~Immune System

~Immune System
Reprinted with permission of Life Extension®.



This protocol is designed to enhance immune function in aging persons, in patients receiving cancer chemotherapy, and in those with chronic viral or bacterial infections.

The first section is written in highly technical form. If you want to bypass this molecular information, skip down to the next section entitled The Harmful Role of Free Radicals.

MOLECULAR IMMUNOLOGY

The immune system is the most diverse and ubiquitous system in the body. If you imagine a fortress, then the immune system consists of the walls outside and the soldiers within. The soldiers have many different functions in the hierarchy of the fort, each having their own job, and yet interacting with each other as a team to effectively defend the fort from invaders. The soldiers of the immune system consist of particular cell types, not all of which have been defined by researchers. The cells are divided into two main groups defined by their place of maturation: B-cells, or bursa/bone marrow derived, and T-cell, or thymus derived.

B-cells are responsible for humoral immunity (e.g., formation of specific antibodies), and T-cells are responsible for cell-mediated immunity and the production of chemicals and messenger molecules that kill the invading foreign materials. The "fort walls" of the body consist of the areas that come into contact with the outside environment--the skin, mucous membranes of the mouth, genitals, nose, and eyes, the lung lining, and the whole intestinal system. These are physical barriers, and injury of any kind or even a change in cellular structure of the membrane can allow invasion. In the GI mucosa, for example, a thinning of the cells that line the gut (as in colitis, for example) can result in leakage of toxins into the blood stream (Hunter 1991; 1998). Any crossing of the barrier by what is considered foreign by the immune system will result in activation of the system and the defense forces will rally.

After an organism has gained entry, the first line of defense are nonspecific effector mechanisms of the body, in particular the phagocytic (cell-eating) cells, such as neutrophils. Macrophages (big eaters) also play a role in phagocytosis, but may require activation. Some toxins will activate what is known as the complement system. The complement system comprises a set of proteins that are designed to eliminate microorganisms and other antigens from tissues and blood. These proteins are present in plasma, other tissue fluids, and on cell surfaces. It is one of the most intricate and rigorously controlled sets of reactions.

Enzymes, cofactors, receptors, and other molecules act in a symphony to elicit proinflammatory and cell killing reactions in response to toxins. The deposition of fragments of complement proteins (especially C3) on the surface of invasive microorganisms is termed opsonisation. This "tags" the cells so that phagocytic cells know to actively ingest and destroy that particular material. Activation of complement will also promote local inflammation at the site of infection, through the release of chemical components--known as cytokines, interleukins, and tumor necrosis factor (TNF-a). In the case of viral infections, infected cells may synthesize interferons and/or be recognized and split apart by natural killer (NK) T-cells. The nonspecific immune mechanisms are particularly important early in infection, because the antigen-specific response takes several days to develop, but the nonspecific mechanisms continue to play a role in the immune response until resolution of the infection and healing of tissue damage.

The second line of defense is antigen processing. When, for example, a macrophage eats bacteria, proteins (antigens) from the bacteria are broken down into short peptide chains and those peptides are then "displayed" on the macrophage cell surface attached to special molecules called Major Histocompatibility Complex Class II (MHC II). Bacterial peptides are similarly processed and displayed on MHC II molecules on the surface of B-lymphocytes. When a T-lymphocyte "sees" the same peptide on the macro-phage and on the B-cell, the T-cell stimulates the B-cell to turn on antibody production.

The stimulated B-cell undergoes repeated cell divisions, enlargement, and differentiation to form a clone of antibody secreting plasma cells. Hence, through specific antigen recognition of the invader, clonal expansion, and B-cell differentiation, you acquire an effective number of plasma cells all secreting the same needed antibody. That antibody then binds to the bacteria making them easier to ingest by white cells.

Cytotoxic T-lymphocytes (CTL) recognize surface markers on other cells in the body that label those cells for destruction. In this way, CTLs help to keep virus-infected or malignant cells in check.

THE HARMFUL ROLE OF FREE RADICALS

Immune cells are highly reactive metabolically, and they have a high turnover. Proinflammatory cytokines will produce free radicals to kill foreign cells in what is called an oxidative burst of activity (Goldsby et al. 2000). Although free radicals kill foreign cells, they can also be deadly to our own cells. Free radicals have been linked to immune system damage that accompanies normal aging. A strong immune system is critical to the prevention of infection by viruses, fungi, and bacteria. It is thought that cancer cells form regularly and that a vigilant immune response is therefore required to kill or deactivate these deformed cells before they become malignant tumors. Members of the Life Extension Foundation have long been encouraged to follow a daily antioxidant regimen that protects against immune-suppressing free radicals.

