Fine-Tuning the Immune System

Self-preservation and self-defense are fairly instinctual. Recent research suggested people who have recently been sick, and would therefore be particularly vulnerable to additional pathogens,  intuitively avoid other people who give off signals of being sick.¹ This early research is far from definitive on the subject, but it exemplifies how the body (and mind) is constantly at work defending against infection and illness.

In addition to the discomforts associated with being sick, the time lost to being sick is problematic to our time-crunched society. Beyond the tick-tock, the financial cost can also be a burden on all impacted by a sick person. In 2011, Walgreen's reported its survey of Americans showed the flu was responsible for 100 million sick days, $68 million dollars in paid leave and 32 million missed school days. Overall, the survey found  all related costs (missed days, child care, health care bills, etc.) cost two-thirds of respondents between $251 and $1,000 each in 2010.

Most ideal is prevention, followed by shortened duration and tamed symptoms; however, none of these goals has a definitive recipe for success. Sufficient sleep, well-rounded nutrition and good hygienic practices go a long way in this fight, but most people still need help. Pharmaceuticals can help address symptoms, but a group of dietary supplement ingredients go beyond this reactionary benefit to offer help strengthening the immune system, improving immune function, inhibiting sickness and shortening the duration of illness. For the vast array of products touting immune benefits, the pudding is the research.

Immune Component Primer

Immune cells are most commonly white blood cells, called leukocytes. They are derived from stem cells and occupy various parts of the body via the blood and lymph systems.

Macrophage from Greek meaning large eater, these cells are derived from monocytes and are a big 21 m in diameter. They digest pathogens and prompt other immune cells to respond.

Dendritic Cells present antigens (foreign invaders) to other immune cells for appropriate responsive action. They function as messengers between the innate and adaptive immune systems.

Neutrophils  granulocyte immune cells that devour bacteria and fungi; they are the most common immune cell in human blood, as well as in early stages of acute inflammation.

Basophils granulocytes that react to inflammatory conditions such as allergies. The least common granulocyte, these cells contain the anticoagulant heparin as well as histamine, which dilates blood vessels when released.

B cells lymphocytes (immune cells found mostly in the lymphatic system) formed in bone marrow. They are essential to adaptive immunity and make antibodies for destruction of pathogens. B cells "remember" the antibody for future reference and manufacture.

Antibodies immunoglobulins falling into one of five classes: immunoglobulin G (IgG), IgA, IgM, IgD and IgE.

T cells These lymphocytes mature in the thymus. Among the numerous types of T cells, T helper cells (aka CD4) bind with certain antigens and present them to B cells for destruction, and cytotoxic T cells (aka CD8) destroy virus-infected cells and tumor cells.

Natural Killer (NK) cells cytotoxic lymphocytes playing a major role in innate response by causing apoptosis (programmed cell death) in virus-infected and tumor cells. They do not require activation to kill these pathogenic cells.

Interferons (IFNs) interfere with viral replication; they also activate immune cells such as macrophages and NK cells.

Interleukins cytokines (signaling molecules) expressed by leukocytes; they are classified in families, each which performs different immune-related functions, including controlling aspects of inflammation.

Next: Vitamins and minerals for immune health

Basic Nutrition

Interest in vitamins for immune health have focused intently on vitamin D. In the skin, vitamin D affects signaling within macrophages and keratinocytes, improving their responsiveness to barrier defense.²  According to a 2011 report, vitamin D may also help protect the gums from bacterial infections associated with development of gingivitis and periodontitis.³ This research reflects one popular theory that vitamin D stimulates immune cells to release chemicals that fight infections and replication.

