Immune-Health Supplements: Supporting Innate and Adaptive Immunity

What are the innate and adaptive immune systems, and how can supplements support them?

  Our immune systems are like our mothers: We never fully appreciate what they do for us until we need them. And with the 2014–2015 flu season turning out to be deadlier than usual, per the  Centers for Disease Control and Prevention (CDC), and with the accompanying vaccine apparently inadequate at fighting it, we need our immune systems fully primed now more than ever.

In fact, human immunity has been much in the spotlight of late, as residual fears over the Ebola virus continue their hum. Moreover, as healthcare cost containment merges with society’s shifting preference for prevention over treatment, defending the body’s built-in defenses is beginning to look downright trendy.

This is one trend the supplement industry is poised to address. Products ranging from single vitamins to antioxidant blends have long helped support the immune system, as the structure-function claim has it. But the more we learn about immunity, the more complex and exquisitely specific this architecture of cells, proteins, and defensive barriers proves to be. Which raises the questions: In an era of emerging immune challenges, what roles can supplements play? And how can we tailor our products to enhance both innate and adaptive immunity-the two interlocked “arms” of the immune response-without sending either into overdrive?

Armed for Battle

Getting a handle on supplements’ role in immunity requires getting a handle on immunity itself, and that’s no easy task. As Don Cox, PhD, senior vice president, healthcare research and development, Biothera (Eagan, MN), notes, “The human immune system is one of the most complex systems of the human body.”

With foot soldiers as varied as circulating proteins and the lining of the gut, the immune system exists to protect the body from foreign microbes and environmental toxins that would otherwise harm it. To do so, it mobilizes two branches of a joint force: innate and adaptive immunity. We can best describe these two branches as “separate but equal” in their contributions to the immune response. But while they’re equally important to mounting the body’s defenses, they differ in the rapidity, length, and specificity of their responses, as well as in the molecules, cells, and tissues involved.

Consider the innate immune system the vanguard force of cells and proteins always on alert and ready to shoot first and ask questions later. Its troops comprise physical barriers like skin and the epithelia of the respiratory and gastrointestinal tracts; phagocytic leukocytes, including neutrophils and macrophages (white blood cells that phagocytose, or “eat,” harmful microorganisms); dendritic cells that not only phagocytose invading microbes but generate signaling chemicals called cytokines, express microbial receptors, and link innate and adaptive immunity; natural killer (NK) cells that attack general classes of bacteria and viruses and eliminate weakened or infected cells; and circulating plasma proteins, including those of the complement system, that bind invaders, promote phagocytosis, and participate in adaptive immunity.

Phew! That’s a lot of work! And the fact that some soldiers of the innate response also participate in adaptive immune functions illustrates the blurry boundary separating the two systems. But generally speaking, while innate immunity acts as the body’s frontline infantry, the adaptive system is more like its special forces, trained not only to catch threats that escaped innate assault, but to target specific invaders and continue targeting them in subsequent attacks.

Adapt or Die

And that difference really is a matter of “training.” While innate immunity “has a number of set strategies for recognizing and destroying infections quickly without needing to be trained to identify them,” Cox says, the adaptive response “isn’t able to respond instantly to infections, as it needs time to adapt-or learn-to recognize them. Once it’s learned, however, it’s extremely effective and able to remember particular pathogens that have previously infected the body so that when they try to infect again, the next response is rapid, accurate, and effective.”

The trick lies in the activation and proliferation of specialized white blood cells called B and T lymphocytes.

B lymphocytes, so named because they come from bone marrow, produce antibodies that project from their membranes and “recognize” antigens-proteins, fats, sugars, other molecules-that are signs of microbial invasion. Once B cell antibodies “notice” these antigens, they differentiate into plasma cells that pump out yet more antibodies that bind the antigens, neutralize their microbial presenters, and mark them for phagocytosis. Part of what makes this response uniquely adaptive is that once it’s activated, “memory” B cells continue circulating, ready to respond quickly and forcefully if the antigen they “remember” invades again.

T lymphocytes, by contrast, recognize antigens not by way of antibodies, but by picking up on protein fragments bound to the surfaces of antigen-presenting cells. Thus stimulated, T cells of two different types get to work. Helper T cells secrete substances that goad B cells into producing antibodies and phagocytes into eliminating microbes. Cytotoxic T cells, meanwhile, secrete their own set of soluble molecules that directly participate in the killing of infected or ailing cells. As with B lymphocytes, “memory” T cells also persist after an infection, on alert should their targets strike again.

