3 MECHANISMS OF Immunomodulation
Our immune systems protect us from infectious or toxic -exposures. They learn to differentiate our own cells from foreign cells and mount a response when appropriate. The intricacies of immune function are so complex, however, that there are many opportunities for it to go awry.
In this interview with Element Senior Writer Sarah Cook, ND, Robert Rountree, MD, explains three foundational mechanisms of immune function, and how nutrition can influence each mechanism. His central message is that through the process of immunomodulation, we can support immune health over a lifetime.
SARAH COOK:
What is immunomodulation?
ROBERT ROUNTREE:
Immunomodulation means balancing immune function. The word has been used in the context of botanicals and herbs for decades—immuno-modulators are herbs or substances that can have a normalizing effect on immune function. We might see that they have one effect in a test tube—such as activating an inflammatory response–and a seemingly opposite effect in the human body, where they can lead to an overall decrease in inflammation.
Some herbs that we think of as immunomodulators are echinacea (Echinacea spp.), Siberian ginseng (Eleutherococcus senticosus), and ashwagandha (Withania somnifera). These herbs are regulating—stimulating when they need to stimulate and calming when they need to calm. They’re like adaptogens for the immune system.
COOK:
Why should clinicians consider immunomodulation in their everyday practice?
ROUNTREE:
Many immune-related conditions are on the rise. As clinicians, we see more allergies, asthma, recurrent infections, and autoimmune diseases than ever. We see resistant infections and a rise in certain types of cancer, like non-Hodgkin’s lymphoma. And these problems are getting worse.
Different immune-related conditions have different mechanisms at play, but they also have a common thread: None of them develop overnight. There are pathophysiologic mechanisms in place that persist for years or even decades. And that begs the question: Is there a rational and systematic approach that we can take to support the immune system in becoming stronger and healthier?
That’s what we can do with immuno-modulation.
When we talk about immunomodulation, we aren’t talking about treating any specific disease or symptom. We’re talking about regulating, balancing, and supporting a healthy immune response. If we can succeed in doing this, our patients may be at a lower risk of developing immune–related conditions and will be able to enjoy a better quality of life.
COOK:
Why do you think immune-related conditions are on the rise?
ROUNTREE:
It used to be that immune problems occurred in the context of severe malnutrition. Vitamin C deficiency caused scurvy and immune problems, or protein and calorie malnutrition increased the risk of infections. There are still severe deficiencies of vitamin A in developing countries. Studies conducted in these environments have shown that we can reduce the incidence of measles by supplementing with vitamin A.
But malnutrition is much less likely to be the cause of immune problems in modern times. Environmental toxins, poor diet, sugar excess, and emotional stress are more likely to influence immune function today. For example, the number one risk factor for developing rheumatoid arthritis is smoking tobacco. Many different toxins and air pollutants have been implicated in other autoimmune diseases. Toxins and stress are also major contributors to oxidative stress and immune cell damage.
Another theory as to why immune-related conditions are on the rise has to do with overly clean environments and the overuse of antibiotics. People living in developed countries have significantly less diversity of their gut microbiomes than those who live closer to nature. According to Dr. Martin Blaser, author of Missing Microbes, each successive generation has less diversity than the one before. The microbes in the gut play such an important role in educating the immune system that their depletion compromises immune health. The molecular mechanisms of immune function become impaired.
COOK:
What are some important molecular mechanisms of immune-system function?
ROUNTREE:
Immune function is extremely complex, so let’s look at three molecular mechanisms that we can reliably support with nutrition and supplementation: barrier integrity, priming innate immunity, and redox balance.
COOK:
Perfect. Tell us more about barrier integrity.
ROUNTREE:
A critical determinant of health is that microbes stay in the right place. Some of the healthiest microbes in the gut become deadly if they enter the bloodstream. If the gut barrier is compromised, fragments of microbes cross into the bloodstream and activate an immune response.
A good example of this are lipopolysaccharides (LPS), which are fragments of the outer membrane of gram-negative bacteria. Also known as endotoxins, they are widely present in the lumen of the intestines. If a large amount breaches the barrier, it causes endotoxic shock. Endotoxemia from LPS is similar to what happened years ago when tampons caused toxic shock syndrome. The tampons irritated the vaginal mucosa enough to create a breakdown of barrier function and allow innocuous vaginal bacteria into the bloodstream, where they became deadly.
If a small amount of LPS crosses from the gut into the bloodstream, it activates an inflammatory response. When this situation becomes chronic, it is called “metabolic endotoxemia.” Metabolic endotoxemia is thought to be one of the primary instigators of inflammatory disorders, including obesity, metabolic syndrome, and type II diabetes.