The incidence of cancer and new infectious diseases increases every year in the United States. In addition, many dangerous bacteria have become resistant to the antibiotics that once kept them in check. These virulent, antibiotic resistant strains of bacteria are increasingly becoming a threat to our well-being. There is strong scientific evidence showing that antioxidants and other natural therapies can play an important role in maintaining and enhancing immune function.

NUTRITIONAL IMMUNOLOGY

The concept that appropriate nutrients can enhance the human immune response is known as nutritional immunology. The foundation of this field of study was laid in the early 1800s when physicians discovered that severe malnutrition led to thymic atrophy. For most of that century, the evidence of a relationship between malnutrition and the immune system was based on anatomical findings. With the discovery of vitamins, it became evident that essential nutrients played a critical role in maintaining immune function (Beisel 1996).

Studies published in the 1980s and 1990s clearly show specific immune-enhancing effects of the proper use of nutritional supplements, proteins, hormones, and certain drugs. Micronutrients are now known to play a key role in many of the metabolic processes that promote survival from critical illnesses (Chandra 1983; Chandra et al. 1986). The paragraphs that follow discuss the correct balance of nutrients, nutrient supplements, proteins, and hormones and examine their role in enhancing the human immune system.

THE ROLE OF VITAMINS

Vitamins are essential for oxidative phosphorylation (the energy generating pathway of the cell) and protection against oxidants. They also act as cofactors in many enzymatic reactions and as signal mechanisms to other cells. Researchers use levels of immune cells, presence of antibody, and response to stimulation by antigens as measures of immune activity in vitro and in vivo, for example, levels of IgA, IgE, B-cells, T-cells, T4/T8 ratios, and response to phytohemagglutinin to name a few (Chandra et al. 1994).

Over the last 30 years, a large amount of literature supports repeatedly the connection between vitamin and mineral balance and immunity, resistance to infection, and allergy (High 1999). The most consistent nutrients linked to immune dysfunction have been low levels of vitamins A, C, E, and B6, copper, iron, and zinc (Johnson et al. 1992; Grimble 1997; Shankar et al. 1998; Ravaglia et al. 2000). Interestingly, many of these nutrients are linked to deficiency in the North American population. Kenneth H. Brown, a University of California at Davis nutrition professor, estimated that as much as half of the world population is at risk for zinc deficiency and 40% of children in low-income countries have stunted growth related to zinc deficiency. Infants, young children, and pregnant or nursing women are especially at high risk for zinc deficiency because they have increased needs for this essential nutrient.

Chandra et al. (1983) have repeatedly demonstrated that groups such as atopic, formula-fed children, low-birth-weight infants, obese adolescents, malnourished hospitalized patients, and the elderly have not only increased immune dysfunction but also increased risk for infection and allergic disorders, such as eczema. Many of these studies have actually shown improvement of immune function when supplemented with appropriate nutrients and foods (Chandra 1999). Although actual protein malnutrition is rare in North America, we experience more undernutrition and overconsumption--that is, we eat too much poor-quality food, namely, fat, sugar, and processed foodstuffs.

Another area where immunity suffers in western civilization is at the gut lining--the walls of the fortress. About 60% of the immune system cells are collected around the small intestine in areas known as Peyer's patches or the GALT (gut associated lymphoid tissue). Any thinning of the gut lining, such as in lactose intolerance, food allergy, gluten sensitivity, ulcerative colitis, Crohn's disease, antibiotic-induced colitis, yeast overgrowth, and so forth, will render the gut leaky. This leakiness allows incompletely digested food proteins, which are immune stimulating, to enter the blood stream. The walls of the fort have been invaded and the immune cells respond by mounting an inflammatory response. If the problem is not dealt with at the source (i.e., the thin gut wall and its causes), then the immune response becomes chronic. This chronic activation and negative cycle leads to further damage. Keeping our gut healthy through a high-residue, nutrient-dense diet can help to protect against this misfortune.

From the above, it can be seen that a strong immune system is dependent on a good foundation of nutrition. There is no single nutrient that, by itself, will enhance immunity (Lesourd 1997; Scrimshaw et al. 1997). In fact, too much of one nutrient can do the opposite of what one might want and decrease immunity (Delafuente 1991). Thus, the descriptions that follow, where individual nutrients are identified as being important, should be taken in the context of "a chain is only as strong as its weakest link."

