Building Bombproof Immunity

References

Humans can look in the mirror and inherently recognize the self—an ability not given to all living beings. And as humans have evolved into complex organisms, so have the microorganisms floating around in the air, or resting invisibly on the nearest door handle. Thankfully, the human immune system has also evolved and is able to recognize the self on a cellular level. Small battles take place regularly with invaders—or antigens—in the form of bacteria, viruses or parasites. The human body is an ideal place for antigens to reside, and if these invaders manage to get past the body’s first lines of defense—the skin and mucosal lining of the digestive and respiratory tracts—an elaborate chain reaction initiates, and the body deploys specialized cellular troops to contain and oust the enemy. Immunity is a team effort among several systems, which each produce efficient cells for specific immune function duties.

 Also, the body doesn’t have to fight alone. Advances in technology have shed light on how various vitamins, minerals, whole foods and other compounds can contribute to immune health. Life expectancy, at least in civilized countries, has drastically increased in the last hundred years because of great strides in food science technology, knowledge dissemination, and the resultant opportunity for humans to shore up natural immunity. Humans can now concentrate on preventing immune system breakdown via a smart diet and habitual supplement regimen. And this, just as with immune function, can be a multi-pronged effort.

A Well-Oiled Machine

Let’s assume an infectious microbe has penetrated the body’s outer defenses. Normal cells are equipped with two classes of distinctive surface proteins, MHC Class I proteins, which are on all cells, and MHC Class II proteins, which are only on certain specialized cells. Any cells not bearing such proteins, called antigens, initiate an immune response. The lymphoid system assists the assault on invading antigens, offering lymphocytes—white blood cells specifically produced to help the body avoid disease. Well known organs such as the spleen, thymus, appendix and tonsils join the fray, as do less obvious players such as lymph nodes and bone marrow.

Cells biologically marked to become immune cells originate as stem cells in bone marrow. Some develop into myeloid progenitor cells, while others become lymphoid progenitor cells. From there, these cells are specialized even further—myeloid cells can become monocytes, erythrocytes, eosinophils, mast cells, basophils, neutrophils or platelets. Lymphoid cells, on the other hand, become B cells, T cells, dendritic cells (macrophages) or natural killer (NK) cells.

B cells secrete soluble substances known as antibodies. Working hand in hand with T cells, B cells consume antigens and begin churning out millions of identical antibodies to fight the invader. Antibodies belong to a family of large protein molecules known as immunoglobulins. There are currently nine chemically distinct classes of human immunoglobulins—four kinds of IgG and two kinds of IgA, plus IgM, IgE and IgD. Each plays a role in the immune response, making up one part of the body’s natural fortress. T cells contribute to immunity in two ways: some play a regulatory role in the workings of the overall immune response, while others are cytotoxic and directly contact infected cells and destroy them—why they’re sometimes called killer T cells.

Helper T cells are a common form of T cells and are needed to activate many immune cells, including B cells and other T cells. From mature T cells come cytokines—interleukins, growth factors and interferons—responsible for communicating with other immune cells. Lymphocytes secrete cytokines called lymphokines, while the cytokines from monocytes and macrophages are called monokines. Many cytokines are also known as interleukins because they serve as messengers between leukocytes, immune warriors from white blood cells. Cytokines enlist the help of other cells for a more effectual immune response; they also encourage cell growth, promote cell activation, direct cellular traffic, and destroy target cells.

Two more specialized varieties of lymphocytes are killer cells— cytotoxic T cells and natural killer (NK) cells. Both cell types are produced to destroy invaders by recognizing them as foreign and delivering destructive chemicals. Cytotoxic T cells need to recognize a specific antigen bound to self-MHC markers before doing their job, whereas NK cells will recognize and attack cells lacking these proteins. Other cells geared for destruction of antigens are phagocytes, including monocytes and granulocytes, eosinophils, basophils and macrophages.