Barrier function is important not only for the gut and vagina, but also for the sinuses and skin. At all of these barriers, immune cells such as dendritic cells, macrophages, and natural killer cells lie just at the surface. Collectively, these immune cells are called sentinel cells, and they extend tendrils through the barriers so that they can continually sample the microbial mix on the other side. It’s where they monitor for pathogens and other threats.
COOK:
How can nutrition influence barrier function?
ROUNTREE:
When it comes to supporting gut-barrier function, l-glutamine rises to the top. L-glutamine is the primary source of metabolic fuel for enterocytes, and it helps maintain and regenerate the gut lining.
Probiotics are useful for supporting barrier function of the gut, sinuses, and other body surfaces. But it’s important to understand that probiotic supplements don’t colonize. Instead, they make the mucosal environments more friendly for colonization with healthy microbes.
For instance, we see that if we supplement a single strain of probiotic (such as Lactobacillus gasseri) for a few weeks and then evaluate the microbiome, there’s an increase in a range of beneficial bacteria. What’s happened is that the probiotic supplement created an environment to support more diversity. This leads to improved barrier function.*
Zinc is another nutrient to consider for barrier function. Zinc carnosine is often used for upper gastrointestinal support, but zinc picolinate is equally effective for general gastrointestinal barrier support. Studies that have looked at in vitro models of intestinal barrier function, using Caco-2 cells, have found that zinc helps restore the gut barrier.
COOK:
Let’s move to the second mechanism. What does it mean to prime innate immunity?
ROUNTREE:
The dendritic cells and other sentinel cells that patrol the barriers of the body have receptors called toll-like receptors (TLRs) on their surfaces. These receptors recognize two types of molecular patterns on other cells: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
Think of these as “strangers” (PAMPs) and “danger” (DAMPs). Here’s how the process works.
PAMPs are the first molecular signal, and they’re ubiquitous. The resident microbes of the gut, sinuses, and other barriers all have PAMPs on their cell surfaces. Our dendritic cells sample those patterns and begin to recognize them as pathogens, but don’t mount a full-on immune response. The PAMPs simply prime innate immunity so that it will be ready to respond when the need arises.
DAMPs are the second molecular signal. DAMPs are molecular fragments that are released when cells have been damaged. For example, if the gut lining erodes from taking medications or drinking too much alcohol, the damaged cells release fragments of mitochondria or nuclear DNA—both of which are recognized by sentinel cells as DAMPs.
The presence of DAMPs alerts the innate immune cells to danger. It switches the primed cells from quiescence into action. Now they’re on fire. They start to program lymphocytes, which differentiate into either regulatory or inflammatory T cell lines and activate B cells to produce antibodies.
The fascinating thing is that many immunomodulating foods and botanical polysaccharides have molecular structures similar to PAMPs. They interact with receptors on dendritic and other innate immune cells to help prime and balance immune function. This mechanism could partly explain the benefits of foods and herbs that have been used for centuries to support immune health.
COOK:
Could you tell us more about the foods and botanicals that prime innate immunity?
ROUNTREE:
I mentioned that probiotics support barrier function, but they also interact with immune cells to support immune programming. The pathways are not entirely understood, but we see that probiotics program dendritic cells to turn naïve T lymphocytes into T regulatory cells, which keep the inflammatory response in check.
This mechanism is especially evident in the developing immune system. When we give probiotics to infants, for example, it helps to program their immune systems and reduce the chance of the onset of immune-related issues.
Medicinal mushrooms have a similar proposed mechanism of action as probiotics. These mushrooms carry molecular structures on their surfaces, known as beta glucans, that are similar to the PAMPs on yeast. The beta glucans interact with the same TLRs on dendritic cells as yeast does. Reishi and other medicinal mushrooms that have been used for thousands of years carry these molecular markers. When consumed as a foods or dietary supplement, they prime the innate immune cells and support a balanced immune response.
Some fascinating evidence of the age-old use of mushrooms was discovered in the early 1990s. Tourists in the Austrian Alps discovered Ötzi the Iceman, a well-preserved mummy of a man who lived around 3300 B.C.E. Scientists were able to deconstruct that the man had been attacked and injured. Wrapped around his waist was a bag of herbs and mushrooms. This was over 5,000 years ago, suggesting that people back then somehow knew that mushrooms were beneficial for wound healing. Now, modern science is informing us of some of the mechanisms at play.
Echinacea species are similar to mushrooms, in that they contain compounds that interact with TLRs on immune cells to keep them primed. Some in vitro studies show that when you expose immune cells to echinacea or mushrooms, they start producing inflammatory cytokines. That has concerned some clinicians and scared them away from using these botanicals in certain patients. But modern immunology simply shows that mushrooms and echinacea have molecular structures that are priming immune cells, which explains the apparent paradox. What appears to be inflammatory in cell culture has a balancing and supportive effect in the human body.
