothesis, by showing that children living in contact with farm animals -- and therefore with more microbial agents -- develop fewer allergies during their lifetime. Conversely, experimental studies have shown that administering antibiotics to mice within the first days of life results in a loss of microbiota, and subsequently, in an increased incidence in allergy.

However, until now, the biological mechanisms underlying this phenomenon remained unclear. In this study published in Science, the team led by Gérard Eberl (head of the Microenvironment and Immunity Unit at the Institut Pasteur) shows that, in mice, symbiotic intestinal microbes act on the immune system by blocking allergic reactions.

Several types of immune response can be generated in order to defend the organism. The presence of bacterial or fungal microbes provokes a response from immune cells known as type 3 cells. These immune cells coordinate the phagocytosis and killing of the microbes. However, in the case of infection by pathogenic agents that are too large to be handled by type 3 cells (such as parasitic worms and certain allergens), the cells that organize the elimination of the pathogen, but also allergic reactions, are known as type 2 cells.

In this study, scientists at the Institut Pasteur have shown that type 3 cells activated during a microbial aggression act directly on type 2 cells and block their activity. Type 2 cells are consequently unable to generate allergic immune responses. This work demonstrates that the microbiota indirectly regulates type 2 immune responses by inducing type 3 cells.

These results explain how an imbalance in microbiota triggers an exaggerated type 2 immune response normally used to fight large parasites, but that also leads to allergic responses....In terms of allergy treatment, a hitherto unexplored therapeutic approach consists therefore in stimulating type 3 cells by mimicking a microbial antigen in order to block allergy-causing type 2 cells.

Textbooks will have to be rewritten with the recent discovery of a system of lymphatic vessels that are a direct link from the immune system to the brain. Amazing that after centuries of studying people, that only now was this system detected (but they are very small and they follow a major blood vessel down into the sinuses). After extensive research,  the researchers determined that these vessels carry both fluid and immune cells from the cerobrospinal fluid, and that they exist in humans. The discovery reinforces findings that immune cells are present even within healthy brains, a notion that was doubted until recently.From Medical Daily:

Discovery Of 'Missing Link' Between Brain And Immune System Could Change How Disease Is Studied

The recent discovery of a "missing link" between the brain and the immune system may lead to a complete revision of biology textbooks. The link, vessels of the lymphatic system that run through the sinuses, were previously unidentified and thought not to exist. However, the true significance of the discovery lies in the potential effects this finding could have on both the study and treatment of neurological diseases such as Alzheimer’s disease and multiple sclerosis.  

The newly discovered "central nervous system lymphatic system vessels" follow a major blood vessel down into the sinuses, an area that has been traditionally difficult to obtain images of. Their presence is causing a stir in the medical world, as the researchers responsible believe the vessels may help to explain current medical mysteries, such as why patients with Alzheimer’s disease have accumulations of large protein plaques in the brain.

The fascinating discovery was made by researchers at the University of Virginia School of Medicine, and a study on the finding is currently available in the online journal Nature....Using a recently developed method, the team mounted the meninges, the membranes covering the brain, on a single slide so that they could be better observed. Only after doing this were they able to notice the brain’s elusive lymphatic vessels.   "It's so close to the blood vessel, you just miss it," Kipnis said. "If you don't know what you're after, you just miss it."

The team believes that the “missing link” between the brain and the immune system could explain why some diseases like Alzheimer’s can cause plaque buildup in the brain. Kipnis believes this plaque may be the result of the meningeal lymphatic vessels not efficiently removing buildup before it reaches the brain. Although scientists are currently not sure what causes cell death and tissue loss in the brains of those with Alzheimer’s, this plaque buildup is believed to play a role.

It’s not just the presence of plaque in the brain that the researchers hope this discovery can shed light on. According to Kipnis, this discovery could completely change the way we perceive the neuro-immune interaction.“We believe that for every neurological disease that has an immune component to it, these vessels may play a major role,” Kipnis said. “Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component.”The vessels also appear to look different with age, which has lead the researchers to suggest that they may play a role in the aging process.

Missing link found between brain, immune system -- with major disease implications Maps of the lymphatic system: old (left) and updated to reflect UVA's discovery.   Credit: University of Virginia Health System

Experiencing positive emotions such as awe, wonder, and amazement are linked with lower levels of inflammation in the body . Another reason to seek out amazing, awe inspiring experiences - it's good for our mental and physical health. From Science Daily:

Add nature, art and religion to life's best anti-inflammatories

Taking in such spine-tingling wonders as the Grand Canyon, Sistine Chapel ceiling or Schubert's "Ave Maria" may give a boost to the body's defense system, according to new research from UC Berkeley. Researchers have linked positive emotions -- especially the awe we feel when touched by the beauty of nature, art and spirituality -- with lower levels of pro-inflammatory cytokines, which are proteins that signal the immune system to work harder.

"Our findings demonstrate that positive emotions are associated with the markers of good health," said Jennifer Stellar, a postdoctoral researcher at the University of Toronto and lead author of the study, which she conducted while at UC Berkeley.

While cytokines are necessary for herding cells to the body's battlegrounds to fight infection, disease and trauma, sustained high levels of cytokines are associated with poorer health and such disorders as type-2 diabetes, heart disease, arthritis and even Alzheimer's disease and clinical depression.

In two separate experiments, more than 200 young adults reported on a given day the extent to which they had experienced such positive emotions as amusement, awe, compassion, contentment, joy, love and pride. Samples of gum and cheek tissue, known as oral mucosal transudate, taken that same day showed that those who experienced more of these positive emotions, especially awe, wonder and amazement, had the lowest levels of the cytokine, Interleukin 6, a marker of inflammation.