Also important in the immunity equation is the complement system, which consists of a series of about 25 proteins that “complement” the work of antibodies in destroying bacteria. This system also helps rid the body of antigen-antibody complexes. In fact, complement proteins are what cause blood vessels to become dilated and leaky, resulting in redness and swelling during an inflammatory response. The complement system embodies the actions of the entire immune response and earns its name from each specialized piece working with the others. The end product is a cylinder that punctures the target cell’s membrane, allowing fluids and molecules to flow in and out, which ultimately destroys it.

Swelling and redness are external signs of inflammation from a traumatic event. But inflammation happens internally, too, bringing with it uncomfortable symptoms such as pain and stiffness. Inflammation is the sensory manifestation of the immune response. Inflammation occurs when a group of cells (tissue) is injured by bacteria, trauma, toxins, heat or any other cause. That trauma is then handled by various specialized cells, or mediators, the third series of which involve substances called prostaglandins.

Prostaglandins’ main role in the inflammatory response is attracting neutrophils, the same role complement proteins play. Neutrophils answering the call for inflammation control come first from the bloodstream and second from bone marrow. Neutrophils contain small lysosomal granules (enzymes) which digest substances the neutrophils surround. Larger macrophages called monocytes follow soon after to help neutrophils marginalize the cause of inflammation, a common immune process called phagocytosis.

When the Machine Breaks Down

Though no one can deny the efficiency of an uncompromised immune system, many internal and external factors can contribute to the system’s malfunction. And the most common disorder of the immune system—allergies—isn’t actually a disorder as much as a malfunction. Once the immune system first encounters an invader— anything from cat dander to tree pollen—B cells begin replication of specific varieties of the IgE antibody. Those antibodies then pair with mast cells common in the lungs, skin, tongue, and linings of the nose and gastrointestinal tract to trigger allergic reaction symptoms upon subsequent contact with the allergen. Immunoglobulin antibodies are also the chief defense against more harmful sorts of invaders such as West Nile Virus.

Autoimmune diseases, on the other hand, are more serious than allergies and can cause major health repercussions such as diabetes, lupus and multiple sclerosis. With diabetes, the immune system’s ability to recognize the self is compromised and begins producing T cells, or autoantibodies, to kill regular cells around the body. Various factors such as elements in the environment, synthetic drugs, sunlight and hormone levels can affect incidence of autoimmunity, as can the uncontrollable patterns of heredity. Autoimmunity can affect nearly any organ system of the body—the pancreas (diabetes), skin (rashes, blisters, etc.), thyroid gland (weight gain, muscle aches) or joints (rheumatoid arthritis), for example.

Immune complexes also jeopardize healthy immunity. These complexes are blobs of antigens and antibodies that may become lodged in tissues of the kidneys, lungs, skin, joints or blood vessels. While usually expelled from the bloodstream before they cause problems, immune complexes can ultimately cause inflammation and damage internal tissues of these organs or organ systems. In fact, these complexes are the cause of autoimmunity and other serious illnesses such as malaria and viral hepatitis, according to the National Institute of Allergy and Infectious Diseases (NIAID).

Obvious Immune Boosters

While countless antigens and other biological factors can affect the efficiency and integrity of normal immune function, an equally large number of naturally occurring substances is gaining ground in the prevention of immune system breakdown.

Obvious compounds associated with immune health and fighting off colds or the flu are vitamins. Daily vitamin C supplementation, in particular, is one of the better known ways to protect immune health, with plenty of science for validation. Aside from being a very effective free-radicals cavenger and thus beneficial for inflammation, vitamin C directly affects immunity by several means, including modulating new leukocyte production, elevating interferon levels (proteins with antibody activity), modulating immunoglobulin function, modulating complement synthesis, and modulating prostaglandin synthesis. Are cent study confirmed vitamin C’s contribution to immune health, noting the vitamin C from an encapsulated fruit and vegetable juice powder concentrate may have accounted for a reduction in lymphocyte DNA damage and increased circulating levels of gamma delta-T cells.¹ Significantly increased plasma levels of beta-carotene, lycopene and lutein from the supplement may have also accounted for these boosted immune factors.

