Immune Health: Back to Basics

Any great defense has multiple layers; the bodys immune system is no different. Mucosal surfaces, skin and various membranes form barriers between the inside and outside, in an effort to dispel potential pathogens (bacteria, virus, allergen, etc.). Immune cells, such as macrophages, also meet any outside invaders that make it through the first layer of defense. Immune cells are mostly white blood cells called leukocytes. Among these, monocytes become either macrophages, which consume pathogens, or dendritic cells, which activate T lymphocytes. Lymphocytes include B cells and T cellsincluding T helper and cytotoxic T cellsas well as natural killer (NK) cells.

B cells travel throughout the lymph system until they are triggered (often by T cells) to produce antibodies, which are designed to target specific antigens (foreign substances that trigger an immune response). Antibodies are immunoglobulins falling into one of five classes: immunoglobulin G (IgG), IgA, IgM, IgD and IgE.

T cells are foundational in cell-mediated immunity, responding to native body cells changed by a virus or cellular mutation. Cytotoxic T cells cause cell death and attract macrophages for ongoing destruction of antigens. Helper T cells, known as CD4 or CD8 cells, stimulate the activity of these cytotoxic T cells. The two subclasses of CD4 cells are Th1 and Th2, both of which release interleukins to trigger particular immune functions. Th1 activates macrophages to kill pathogens, create inflammation, stimulate antibody production and secrete interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). Th2 stimulate production of antibodies and IL-4, IL-5, IL-10 and IL-30.

Among the other immune cells that often figure in immune research, neutrophils search for bacteria and fungi, eosinophils target larger parasites, and basophils are responsible for releasing histamine.

The immune system also involves two fluid-like systems called the lymph and complement. A mixture of proteins and proteases triggers production of cytokines that help kill foreign cells in membranes. Lymph is a plasma-like interstitial (between body cells) fluid that contains nutrients and white blood cells; it travels to and from lymph nodes, where lymphocytes engage antigens (foreign substances) caught in the nodes.

All these layers of immune cells and compounds work toward one goal: health. They achieve this by reacting to potential pathogens, either inhibiting them or working to destroy/eject them once in the body. This system of health uses tools such as inflammation and apoptosis (cell death); these tools or actions are often manifested as symptoms of illnesses. The key to the efficacy and efficiency of this system is balance; as much as it is important to boost the ability to react and deal with pathogens, illness and injury, it is crucial to turn these actions off, and reduce the production of certain immune compounds (i.e. inflammatory cytokines) when the threat has been handled. Failure to balance immune function can lead to chronic inflammation and hyper-immunity, which can develop into autoimmune disease.

The most common invaders to the immune systems are rhinoviruses (common cold) and influenza viruses (flu). With at least 100 known rhinoviruses, new ones are still being found. In fact, in 2010, Australian researchers noted this category of virus causes at least 70 percent of virus-related wheezing afflictions and cold/flu-like symptoms, and they are associated with sinusitis and pneumonia.¹ The sheer number of cold viruses make it difficult to address via vaccination, and most over-the-counter (OTC) pharma products help relieve symptoms, but come with side effects. Likewise, flu viruses arent as numerousinfluenza A and B are the main typesbut there are various subtypes that can surface and dominate any given season (not to mention the emergence of new types, such H1N1), making vaccination a guessing game on the part of health officials.

All this shows conventional medicine struggles to inhibit viruses and other pathogens, and only delivers symptom relief along with undesirable side effects (drowsiness, etc.). This really opens the door to natural products to demonstrate they can strengthen the immune system and help ward off, limit and temper infections and illnesses. Research will be the vehicle for such achievement, and this past year has seen a long list of positive research results on basic nutrients, as well as herb and specialty ingredients.

Back to Basics

Like a depressed economy, sometimes the best stimulus is a return to basics, which, in the case of immune health, means vitamins and minerals. Historically, vitamin C was the go-to nutrient for warding off the common cold, but the research debate has become something of an old horn, while the interest in vitamin D has generated promising and interesting results.