This paradox of both stimulating and balancing immune function captures the concept of immunomodulation perfectly. I’ve seen no convincing studies that show echinacea, mushrooms, or other immunomodulating herbs aggravate immune-related conditions in the vast majority of individuals. Given the millions of people around the world who have taken these substances for years on end, if this was a common problem one would expect to see numerous reports of adverse events. It’s a theoretical concern that is not supported by the published evidence.
When clinicians ask me if they should be wary of using certain herbs in certain immune-related conditions, my motto after practicing 40 years of medicine is that anyone can react to anything. If you recommend an herb for a patient and they have an adverse response, that’s an isolated idiosyncratic event until proven otherwise. It doesn’t mean that herb should never be used in a similar situation for another individual. Remember that immunomodulating herbs have a regulatory and balancing effect. They can be useful in a variety of situations.
COOK:
There’s one last immune mechanism you mentioned. Tell us more about redox balance.
ROUNTREE:
Redox balance means the balance between free-radical and antioxidant activity inside cells. Environmental toxins are some of the biggest offenders when it comes to disrupting redox balance. A good example is arsenic, which raises free radicals.
Dendritic cells are exquisitely sensitive to intracellular redox balance. If redox balance is disrupted, dendritic cells can become either underactive or overactive. This type of mechanism explains why too many free radicals can lead to immune–related problems.
COOK:
How does nutrition interact with redox balance?
ROUNTREE:
Nutrition and supplementation can make a huge difference when it comes to antioxidant defenses. One simple intervention is supplementation with glutathione or glutathione precursors. Glutathione is a potent cellular antioxidant, and N-acetylcysteine (NAC) is its rate–limiting precursor. These compounds can be taken internally for systemic support.
Other antioxidant nutrients, like zinc and vitamins A, C, D, and E, can synergize to support redox balance. Many herbs also support redox balance—especially turmeric or its active compound, curcumin.
COOK:
Are there nutritional supplements that support all three molecular pathways at once?
ROUNTREE:
Many of the nutrients that I already mentioned work via multiple mechanisms and support multiple pathways. L-glutamine is a good example. L-glutamine supports barrier function, serves as a fuel source for immune cells, and is a building block for glutathione.*
Zinc is another overall immune modulator. It supports barrier function and the immune response, and acts as an antioxidant.* That’s also true for turmeric or curcumin. There’s good evidence that curcumin helps restore barrier function and normal dendritic cell programming, and supports redox balance.*
There’s another master immunomodulator that I haven’t yet mentioned: vitamin D. We have two decades of research showing that vitamin D regulates immune cells and supports immune function.*
One thing to know about vitamin D supplementation is that giving a large bolus (like 100,000 IU once a month) is not as effective as giving smaller amounts more frequently. The best way to give vitamin D is daily and to aim for a serum level around 50 ng/mL. Vitamin D is part of a strong foundation of immune function.*
COOK:
What other words of wisdom do you have when it comes to helping optimize immune function?
ROUNTREE:
I do frequently recommend immune supportive dietary supplements in my clinical practice, but optimal health can’t all be about supplements. If a person is under a huge amount of stress, not exercising, or living in a polluted environment, supplementation will not be enough to turn things around.
A recent study published in Scientific American revealed incredible evidence of how stress affects immunity. Researchers told people that they were accused of something horrible that they never actually did. It created an acute sense of stress. The researchers measured the level of mitochondrial fragments in the subjects’ bloodstream after exposure to this stress and saw that the levels went through the roof. We don’t know how this happens, but it’s pertinent because mitochondrial fragments are recognized as DAMPs by immune cells. They alert the immune system to danger and trigger immune pathways.
The study showed that every time a person is under stress, their immune system is being told it’s under attack. Whereas stress used to be thought of as only a threat to adrenal health, now we know it’s also a threat to immune health.
This example of recent research on stress brings things full circle. While most practitioners have observed the influence of stress on the immune system, this scientific validation underscores the need for an integrative approach addressing diet, lifestyle, environmental exposures, toxic burden and stress as multiple factors that affect the immune pathways we have discussed here. As integrative clinicians, the best thing we can do for our patients is maintain awareness of how all of these influences interact and impact immune health. n
Robert Rountree, MD, has been practicing integrative family medicine in Boulder, Colorado, since 1983. He is the medical editor of Delicious Living magazine, clinical editor of Alternative and Complementary Therapies journal, and coauthor of numerous books about integrative medicine and nutrition. Dr. Rountree is also a founding core faculty member at the Institute of Functional Medicine (IFM), where he received the Linus Pauling Award from IFM in 2015 for his many years of training and mentoring other healthcare practitioners. In addition, Dr. Rountree serves as chief medical advisor for Thorne nutritional supplements.
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