On the other hand, vitamin D is credited with controlling the immune response, especially inflammation, in respiratory health. However, this double-sided benefit has mostly been studied by looking at vitamin D deficiency and incidence of illness. In 2009, researchers studying data from the Third National Health and Nutrition Examination Study (NHANES) found serum 25(OH)D levels were inversely associated with recent upper respiratory tract infection (URTI), with the strongest associations amongst those with respiratory diseases.⁴

Still other researchers have tried to connect the dots between higher flu rates in winter versus summer, which would correlate with the increased levels of vitamin D in times of increased sunlightthe nutrient requires sunlight for synthesis in the body.  Yale University researchers followed 198 healthy adults during the fall and winter 2009 to 2010 to compare seasonal deficiencies with seasonal increases in prevalence of respiratory viral infections, including the flu.⁵ They found  only three of the 18 participants who maintained vitamin D levels of 38 ng/ml or higher during the study period reported developing viral infections, while 81 of the other 180 participants developed such infections. In addition, compared to those with lower D levels, those with higher levels of vitamin D reported significant reductions in the duration of illness.

Immune cells have vitamin D receptors (VDRs), as do various genes. University of Oxford, England, scientists mapped the molecular interactions of VDRs across the human  genome, finding VDR binding influences genes involved in various diseases, including autoimmune diseases and cancers.⁶ Sreeram Ramagopalan, Ph.D., of the Wellcome Trust Centre for Human Genetics at Oxford University,  said the findings support the hypothesis that vitamin D interacts with genes in the pathogenesis of these diseases and punctuates the serious risks of vitamin D deficiency.

Genetic research has also been done on vitamin E, with researchers from  Jean Mayer USDA Human Nutrition Research Center, Boston, reporting genes influence the differences in vitamin Es immune actions.⁷ A study out of Spain found evidence of a few such immune benefits from vitamin E supplementation (200 mg/d) including blood neutrophil, lymphocyte and NK cell activities.⁸

A further genetic study was conducted by researchers from Tufts University, Boston, who analyzed data and DNA from a previous vitamin E intervention study.⁹ They found vitamin E's ability to decrease respiratory infections was influenced by gender and gene factors, including specific single nucleotide polymorphisms (SNPs) at immunoregulatory genes.

Tufts researchers have also looked at vitamin E tocotrienols (as Tocomin®SupraBio palm tocotrienol, from Carotech Inc.) and declining T cell function due to aging.¹⁰ Their animal study showed lymphocyte proliferation was lower in older animals, whose spleen cells produced lower interleukins (ILs), compared to younger animals.  Supplementation with Tocomin appeared to increase IL-1beta in both young and old animals. In a Malaysian trial, supplementation with Tocomin tocotrienols in subjects who were then injected with a tetanus vaccine increased plasma vitamin E levels and production of interferon-gamma and IL-4, compared to those taking the supplement, but not injected with vaccine. Subjects taking the supplement also had lower IL-6 levels and increased production of immunoglobulin-G (IgG), which inhibits tetanus.

Another popular micronutrient for immune function is the mineral zinc which, like vitamin D, is a signaling molecule for immune cells. Zinc deficiency has been linked to increased production of pro-inflammatory cytokines and oxidative stress, while maintaining adequate levels has been tied to decreased risk of various  infections.¹¹ Tufts researchers found elderly individuals with low levels of blood zinc concentrations have a 50-percent greater risk of developing pneumonia than individuals with normal zinc concentrations, and those with normal zinc status had fewer new prescriptions for antibiotics, a shorter duration of pneumonia, fewer days of antibiotic use and lower mortality rates compared with seniors who had low zinc levels.¹²

Ten days of zinc administration enhanced innate immunity against Escherichia coli (E. coli) infection, the primary bacterial cause of diarrhea in children.¹³ Compared to children not supplementing with zinc, those taking the mineral showed higher phagocytic activity, improved ratio of naïve T cells to memory T cells and increased serum complement C3, a protein that contributes to innate immunity.

Next: Botanicals

Botanicals

Echinacea has garnered a good deal of the attention paid botanicals for improved immune function, but it certainly has been mixed signals from the research world. Its history of use includes Native Americans who turned to the herb for its antimicrobial and anti-inflammatory effects.  A 2003 review from University of Wisconsin noted several immunomodulatory properties, including activation of macrophages,  leukocytes and NK cells.¹⁴ However, the report stated effects on T and B cells were not definitively shown, and overall, the effectiveness of E. purpurea in immune health had not been proven beyond reasonable doubt at the time of the review. Subsequent study at the University on E. purpurea, the common cold and URTIs was no more definitive, although there was a significant trend in subjects taking the herb who came down with a second cold less frequently than those not taking echinacea.¹⁵ Then in 2010, a randomized trial on the common cold in 719 patients aged 12 to 80 years found only a half-day benefit in illness duration among those taking echinacea.