In addition to autoimmune diseases, elevated cytokines have been tied to depression. One recent study found that depressed patients had higher levels of the pro-inflammatory cytokine known as TNF-alpha than their non-depressed counterparts. It is believed that by signaling the brain to produce inflammatory molecules, cytokines can block key hormones and neurotransmitters -- such as serotonin and dopamine -- that control moods, appetite, sleep and memory.

In answer to why awe would be a potent predictor of reduced pro-inflammatory cytokines, this latest study posits that "awe is associated with curiosity and a desire to explore, suggesting antithetical behavioral responses to those found during inflammation, where individuals typically withdraw from others in their environment," 

It seems like the more microbe exposure in the first year of life, the better for the immune system. From Science Daily:

Newborns exposed to dirt, dander, germs may have lower allergy, asthma risk

Infants exposed to rodent and pet dander, roach allergens and a wide variety of household bacteria in the first year of life appear less likely to suffer from allergies, wheezing and asthma, according to results of a study conducted by scientists at the Johns Hopkins Children's Center and other institutions.

Previous research has shown that children who grow up on farms have lower allergy and asthma rates, a phenomenon attributed to their regular exposure to microorganisms present in farm soil. Other studies, however, have found increased asthma risk among inner-city dwellers exposed to high levels of roach and mouse allergens and pollutants. The new study confirms that children who live in such homes do have higher overall allergy and asthma rates but adds a surprising twist: Those who encounter such substances before their first birthdays seem to benefit rather than suffer from them. Importantly, the protective effects of both allergen and bacterial exposure were not seen if a child's first encounter with these substances occurred after age 1, the research found.

"What this tells us is that not only are many of our immune responses shaped in the first year of life, but also that certain bacteria and allergens play an important role in stimulating and training the immune system to behave a certain way."

The study was conducted among 467 inner-city newborns from Baltimore, Boston, New York and St. Louis whose health was tracked over three years.

Infants who grew up in homes with mouse and cat dander and cockroach droppings in the first year of life had lower rates of wheezing at age 3, compared with children not exposed to these allergens soon after birth. The protective effect, moreover, was additive.  In addition, infants in homes with a greater variety of bacteria were less likely to develop environmental allergies and wheezing at age 3.

When researchers studied the effects of cumulative exposure to both bacteria and mouse, cockroach and cat allergens, they noticed another striking difference. Children free of wheezing and allergies at age 3 had grown up with the highest levels of household allergens and were the most likely to live in houses with the richest array of bacterial species. Some 41 percent of allergy-free and wheeze-free children had grown up in such allergen and bacteria-rich homes. By contrast, only 8 percent of children who suffered from both allergy and wheezing had been exposed to these substances in their first year of life.

An argument for the need for human exposure to the microbes in rural environments. However, the role of diesel exhaust and other urban air pollutants is not discussed here (for example, diesel exhaust is linked to asthma). From Science Daily:

Rural microbes could boost city dwellers' health, study finds

The greater prevalence of asthma, allergies and other chronic inflammatory disorders among people of lower socioeconomic status might be due in part to their reduced exposure to the microbes that thrive in rural environments, according to a new scientific paper co-authored by a University of Colorado Boulder researcher.

The article, published in the journal Clinical & Experimental Immunology, argues that people living in urban centers who have less access to green spaces may be more apt to have chronic inflammation, a condition caused by immune system dysfunction.

When our immune systems are working properly, they trigger inflammation to fight off dangerous infections, but the inflammation disappears when the infection is gone. However, a breakdown in immune system function can cause a low level of inflammation to persist indefinitely. Such chronic inflammation can cause a host of health disorders.

Some scientists have hypothesized that the increase of chronic inflammation in wealthier Western countries is connected to lifestyles that have essentially become too clean. The so-called "hygiene hypothesis" is based on the notion that some microbes and infections interact with the immune system to suppress inflammation and that eliminating exposure to those things could compromise your health.

The authors agree that microbes and some types of infections are important because they can keep the immune system from triggering inflammation when it's not necessary, as happens with asthma attacks and allergic reactions.

But they say the infections that were historically important to immune system development have largely been eliminated in developed countries. The modern diseases we pick up from school, work and other crowded areas today do not actually lead to lower instances of inflammatory disorders.

During our evolutionary history, the human immune system was exposed to microbes and infections in three important ways: commensal microbes were passed to infants from their mothers and other family members; people came into contact with nonpathogenic microbes in the environment; and people lived with chronic infections, such as helminths, which are parasitic worms found in the gut and blood.

In order for those "old infections" to be tolerated in the body for long periods of time, they evolved a mechanism to keep the human immune system from triggering inflammation. Similarly, environmental bacteria, which were abundant and harmless, were tolerated by the immune system. According to Rook, a professor at UCL, "Helminthic parasites need to be tolerated by the immune system because, although not always harmless, once they are established in the host efforts by the immune system to eliminate them are futile, and merely cause tissue damage."

In contrast, relatively modern "crowd infections," such as measles or chicken pox, cause an inflammatory response. The result is that either the sick person dies or the infection is wiped out by the inflammation and the person becomes immune from having the same infection again in the future.

Collectively, the authors refer to the microbes and old infections that had a beneficial impact on the function of our immune systems as "old friends." Exposure to old friends plays an important role in guarding against inflammatory disorders, the authors said. Because the "old infections" are largely absent from the developed world, exposure to environmental microbes -- such as those found in rural environments, like farms and green spaces -- has likely become even more important.

The authors say this would explain why low-income urban residents -- who cannot easily afford to leave the city for rural vacations -- are more likely to suffer from inflammatory disorders. The problem is made worse because people who live in densely populated areas also are more likely to contract crowd infections, which cause more inflammation.