While adaptive immunity is critical, Cox makes an important point. “Researchers often focus on adaptive or acquired immunity because it has specific memory of immune challenges. But the innate immune system contains the largest population of immune cells in the body. In fact, neutrophils, macrophages, and monocytes account for approximately 65% of the body’s entire immune cell population.” And though innate and adaptive immunity are intertwined, he says, innate immunity has historically attracted most of industry’s attention. “We’re interested in understanding how supplementation can help the innate system fully function,” he says, “so that it’s ready when it’s most needed.”

Probiotic Protection

One way to do this involves supporting the gastrointestinal tract. After all, says David Keller, vice president, scientific operations, Ganeden Biotech (Mayfield Heights, OH), “The gut is the first line of defense of the innate immune system.”

Of all the supplements known to promote GI health, perhaps none holds as much promise as probiotic bacteria. From a digestive standpoint, Keller notes, research shows that those who consume probiotics end up with a healthier digestive tract. A variety of mechanisms explain why, he adds, “whether through helping you make better use of the nutrients you eat, or reducing pathogens by adjusting the pH of the gut.”

A 2006 study¹ published in Nutrition Reviews notes that probiotics may reinforce the barrier function of the gut mucosa, perhaps via their influence on cell adhesion or cell-to-cell signaling. Through their action on GI receptors, probiotics appear essential not only to our innate defenses but to triggering the adaptive immune response, as well. In vitro models even show that some probiotic strains promote a type of helper T cell known as Th1 while down-regulating pro-inflammatory cytokines and allergic responses associated with helper cells of the Th2 type. Regardless of what’s going on, Keller says, “Overall, the gut itself is healthier.” And so is the immune system.

All of which is why people should be thinking about the role probiotics can play in immune modulation, he continues. “Parents, kids, anyone who deals with lots of people on a regular basis should be taking a probiotic every day, and one that has data supporting how it affects the immune system.”

He points to studies showing that his company’s patented probiotic GanedenBC30 (Bacillus coagulans GBI-30, 6086) modulates a number of blood markers, including some of the positive cytokines and anti-inflammatory cytokines that participate in the immune response. Results of a randomized, double-blind, placebo-controlled crossover study of healthy seniors conducted at the University of Reading, England-full results of which await publication-demonstrated both digestive and immune benefits associated with the ingredient as measured in increases in healthy gut bacteria and levels of protective cytokines.

“We’ve also recently published a study on HIV-positive patients where we showed increases in beneficial blood markers even within that immunocompromised population, without having any negative side effects,” he continues. The randomized, double-blind, placebo-controlled study², published last October in AIDS Research and Human Retroviruses, found that 90 days of supplementation with two billion CFU of the probiotic ingredient correlated with increased blood percentages of “helper” T cells compared to the placebo, while also proving safe, well-tolerated, and effective at ameliorating chronic gastrointestinal symptoms in the subjects.

LAGging Ahead

That adds another brick to the growing wall of evidence supporting probiotics’ immune benefits. But good gut bugs need support themselves, and they get it from prebiotic fiber, which not only feeds them but benefits our own immune systems, as well.

Bryan Rodriguez, global product manager, Lonza Inc. (Allendale, NJ), points out that prebiotics possess “noted immune-modulating activity, in part by increasing lactic acid bacteria and the production of short-chain fatty acids in the GI tract.” Among the prebiotic fibers designed to do this is Lonza’s ResistAid, a proprietary larch arabinogalactan (LAG) that Rodriguez says “helps aid the digestive tract, where 70% of the immune system is located.”

Because of the fiber’s unique structure-it’s a soluble polysaccharide comprising arabinose and galactose monomers-it escapes hydrolysis by stomach acid and absorption through the small-intestinal walls, letting it reach the large intestine intact, where it “has the ability to optimize the immune system by utilizing direct and indirect modes of action,” Rodriguez explains.

As a prebiotic, the ingredient’s contribution to innate immunity is straightforward: it serves as a fermentable substrate for beneficial colonic microflora that then proliferate and “produce substances that provide localized protection against pathogenic bacteria, while also influencing other parameters of the immune system,” Rodriguez says.

But the LAG also helps modulate the adaptive immune response. Because galactose and arabinose are common structural components of microbial cell walls, including those of pathogenic bacteria, “Immune cells directly recognize these components and bind” the ingredient, Rodriguez says. The upshot: the LAG acts as a “biological response modifier via receptor sites on immune cells.”

Lastly, antioxidant activity courtesy of polyphenolic flavonoids represents what Rodriguez calls “the third pathway” of the product’s “triple-action immune support benefits.”