Like vitamin C, the health benefits of vitamin E include strengthening immunity, especially in the elderly. A 2005 study found vitamin E supplementation above current dietary reference intake (DRI) levels delayed hypersensitivity skin response and antibody production in response to vaccination (mediated through increased production of interleukin (IL)-2 and reduced production of prostaglandin (PG) E2, a T cell suppressive factor), leading to enhanced T cell proliferation and decreased peroxynitrite formation.² The vitamin also increased both cell dividing and IL-2 production capacities of naïve T cells, but not memory T cells. Researchers related these positive changes to decreased risk of upper respiratory tract infections in the elderly cohort.

Zinc is increasingly associated with healthy immunity, as individuals at any age with zinc deficiency may have depressed immune response. An investigation into this phenomenon involving 19 healthy elderly subjects age 69.8 (+/- 5.1 years) revealed improved serum zinc levels significantly reduced levels of activated T helper cells, suggesting elderly individuals may benefit from moderate zinc supplementation due to improved immune response (leading to reduced incidences of autoimmune diseases and infections).³ Another study to determine the effect of zinc on the incidence of total infections in healthy elderly subjects found supplementation significantly lowered incidence of infections, raised plasma zinc concentration, and lowered generation of tumor necrosis factor alpha (TNF-a) and oxidative stress markers more than in the placebo group.⁴

Carotenoids

Many specific carotenoids have been studied for specific contributions to the immune response. One review explored their effects on the immune system, both in vitro and in vivo, and concentrated on their transfer from the maternal diet to the child and their effects or potential effects on the developing immune system, determining them to be “nutritionally relevant compounds.”⁵ A recent study showed the vitamin A metabolite retinoic acid is a key regulator of TGF-beta-dependent immune responses, capable of inhibiting the IL-6-driven induction of proinflammatory T cells and promoting anti-inflammatory T cell differentiation.⁶ Other recent research acknowledged supplementation with vitamins E and C and carotenoids singly and in combination had positive effects on selected aspects of immunity, including the functional capacity of innate immune cells, lymphocyte prolife ration, and the delayed- type hypersensitivity (DTH) response.⁷

Lycopene is one carotenoid on which research is mounting. Regular consumption of tomato and its byproducts appears to be consistently associated with lower risk of several types of cancer and inflammatory diseases of all kinds.⁸ One such tomato-based drink (Lyc-O-Mato® from LycoRed) lowered TNF-a inflammatory mediators in 26 healthy volunteers. The study also acknowledged past proven health benefits of the drink, including DNA protection from oxidative stress, modulation of immune and inflammatory markers (by enzyme immunoessay), and basal lymphocyte DNA damage protection.

Another member of the carotenoid family, astaxanthin, has been shown to boost immune system abilities. Past studies on astaxanthin showed the compound enhanced two different form so f immunoglobulin; astaxanthin had a moderate effect and beta-carotene had a slight effect at much higher doses.⁹ More recent studies on the product indicate astaxanthin: stimulates lymphocyte proliferation, increases the total number of B-cells, increases production of T cells, amplifies NK cell cytotoxic activity, increases delayed-type hypersensitivity response, decreases DNA damage, and suppresses various inflammatory mediators such as prostaglandin E-2 (PGE-2), interleukin 1B (IL-1b), nitric oxide (NO), cyclooxygenase-2 (COX-2) enzyme and NF kappa-B.¹⁰ In another study, plasma lutein (another member of the carotenoid clan) and astaxanthin levels were proportion with NK cells levels in the blood.¹¹

Immunomodulators

Mushrooms are increasingly regarded as a powerful immune system modulator. As is the case with many other natural products, mushrooms have valid science and traditional medicinal history to support their use. Aside from being rich sources of the B vitamins thiamin, riboflavin and niacin, specific fractions of certain varieties of mushrooms have shown potential in boosting the immune system, inhibiting tumor growth, and decreasing inflammation. Research exploring the traditional use of Grifola frondosa, or maitake, (as Maitake D-Fraction®, from Maitake Products Inc.) centered on its beta-glucan compounds. These polysaccharide molecules bolstered the strength of macrophages, increasing their efficiency at swallowing invading antigens or tumor cells.¹² Because of this, and because macrophages release cellular messengers IL-2 and interferon-gamma, beta-glucans also positively affect T cells and NK cell function, as well as antibody-producing B cells and cytotoxic T cells.