Vitamin D appears to impact signaling within macrophages and keratinocytes in the epidermis, enhancing their responsiveness to barrier defense.² Deficiency has been linked with increased progression and mortality from lymphoma, and researchers suggested vitamin D supplementation would be useful in this and other cancers.³

In 2010, a study reported in Genome Research mapped the molecular interactions of the vitamin D receptor (VDR) across the genome, finding numerous locations where VDR binding influences genes involved in various diseases, including autoimmune diseases and cancers.⁴ Researcher 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.

Vitamin D deficiency typically occurs in the fall and winter, so researchers from Yale University followed 198 healthy adults during the fall and winter 2009 to 2010 to determine if such seasonal deficiency could be related to seasonal increases in prevalence of respiratory viral infections, including the flu.⁵ While 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, 81 of the other 180 participants developed such infections. Further, those with higher levels of vitamin D reported significant reductions in the duration of illness, compared to those with lower D levels.

Moving through the alphabet, vitamin E has displayed immunostimulatory actions. In 2008, scientists from Complutense University of Madrid, Spain, reported 200 mg/d vitamin E ingestion affects several immune functions, including blood neutrophil, lymphocyte and NK cell activities.⁶ And similar to gene work on vitamin D, scientists at Jean Mayer USDA Human Nutrition Research Center, Boston, discovered differences in vitamin Es immune actions are influenced by genes.⁷

Most recently, 2010 publications have increased the scientific knowledge on vitamin E in immune health. Researchers from Tufts University, Boston, analyzed data and DNA from a previous vitamin E intervention study200 IU/d of vitamin E or a placebo for one year in elderly nursing home residentsand found the nutrients ability to lower respiratory infections was influenced by gender and gene factors, including specific single nucleotide polymorphisms (SNPs) at immunoregulatory genes.⁸

Another Tufts study looked at tocotrienolsvitamin E analogueson age-related declines in T cell function.⁹ The researchers pair-fed young (4 months old) and old (23 months old) C57BL/6 mice 0.1 percent Tocomin 50 percent, a mixture of T3 and alpha-tocopherols, or a control diet containing an equal amount of alpha-tocopherols for six weeks. They found lymphocyte proliferation was lower in old mice compared to young mice; however, old mice taking T3 had higher lympocyte proliferation than did young control mice. Similarly, splenocytes from old mice produced less interleukin (IL)-2, IL-4, IL-6 and IL-10 compared with young mice, whereas no significant age-related difference was found in IL-1beta, tumor necrosis factor-alpha (TNFa) and interferon-gamma. T3 feeding was associated with a higher IL-1beta production in old mice, but not in young mice. Peritoneal macrophages from old mice produced significantly more IL-1beta, IL-6, IL-10, and prostaglandin E2 (PGE2), compared with those from young mice, and animals of both age categories who took T3 had higher production of IL-1beta, but not PGE2 or other cytokines.

Malaysian researchers also investigated tocotrienols, focusing specifically on the effects of a tocotrienol-rich fraction (TRF, as Tocomin®SupraBio palm tocotrienol, from Carotech Inc.) on immune response following tetanus toxoid (TT) vaccine challenge in healthy female volunteers.¹⁰ The double blinded, placebo-controlled clinical design randomly assigned participants to receive either 400mg/d of TRF supplementation or placebo for two months; all participants were vaccinated with the TT vaccine (20 Lf) intramuscularly, and blood was drawn during follow-up. The intervention not only increased vitamin E plasma levels, but also enhanced production of interferon-gamma and interleukin (IL)-4 by the mitogen or TT-stimulated leukocytes compared with the control group. Those taking TRF also had lower IL-6 levels and increased production of IgG, which inhibits TT.

The mineral zinc plays an important role as an intracellular signal molecule for immune cells and has shown positive actions in recent immune research. Similar to the other nutrients, zinc deficiency has been correlated to increased production of pro-inflammatory cytokines and oxidative stress, whereas sufficient zinc levels have been credited with decreased risk of pneumonia and other infections.^11,12,13

In 2010, many publications highlighted zincs effect on immune function, including an Indian trial showing zinc administration enhances innate immunity against Escherichia coli (E. coli) infection, the primary bacterial cause of diarrhea in children.¹⁴ In this trial, 148 children aged 6 to 24 months and with E. coli infection were followed for nine months after either a 10-day zinc treatment (20 mg/d, n=74), a 10-day zinc treatment plus three-months supplementation (10 mg/d, n=74) or no zinc treatment (n=50). Serum complement C3 was higher immediately after zinc administration in both treatment groups, compared to the non-treatment group. Phagocytic activity (consume or remove pathogens) was also higher in the zinc groups than in the control, as was the ratio of naïve T cells to memory T cells.