Clinical substantiation for those benefits appears in a randomized, double-blind, placebo-controlled study published in October 2013 in The Journal of the American College of Nutrition. In the study³, 75 healthy adults received 1.5 g/day or 4.5 g/day of the ingredient or a placebo for 60 days. At 30 days, they underwent both tetanus and influenza vaccinations-a research model “widely used to evaluate the impact a nutrient has on normal immune function and provide high-quality information on its protective in vivo effect on immune responsiveness,” Rodriguez explains. At 15 and 30 days following vaccination, subjects underwent measurements of IgG antibodies for tetanus and IgG and IgM antibodies for influenza A and B. The researchers found that while all three groups’ IgG levels for tetanus had increased by days 45 and 60, subjects receiving 1.5 g/day of the LAG saw a significant (p = 0.008) rise in tetanus IgG levels compared to the placebo, validating, Rodriguez says, the ingredient’s “capability to influence an expected and beneficial serum antigenic response from the immune system while simultaneously confirming its ability to do so at a low dosage.”

Beta Testing

While prebiotic fibers help support immunity, in part, by helping support beneficial microbial growth, one form of beta-glucan boosts immune function using a very different mechanism.

The product, Biothera’s Wellmune, is a natural beta 1,3/1,6 glucan derived from the cell walls of a proprietary strain of Saccharomyces cerevisiae, or baker’s yeast. According to the company’s website, immune cells in the GI tract take up the beta-glucan and transport it to immune organs where macrophages break it down into fragments released gradually over the course of days. These fragments then bind complement receptor 3 (CR3) sites on neutrophils, priming and strengthening the cells to circulate more rapidly throughout the body.

Biothera’s Cox notes that “one of our goals is to identify biomarkers for measuring the significant health benefits observed in clinical studies with our immune-health ingredient. We evaluate outside research that can help us develop reference values better to define at a cellular level how it benefits the immune system.”

He points to a Journal of Dietary Supplements paper⁴ based on the results of two clinical studies conducted by Brian McFarlin, PhD, FACSM, assistant professor, department of kinesiology, health promotion and recreation, University of North Texas, as providing evidence. As Cox puts it, “Dr. McFarlin sought to answer one question: Does supplementation with Wellmune improve mucosal immunity-the first line of defense against bacteria and viruses-in athletes?” In one study of marathoners, he found that unlike the placebo group, those taking the ingredient had a 37% reduction in the number of cold/flu symptom days reported for 28 days following their marathons, indicating a higher degree of immune support against upper respiratory tract infections both before and after exercise.

The other study measured changes in mucosal immunity among stationary cyclists exercising in a heat-stress lab. Those who supplemented for 10 days with the beta-glucan saw a 32% increase in salivary immunoglobulin-“considered the gold-standard measure for mucosal immunity,” Cox says-at two hours following exercise. “Overall,” he concludes, “these published studies demonstrate that not only can Wellmune cause a statistical reduction in the number of symptomatic days, but it can also clinically reduce symptoms so that athletes can recover quickly and get back to training.”

Everything in Modulation

Cox is quick to note that the ingredient improves the immune system’s defenses without sending them into overdrive. There are, on the other hand, immune-health ingredients out there “that stress the immune system in ways that may be harmful over time,” he says. “Overstimulation may cause immune-health issues such as inflammation, causing suppression of normal immune functions.”

Increasingly, immune-supplement formulators are designing products specifically to avoid such overstimulation, taking a path of modulation instead. The difference, Rodriguez says, is that immune-modulating supplements “enhance the appropriate response to an antigen, as opposed to indiscriminately up-regulating other arms of the immune system that wouldn’t be expected to respond.”

Keller agrees, noting that simply “ramping up” the immune system is not what you want to do. An effective supplement helps the immune system in a manner proportional to the challenge. “Sometimes,” he says, “that means you want to up-regulate it, and sometimes you want to down-regulate it.” Either way, “there are a lot of good ingredients out there that we can take preventatively to help the body be prepared when it’s challenged to react more appropriately.” And we can all feel better about that.

References

1. Ezendam J et al., “Probiotics: Immunomodulation and evaluation of safety and efficacy,” Nutrition Reviews, vol. 64, no. 1 (January 2006): 1-14
2. Yang OO et al., “Immunomodulation of antiretroviral drug-suppressed chronic HIV-1 infection in an oral probiotic double-blind placebo-controlled trial,” AIDS Research and Human Retroviruses, vol. 30, no. 10 (October 2014): 988-995
3. Udani JK, “Immunomodulatory effects of ResistAid: A randomized, double-blind, placebo-controlled multidose study,” The Journal of the American College of Nutrition, vol. 32, no. 5 (2013): 331-338
4. McFarlin BK et al., “Baker’s yeast beta glucan supplementation increases salivary IgA and decreases cold/flu symptomatic days after intense exercise,” Journal of Dietary Supplements, vol. 10, no. 3 (September 2013): 171-183

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