A separate team of researchers found mycelia fractions of G. frondosa enhanced phagocytosis of human polymorphonuclear neutrophils (PMN) and increased human peripheral blood NK cell cytotoxicity.¹³ Another recent study in mice showed an intervention with mixed polysaccharides extracted from Lentinus edodes, Ganoderma lucidium and Grifola frondosa fungi varieties significantly increased thymus and NK cell activities, as well as the ability of macrophages to phagocyte latex particles and the activity of macrophages.¹⁴ Other recent research on the Ganodermataceae mushroom family has focused on the polysaccharide and triterpene/triterpenoid compounds of the Lingzhi.¹⁵

Additional research suggests yeast-sourced beta-glucans (as WGP® 3-6, from Biothera) can significantly increase phagocytic capacity and the ability of innate immune cells to consume and destroy foreign intruders.¹⁶ In this study, WGP 3-6 increased plasma cytokines INF-gamma and TNF-a and protected against an increase in cytokine IL-1. A second, unpublished clinical study from Biothera involving 62 subjects (54 completed the trial) in a placebo-controlled, double blind study assessed the impact of WGP 3-6 beta-glucan on immune biomarkers for subjects exposed to rhinovirus (common cold), The results showed the number of NK cells for the beta-glucan treatment group was higher than for the placebo, which researchers supposed was attributable to lectin-like receptors on the NK cell surface that bind both beta-glucan and complement.

Another polysaccharide sourced from Aloe vera exhibits immunomodulatory effects and underscores the scope of this succulent’s power. At least six polysaccharides have been characterized in aloe gel ;¹⁷ most are glucomannans (polysaccharide polymers containing glucose and mannose subunits), but other polymers containing galactose and arabinoses are also present. The major polysaccharide has been identified as a highly acetylated glucomannan, and research on aloe polysaccharides has been primarily focused on this compound. In one study, crude modified aloe polysaccharide (MAP) (as ACTIValoe™ from Aloecorp) activated macrophage cells by increasing cytokine production, NO release, expression of surface molecules, and phagocytic activity.¹⁸ MAP also prevented ultraviolet-B (UVB) irradiation-induced immune suppression as determined by contact hypersensitivity response in mice.¹⁹

Still other polysaccharide derivatives are entering immune health discussions. The carbohydrate arabinogalactan (AG) caused mouse spleen lymphocytes to become cytotoxic to tumor cells after culture with AG and fucoidan (FU).²⁰ Further, AG and FU were mitogenic in spleen lymphocytes and peripheral macrophages. Macrophages treated with AG and FU exhibited induced tumoricidal activity and increased phagocytosis, lysosomal enzyme activity, and production of nitrite, H2O2, TNF-a and IL-6. Another study had similar results, indicating various AG fractions primed macrophages for an enhanced respiratory burst, directly stimulated NO production via induction of NO synthase, and induced macrophages to secrete both inflammatory (IL-1, IL-6, TNF-a, and IL-12) and anti-inflammatory (IL-10) cytokines.²¹

Research suggests lactoferrin is a valid addition to the immunomodulator category, especially in relation to cancer. This globular, multifunctional protein originally isolated from bovine milk but also naturally occurring in neutrophil granules and mucosal secretions,²² may have antimicrobial, antioxidant and anti-inflammatory properties, and may also promote the growth and differentiation of T lymphocytes.²³ Further, lactoferrin appears to play a role in the regulation of cytokines and lymphokines such as TNF-a and IL-6. A recent study investigating lactoferrin as an adjuvant to enhance the efficacy of the Mycobacterium Bovis Calmette Guerin (BCG) vaccine, specifically because of previous reports of lactoferrin enhancing IL-12 production from macrophages infected with BCG, found the addition of lactoferrin to the vaccine led to reduced pathological damage upon subsequent infection with virulent mycobacteriumtuberculosis(MTB).²⁴ Researchers concluded adding lactoferrin to the vaccine allowed for reduced related tissue damage and pulmonary histopathology.