In 2011, Japanese researchers compared echinacea to two traditional remedies from India, ashwagandha (Withania somnifera) and brahmi (Bacopa monnieri).¹⁶ Each herbal product increased IgA, IgG and IgM in splenocytes, but brahmi stimulated more secretion of IgA and IgG in the serum compared to either echinacea or ashwaghanda. The researchers concluded, "These herbal medicines might regulate antibody production by augmenting both Th1 and Th2 cytokine production."

 Astragalus also has a long history, used for its adaptogenic properties in Traditional Chinese Medicine (TCM) for thousands of years. According to research, astragalus may influence inflammatory cytokines, macrophage phagocytic activities, and lymphocyte response to immune suppression.^17,18  Astragalus administration has also been connected to improved T lymphocyte function and splenic dendritic cell differentiation.¹⁹

In 2010, Arizona State University, Tempe, researchers looked at the effect of several botanicals including astragalus, fellow TCM herb Andrographis paniculata and elderberry on inflammatory genes.²⁰ They treated peripheral blood mononuclear cells (PMBCs), which are rich in T-cells, B-cells, NK cells, monocytes, macrophages and dendritic cells, and found astragalus induced expression of several hundred cellular genes, as did elderberry, while andrographis expressed fewer genes. They cited the presence of lipopolysaccharides (LPS) in the extracts, but noted evidence suggesting the benefits were not all to the credit of LPS.

Andrographis may act on inflammation and cytotoxicity on its own. A 2010 study showed andrographis extract and isolated andrographolide administered to animal metastatic tumor cells improved antibody-dependent cell-mediated cytotoxicity, compared to no treatment, and increased serum levels of helpful immune proteins such as  IL-2, while reducing levels of pro-inflammatory cytokines including Il-1B, IL-6 and TNFa.²¹

Longtime immune health herb garlic continues to generate positive research results to add to its library.  Aged garlic extract (AGE, as  Kyolic®, from Wakunaga) can increase NK cell numbers and activities, and can stimulate splenocytes, cytokines and macrophages.^22,23 While allicin has most often been credited with garlic's antimicrobial properties, other compounds in garlic may contribute to the herb's immune benefits. In 2010, in vitro research on immunomodulatory proteins from raw garlic and various immune cells, including lymphocytes, mast cells and basophils, found the proteins were mitogenic (promotes cell duplication) toward human peripheral blood lymphocytes, murine splenocytes and thymocytes.²⁴ And a report published in 2011 demonstrated fructans in garlic also contribute to the immunomodulatory properties of AGE.²⁵ The researchers noted the fructans displayed mitogenic activity and activation of macrophages, including phagocytosis, comparable to polysaccharide immunomodulators such as zymosan and mannan.

Zymosan is found in the cell wall of the yeast Saccharomyces cerevisiae. Wellmune WGP®, from Biothera, is a proprietary 1,3/1,6 glucopolysaccharide derived from the cell walls of this yeast and has been found to reduce URTIs in populations typically experiencing high stress. In one study, firefighters taking Wellmune or placebo for 12 days were considerably less likely to develop URTIs, while another trial found Wellmune significantly reduced the incidence of URTIs in marathon runners.^26,27 Results from a study presented in 2010 at the 51st Annual Meeting of the American College of Nutrition, New York, showed women with moderate to high stress who took Wellmune experienced fewer cold/flu symptoms and higher energy levels. A 2011 study planned for presentation in 2012 featured 182 marathon runners taking Wellmune or a placebo, and found subjects taking the supplement experienced fewer days with URTI symptoms than did subjects taking a placebo.