Whats good for the young is also good for the old, as researchers from the Nutritional Immunology Laboratory at Jean Mayer USDA Center for Aging at Tufts 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.¹⁵ In fact, seniors with normal zinc status also had fewer new prescriptions for antibiotics, a shorter duration of pneumonia and fewer days of antibiotic use, compared with residents who had low zinc levels. They also had lower mortality rates.

Another 2010 report detailed how zinc supplementation for 18 months in HIV-infected adults substantially reduced the risk of immunological failure in a multi-university study, including Johns Hopkins University, University of Miami and Florida International University.¹⁶ Zinc deficiency is found in about 50 percent of HIV patients, according to the researchers, who randomly assigned 231 HIV-infected adults (average age of 43, 73 percent men) with low plasma zinc levels (<0.75 mg/L) to receive either zinc (12 mg of elemental zinc for women and 15 mg for men) or placebo for 18 months. Among the participants, 62 percent were on an anti-retroviral (ARV) drug regimen, and 69 percent had detectable viral loads. About 34 percent of the patients had CD4 counts below 200 upon entering the study; 22 percent had CD4s between 200 and 350, and 44 percent had CD4s above 350. Controlling for numerous factors, researchers found those taking zinc had a four-fold reduction in risk of immune failure. Zinc supplementation also reduced diarrhea incidence by half, although it had no effect on mortality compared to placebo.

 References are on the next page...

References for  "Immune Health: Back to Basics"

1. Arden KE and Mackay IM. Newly identified human rhinoviruses: molecular methods heat up the cold viruses. Rev Med Virol. 2010 May;20(3):156-76.

2. Bikle DD. Vitamin D and the immune system: role in protection against bacterial infection. Curr Opin Nephrol Hypertens. 2008 Jul;17(4):348-52.

3. Drake MT et al. Vitamin D insufficiency and prognosis in non-Hodgkin's lymphoma. J Clin Oncol. 2010 Sep 20;28(27):4191-8.

4. Ramagopalan SV et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010 Oct;20(10):1352-60.

5. Sabetta JR et al. Serum 25-Hydroxyvitamin D and the Incidence of Acute Viral Respiratory Tract Infections in Healthy Adults. PLoS One. 2010 Jun 14;5(6):e11088.

6. De la Fuente M et al. Vitamin E ingestion improves several immune functions in elderly men and women. Free Radic Res. 2008 Mar;42(3):272-80.

7. Belisle SE et al. Polymorphisms at cytokine genes may determine the effect of vitamin E on cytokine production in the elderly. J Nutr. 2009 Oct;139(10):1855-60.

8. Belisle SE at al. IL-2 and IL-10 gene polymorphisms are associated with respiratory tract infection and may modulate the effect of vitamin E on lower respiratory tract infections in elderly nursing home residents. Am J Clin Nutr. 2010;92: 106-114.

9. Wu D et al. Dietary Supplementation with Tocotrienols Enhances Immune Function in C57BL/6 Mice. J. Nutr. 2010;140(7):1335-41.

10. Mahalingam D et al. Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers. Eur J Clin Nutr. 2011 Jan;65(1):63-9.

11. Prasad AS. Zinc: mechanisms of host defense. J Nutr. 2007 May;137(5):1345-9.

12. Meydani SN et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr. 2007 Oct;86(4):1167-73.

13. Prasad AS et al. Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 2007 Mar;85(3):837-44.

14. Sheikh A et al. Zinc Influences the Innate Immune Responses in Children with Enterotoxigenic Escherichia coli-Induced Diarrhea. J Nutr. Published online ahead of print, Mar. 17, 2010.

15. Meydani SN et al. Serum zinc and pneumonia in nursing home elderly. Am J Clin Nutr. 2007 Oct;86(4):1167-73.

16. Baum MK et al. Randomized, Controlled Clinical Trial of Zinc Supplementation to Prevent Immunological Failure in HIV-Infected Adults. Clin. Infect. Dis. 2010; 50(12): 1653-1660.