Corralling Inflammation

Hops (Humulus lupulus L.) are another unconventional approach for controlling the inflammatory aspect of immune function. This botanical substance, normally a centerpiece in beer making, has shown potential in reducing inflammation by zeroing in on the compound’s ability via its alpha and beta acids (humulone and lupulone, respectively) to significantly inhibit pro-inflammatory PGE2 while not affecting healthy prostaglandins. Researchers applied the findings into a followup study using hops extract (as Perluxan™, from Pharmachem Laboratories) as an alternative to non-steroidal anti-inflammatory drugs (NSAIDs).²⁵ They found human oral consumption of a high-alpha acid hops dietary supplement inhibited inflammation via the COX-2 pathway, with a nine-hour potency comparable to a 400 mg dose of ibuprofen and more favorable selectivity.

Other natural substances have shown promise in effectively addressing inflammation. One particular antioxidant extract combination from cantaloupe melon, superoxide dismustase (SOD) and wheat gliadin biopolymer (as GliSODin®, from P.L. Thomas), reduced the production of reactive oxygen species (ROS) associated with macrophage activation, during which macrophages release various cytokines involved in inflammation.²⁶ In the study, mice supplemented with GliSODin (10 IU for 28 days) showed increased levels of circulating SOD, catalase and glutathione peroxidase, the primary antioxidants employed in fighting inflammation-related oxidative stress. Additionally, a separate study revealed spleen cells isolated from mice in each of the groups showed the mice supplemented with GliSODin had increased production of type1 helper T lymphocytes (Th1) and INF-gamma and IL-4; IgG response was stimulated, while the response of IgE was only marginally affected.²⁷

The same effects were seen in AIDS patients receiving GliSODin.²⁸ Patients supplemented with GliSODin for 21 days normalized circulating SOD1 activity and total antioxidant status and reduced circulating levels of beta-2-microglobulin, indicating a correlation between reduced oxidative stress and reduced macrophage activation.

A polysaccharide (AM3) from yeast may also inhibit certain inflammatory markers. A study involving 14 professional male volleyball players found the immunomodulator AM3 (as GLPH-1™, from Gourmetceuticals) significantly reduced serum concentrations of biochemical marker proteins associated with muscle damage such as creatine kinase, myglobin, aspartate aminotransferase and lactate dehydrogenase.²⁹ GLPH-1 has demonstrated further control of inflammatory function in patients suffering from chronic obstructive pulmonary disease (COPD), according to Gourmetceuticals. AM3 also inhibits DC-SIGN function in HIV transmission scenarios.³⁰ In one study, the polysaccharide moiety of AM3 (IF-S) inhibited the binding of viral, fungal and parasitic pathogens by human monocyte-derived dendritic cells in a dose-dependent manner. Researchers concluded the immunomodulatory actions of AM3 are mediated, at least partly, by altering DC-SIGN functional activities and ultimately preventing HIV replication.

Essential fatty acids

(EFAs) must also be included in any discussion of inflammation, as numerous trials have proven their ability to fight inflammation in diseases such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and even migraine headaches.³¹ In a recent study, alpha-linolenic acid (ALA) demonstrated a strong inhibitory effect on the production of NO.³² It also inhibited inducible NO synthase (iNOS), COX-2, and TNF-a gene expressions induced by lipopolysaccharide (LPS). Another study concluded omega-3 and -6 fatty acids reduced inflammation via induction of COX-2 in HaCaT human keratinocyte cells.³³ Further, a general review of long chain omega-3 EFAs found supplementation accounts for significant decreases in inflammatory cytokine production by monocytes in all instances,³⁴ while another study concluded these fatty acids also decrease the production of the classic inflammatory cytokines TNF, IL-1 and IL-6, and the expression of adhesion molecules involved in inflammatory interactions between leukocytes and endothelial cells.³⁵