A study presented at International Society of Exercise and Immunology 2011 and submitted to a peer-reviewed journal, utilized an exercise stress model to demonstrate how Wellmune WGP enhances immune response of monocytes and other immune cells. The University of Houston trial involved 60 recreationally active subjects who took either Wellmune (250 mg/d) or placebo for 10 days before exercising intensely. Supplementation boosted LPS-stimulated production of IL-2, IL-4, IL-5 and IFN-gamma both before and after exercise, raising plasma concentration of these and other immune compounds.  

EpiCor®, from Embria Health Sciences, is derived from fermentation of S. cerevisiae and has been researched for effects on cold and flu illness. Supplementation with 500 mg/d EpiCor in flu-vaccinated adults has been linked to decreased incidence of URTIs and shorter duration of symptoms.²⁸ In other research using this same dosage, EpiCor increased IgA and IgE, as well as levels of hematocrit (indicator of red blood cell count). In 2010, University of Michigan Medical Center researchers reported 12 weeks of Epicor supplementation in an at-risk population reduced incidence of cold- or flu-like symptoms, but had no significant reduction on duration or severity of symptoms compared to placebo.²⁹

In 2011, Embria released results of a study  involving City of Ankeny,IA, employees taking EpiCor for six months during cold/flu season as apart of the city's wellness program. The citys human resource department noted a 28-percent decrease during the study period in employee doctors visits for cold, flu and URTIs.

Next: More immune-boosting botanicals

Polysaccharides such as those found in S. cerevisiae are also found in mushrooms. Beta 1,3/1,6 glucans found in maitake mushroom (Grifola frondosa) play a central role in the mushroom's ability to influence cytokines and neutrophils.³⁰ Maitake extract (as D-Fraction®, from Mushroom Wisdom) has been found to activate immune cells, macrophages dendritic cells and T cells, and may boost the cytotoxicity of NK cells.³¹

Agaricus blazeii Murill also affects NK cell activity and can increase IgG levels, stimulate T cell production in the spleen, enhance phagocytosis and improve the bodys resistance to bacterial infection.^32,33,34 Reishi takes a slightly different approach, modulating T-cell activation by acting directly on monocytes, promoting splenic B cell activation and antibody secretion, and stimulating TNF-alpha and IL-6 production and IFN-gamma release.^35,36,37  Results from a 2010 Taiwanese study showed reishi proteins can activate macrophages and T cells, and the mushrooms polysaccharides can activate macrophages.³⁸

Active Hexose Correlated Compound (AHCC®, manufactured by Amino Up Chemical Co., U.S. distribution by Maypro Industries), a proprietary mushroom-based ingredient derived from the mycelia of select basidiocymetes, is rich in  polysaccharides and can modulate both adaptive and innate immunity.³⁹ It has been shown to improve immune response to infections such as influenza and West Nile encephalitis.^40,41 In 2010, Yale University School of Medicine researchers published results on the effects of AHCC administration in healthy adults (aged 50 years or older), including increased frequency of CD4 and CD8 T cell-production of INF-gamma and TNFa.⁴² Results appeared after 30 days of AHCC supplementation and remained 30 days after discontinuing the intervention.

A proprietary blend containing MaitakeGold 404® (maitake mushroom extract) and Sensoril® (a standardized extract of ashwagandha), called Wellbody 365 (from NutraGenesis LLC), was studied on stress-related immunity at University of Louisville, KY.⁴³ The 2011 study report detailed how animals under stress had higher levels of corticosterone (equivalent to cortisol in humans) and decreased immune function compared to non-stressed animals. In the stressed animals, Wellbody 365 administration reduced corticosterone to levels found in non-stressed animals; the supplement also resulted in significantly higher levels of phagocytosis and cytokines, including IL-6 and IL-12, in both stressed and non-stressed conditions. 

University of Mississippi scientists identified potent monocyte-/macrophage-activating bacterial lipoproteins and lipopolysaccharides in several botanicals such as echinacea, American ginseng and Tinospora cordifolia.⁴⁴ In a 2005 trial, T. cordofolia (as Tinofend®, from Verdure Sciences) significantly decreased allergic rhinitis symptoms, compared to placebo.⁴⁵ Researchers noted the supplement significantly decreased eosinophil and neutrophil count, compared to placebo.