Vitamin A. During the 1920s and 1930s, vitamin A became known as the anti-infective vitamin, and the first attempts were made to use vitamin A therapeutically during the course of infectious illnesses. Abraham E. Axelrod and his students initiated the first systematic studies of immunonutritional interrelationships in laboratory animals in 1947. Human studies soon followed, and by the late 1970s, the field of nutritional immunology was well-established. Newer research into vitamin A shows its importance to overall good health and its protective effects against tumor growth. Specifically vitamin A is a cell-signaling vitamin and supports immunity by helping to maintain the integrity of the body's mucosal surfaces (Villamor et al. 2000). Human sources are from liver. The carotenes from plant foods are converted to vitamin A as needed by the body. Large doses of vitamin A can be toxic, and pregnant women should never take vitamin A above the RDA because it is cancer-causing to the fetus. Refer to Appendix A: Vitamin A Precautions when taking more than 5000 IU a day of vitamin A.

Beta-Carotene. Beta-carotene has been shown to have a powerful effect in boosting natural killer (NK) cell activity in elderly men. In a controlled, double-blind study, the effects of 10-12 years of beta-carotene supplementation on NK cell activity were evaluated. Although no significant difference was seen in NK cell activity in the middle-aged groups, elderly men supplemented with beta-carotene had significantly greater NK cell activity than the corresponding control group (of elderly men) who were receiving placebo (Santos et al. 1996).

Results show that long-term beta-carotene supplementation may be beneficial for immune viral and tumoral surveillance. A French study using mice concluded that, although beta-carotene supplementation resulted in a nonsignificant increase in NK cells in the spleen, their killing capacity was significantly enhanced after beta-carotene supplementation. The treatment had no adverse effects (Carlos et al. 1997). It is safer to take large doses of beta-carotene than vitamin A, although a yellowing of the skin that is harmless will occur at higher levels. Because we do not know which carotenes of the many varieties are needed, a supplement of mixed carotenes is advised--or better still, eat red-, orange-, and yellow-colored vegetables, which contain high levels of all the carotenes.

Vitamin E. The best-publicized study of the use of vitamin E to boost immune function appeared in 1997 (Meydani et al. 1997). The double-blind, placebo-controlled study looked at healthy humans at least 65 years of age. Supplementation with vitamin E for 4 months improved certain clinically relevant indices of cell-mediated immunity. These results clearly show that a level of vitamin greater than that currently recommended by the FDA enhances certain clinically relevant in vivo indices of T-cell-mediated immune function in healthy elderly persons.

Oral alpha-tocopherol supplementation at the rate of 100 mg/day significantly increased NK cell activity in a 16-month-old Japanese boy with Shwachman syndrome (a syndrome associated with severe vitamin E deficiency). The study showed that severe vitamin E deficiency causes impaired NK cell activity but that the condition is reversible with alpha-tocopherol supplementation (Adachi et al. 1997).

Vitamin C (Ascorbic Acid). High levels of vitamin C can protect levels of vitamin E in tissue and may contribute to the immune-enhancement of vitamin E (Niki 1987; Chan 1993; Stahl et al. 1997). Being an antioxidant, adequate vitamin C is an essential ingredient for "mopping up" the free radicals left behind after the immune system produces its oxidative burst killing activity. A steady supply of vitamin C is vital to good health. Because the human body can neither manufacture nor store vitamin C, our requirements must be met from dietary sources, such as citrus fruit, vegetables, and supplements. Vitamin C's antioxidant protection is especially important to healthy lungs. Numerous studies have shown that vitamin C protects the airways against inhaled (environmental) and internal oxidants. Individuals with asthma, allergies, and sensitive respiratory systems will receive significant protection from adequate doses of vitamin C.

Vitamin B6 (Pyridoxine). Deficiencies are associated with marked immune depression. This vitamin has many functions throughout the human body in addition to its support of the immune system. Chandra et al. (1980, 1986) have reported that deficits of pyridoxine in addition to calories and zinc resulted in a significant lowering of serum thymic factor, a hormone involved in cell-mediated immunity. Others have demonstrated in animal studies that both low and high levels of this vitamin can lead to immune suppression (Rall et al. 1993; Katunuma et al. 2000). Vitamin B6 is an activator of the enzymes necessary for transferring methyl (-CH3) groups to other molecules involved in immune function, so this vitamin's impact is not only on immunity but on all body functions. Once again, balance is always important. Although the known obvious side effects of excessive vitamin B6 should be watched for (tingling and numbness in the extremities at doses of greater than 300 mg a day for some weeks), it is not known at what dose the immune suppressive effects may occur.

Continued . . .
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