Tea may also affect healthy immunity by regulating acute and chronic inflammatory responses,³⁶ and decreasing frequency of cancer development,³⁷ via modulation of components of cell signaling pathways.³⁸ The polyphenol epigallocatechin gallate (EGCG) found in green and black tea may affect immune function by suppressing production of TNF-a by macrophages, microglial cells and mast cells stimulated with LPS and others via toll-like receptors (TLRs); reducing NO production; and up- or down-regulating activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C. Past research also suggests EGCG may influence osteoarthritic inflammation by inhibiting the IL- 1beta-induced production of NO in human chondrocytes by interfering with the activation of NF-kappaB.³⁹

Another polyphenol affecting inflammation via inhibiting formation of inflammatory prostaglandins and leukotrienes is quercetin.⁴⁰ The compound also exhibits antioxidant, anti-viral, immunomodulatory, anticancer and gastroprotective activities. In vitro and animal studies have shown quercetin inhibits degranulation of mast cells, basophils and neutrophils; other in vivo studies show it inhibits tyrosine kinase and NO synthase and modulates the activity of the inflammatory mediator, NF-kappaB. In one study, quercetin decreased the gene expression and production of mast cell-mediated allergic inflammation, involved in many diseases such as asthma, sinusitis and rheumatoid arthritis; the compound particularly affected TNF-a, IL-1beta IL-6, and IL-8 in PMACI-stimulated HMC-1 cells.⁴¹ Other researchers concluded assorted research trials validate quercetin as a therapeutic compound for neurological diseases mediated by mast cell degranulation.⁴²

Healthy Gut, Healthy Individual

In recent years, significant scientific progress has revealed certain “friendly” bacteria such as bifidobacteria and lactobacilli can protect proper gut function. The dietary use of prebiotics such as inulin and oligofructose that support the growth of such lactic acid producing bacteria (LAB) offer the potential of improving the barrier function of the intestines.⁴³ Densities of LAB have been associated with improved resistance to enteric and chemical pathogens via stimulation by both non-specific host defense mechanisms and some cells involved in a given response, which often results in increased phagocytic activity and/or elevated levels of immune molecules such as secretory IgA.

Indeed, a recent study noted the effects of inulin enriched with oligofructose on immune function in 34 colon cancer patients.⁴⁴ Subjects received either encapsulated lactobacillus rhamnosus and 10g of inulin enriched with oligofructose, or encapsulated maltodextrin and 10 g of maltodextrin. IL-2 secretion by activated peripheral blood mononuclear cells (PBMC) from the polypgroup increased significantly between baseline and six and 12 weeks after intervention initiation, compared to placebo. Another study involving inulin in a mixture of prebiotics noted administration of this synbiotic formula in critically ill, mechanically ventilated, multiple trauma patients seemed to exert beneficial effects in respect to infection and sepsis rates and to improve the patient’s immune response.⁴⁵

Scientific investigation of these substances, however, is still young, and research suggests modification of intestinal flora via probiotics, prebiotics and synbiotics can interact with the immunological components of the intestine to yield gastro intestinal protective effects and systemic effects, such as the modulation of cellular response to antigens and the humoral responses that may have significance in other mucosal surfaces, such as the skin and respiratory tract.⁴⁶ But the consensus throughout the research community is that the “effect [of prebiotics] should be confirmed either in studies with a larger number of patients or by applying strategies that more effectively modify the composition of intestinal flora”,⁴⁷ and that “future studies [on pre- and probiotics] should focus to determine the characteristics of a healthy gut and the evaluation of specific health benefits by well-designed, controlled human studies of adequate duration.”⁴⁸

Using a spectrum of nutritional ingredients, manufacturers are helping consumers address immune health. As research advances, science is sure to discover more natural approaches to strengthening immunity—approaches consumers can easily to adapt to everyday lifestyles. 

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