Verdure announced in 2011 Tinofend underwent a Verdure Botanical Active Testing System (VBATS) analysis, which found a total polysaccharide fraction of no less than 20-percent of the total extract. The company noted the extract was measured and validated for sensitivity, specificity and precision using AOAC guidelines for single lab validation. 

Another branded ingredient featuring polysaccharide content (larch arabinogalactan extracted from Larix occidentalis)  is Resistaid, from Lonza. Research has demonstrated LAG stimulates NK cell cytotoxicity, cytokines and monocyte production.^46,47 One study on ResistAid found the supplement selectively enhanced antibody response to a pneumonia vaccine in healthy subjects, without increasing the nonspecific innate immune response.⁴⁸ While subjects taking ResistAid had increased IgG response, the intervention had no effect on salivary IgA, white blood cell count, inflammatory cytokines or complement.

In 2010, results from a randomized, double blind, placebo-controlled, parallel-group pilot study conducted by Medicus Research, Northridge, CA,  showed  ResistAid increased antibody response to a 23-valent pneumococcal vaccine.⁴⁹ In the trial, healthy volunteers received ResistAid for 30 days prior to vaccination and up until day 72; supplemented subjects had significantly higher pneumococcal IgG levels in two antibodies subtypes (18C and 23F) at both day 51 and at day 72, compared to those who took placebo. Jay Udani, M.D., lead investigator and CEO of Medicus Research, explained modulating the immune system in direct response to antigenic stimulation rather than nonspecific augmentation represents a more physiologic approach to immune enhancement.

Next: Gut-Mediated Immunity

Gut-Mediated Immunity

Between 70 percent and 80 percent of immunity is mediated in the gut. Membranes in the gut are part of the innate immune system and respond to pathogens in a non-specific way.  Gut mucosa, enzymes and microflora all play key roles in gut-mediated immunity.

Probiotics, both naturally present in the gut and supplemented in the diet, can improve phagocytosis, NK cell activity and antibody production and may decrease the risk of allergic illness.50 Supplementation with either Bifidobacterium bifidis BB-12 and Lactobacillus casei 431 (both from Chr. Hansen) was shown to increase antibody response to influenza.⁵¹ BB-12 supplementation may also reduced URTIs in children.⁵²

Combining probiotics with prebiotics in a synbiotic formula can benefit immune health. In one study, three months of supplementation with a synbiotic combination of L. helveticus R0052, B. infantis R0033, B. bifidum R0071 and fructooligosaccharide (as Probiokid, from Institut Rosell) for three months decreased the risk of occurrence of common infectious diseases in children and limited the risk of school-day loss.⁵³ Similar synbiotics studied in toddlers reduced pneumonia by 24 percent and severe acute lower respiratory infection (ALRI) by 35 percent, compared to controls.⁵⁴ In this trial, children taking synbiotic milk had a 16-percent and 5-percent reduction in days with severe illness and high fever, respectively.

Many nutritional ingredients are touted for benefits to immune health and function, but not all such products have recent research backing their marketing.  A number of micronutrients, botanicals and digestive health ingredients have enjoyed a growing body of research on specific actions influencing immune components to help inhibit or shorten the negative effects of infections.

References listed on the next page.

References:

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48. Presented at the 50th Annual Meeting of the American College of Nutrition in Orlando, Fla., October 2009.

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50. Olivares M et al. " The consumption of two new probiotic strains, Lactobacillus gasseri CECT 5714 and Lactobacillus coryniformis CECT 5711, boosts the immune system of healthy humans." Int Microbiol. 2006 Mar;9(1):47-52.

51. . Probiotic strains BB-12® and L. casei 431® increase the immune response to an influenza vaccine: A randomized, double-blind, placebo-controlled study." Presented on Oct. 28, 2010 at the 2nd World Congress on Immunity Ingredients, Malta.

52. Taipale T et al. Bifidobacterium animalis subsp. lactis BB-12 in reducing the risk of infections in infancy." Br J Nutr. 2010 Sep 24:1-7. Published online ahead of print.

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