Strengthening the Immune System

When a country is threatened by its enemies, its government responds with a declaration of war, and the country mobilizes and prepares for battle. Similarly, when the body is under attack from foreign bodies and pathogens, the immune system mobilizes to protect organisms from infection with layered defenses.

The human immune system is an intricate and complex system that is constantly working to protect our bodies from harm. Its defenses are organized into three layers: the physical barrier, the innate immune system and the adaptive immune system. The physical barrier prevents pathogens such as bacteria and viruses from entering the body. If this barrier is breached, the innate immune system responds. This system is found in all plants and animals defending the host in a non-specific matter, meaning it doesn’t offer long-lasting immunity to the host. In addition, it does not have immunological memory.

The final layer of protection is the adaptive immune system, which is only found in vertebrates. The adaptive system does just that—adapts its response during an infection to improve its recognition of a pathogen, i.e., bacteria and viruses. The body uses y-shaped antibodies, produced by white blood cells, to identify and neutralize foreign substances, as known as antigens. Antigens trigger a reaction from the immune system and are often found on the surfaces of bacteria and viruses. After the pathogen has been eliminated, the antibodies stay in the body as an immunological memory. This helps the adaptive immune system launch a stronger attack each time the pathogen is met. Antibodies can be transferred from one individual to another, often from a mother to the fetus through the placenta. This is known as passive immunity and is a short-term transfer.

Many different types of immune cells travel through the body identifying pathogens. White blood cells, leukocytes, defend the body against antigens. There are two major types of leukocytes: lymphocytes and phagocytes. Lymphocytes are found in the adaptive immune system where immunological memory takes place and allows the body to recognize previous invaders. The two major types of lymphocytes are T cells and B cells. They start out in the bone marrow and either stay and mature (B cells), or depart for maturation in the thymus gland (T cells). B cells search for antigens and send antibodies to lock on to them; T cells destroy the antigens that the B cells identified. There are two types of T cells: helper T cells and killer T cells. Killer T cells destroy the antigens tagged by antibodies. Helper T cells help signal other cells (like phagocytes) to perform their job.

Phagocytes are biological cells that ingest and destroy foreign matter, bacteria, etc. There are three main categories of phagocytes: macrophages, microphages (mainly neutrophils, which fight bacteria) and dendritic cells. Each type of cell targets a specific type of foreign body such as parasites, bacteria or fungi. Neutrophils are the main cell found in pus, eosinophils mainly deal with parasite infections and are the predominant cell in allergic reactions, and basophils are present during an allergic reaction causing inflammation. Inflammation is the body’s protective attempt, triggered by dying cells, to remove the foreign bodies and start the healing process for the tissue; it is not a symptom of infection.

Immune disorders occur when the body’s immune system is deficient and cannot perform at its potential. Immunodeficiency is when one or more of the components of the immune system are inactive and it is unable to launch a normal immune response. Autoimmunity occurs when the immune system fails to properly distinguish between itself and non-self; basically, the body is attacked by its own immune system. Lastly, hypersensitivity is an immune response that damages the body’s own tissues.

Fortunately, the body doesn’t have to fight these battles on its own. Natural supplements have been proven to help boost the body’s immune system and strengthen its defenses.

Magic Mushrooms

The medicinal benefits of mushrooms have long been known and used. Active hexose correlated compound (AHCC™; from Maypro) is a functional food obtained from basidiomycetes mushrooms. A Japanese prospective cohort study was performed from Feb. 1, 1992 to Dec. 31, 2001 with 269 consecutive patients with histologically confirmed hepatocellular carcinoma (HCC).¹ Of those, 113 received AHCC orally after undergoing curative surgery (AHCC group). The AHCC group had a significantly longer no recurrence period (P=0.0277) and an increased survival rate (P=0.0009) when compared to the control group by Cox’s multivariate analysis. The study concluded AHCC intake could improve the prognosis of postoperative HCC patients. Similarly, another study found AHCC improved the prognosis of HCC patients following surgical treatment.² The prospective cohort study was performed with 44 patients with histologically confirmed liver cancer. Thirty-four patients received AHCC and 10 patients received a placebo (control) orally. Patients in the AHCC treated-group had a significantly prolonged survival when compared to the control group. Quality of life in terms of mental stability, general physical health status and the ability to have normal activities were significantly improved after three months of AHCC treatment. The apparent different clinical parameters between the two groups were the levels of albumin and percentage of lymphocytes. Unlike the control patients, AHCC treated-patients with longer survival time had the tendency of better outcomes since the levels of AST and ALT had not increased rapidly from their baselines at follow-up. The levels of total IL-12 and neopterin were slightly increased in AHCC treated-patients.

In a study at Drexel University, Philadelphia, young C57BL/6 mice were supplemented with 1 g of AHCC (from Maypro) for one week prior to and throughout infection with influenza A (H1N1, PR8).³ Supplementation increased survival, decreased the severity of infection and shortened recovery time following intranasal infection with flu. AHCC increased natural killer (NK) cell activity in the lungs at day one (P<0.05) and day four (P<0.01), and in the spleen at day two post-infection (P<0.01). Supplementation increased the percentage (P<0.05) and number (P<0.01) of NK1.11 cells in the lung and reduced the infiltration of lymphocytes and macrophages compared with controls (P<0.01). The study results suggested AHCC supplementation boosts NK activity, improves survival and reduces the severity of influenza infection in young mice.

Another mushroom with immunity-boosting abilities is Maitake. A recent study published in the Journal of Clinical Oncology found a polysaccharide extract from Grifola frondosa (Maitake extract) was associated with measurable changes in the immunomodulatory cell counts in peripheral blood.⁴ In the phase I/II dose escalation trial, 30 menopausal breast cancer patients free of disease after initial treatment were enrolled sequentially into five cohorts of six patients each. Maitake extract was taken orally at 0.1, 0.5, 1.5, 3, or 5 mg/kg twice daily for three weeks. Quadratic dose curve analysis showed a daily dosage of 2 mg/kg was associated with the greatest increases of CD3+CD25+ or CD4+CD25+ T cells in the peripheral blood (P<0.001); a daily dosage of 6 mg/kg was associated with the most significant increases in intracellular IL-2 production by NK-T cells (P=0.002); IL-10 production by T cells (P=0.002). Interferon gamma production by memory CD4+ T cells was attenuated to 27 percent of baseline at a daily dose of 7.4 mg/kg (P=0.002).

A study at the Veterans Affairs Medical Center and University of Kentucky Medical Center, Lexington gave mice total body irradiation (TBI) followed by treatment with CorImmune™ (from Xenos Nutraceuticals Inc.), an extract powder of the cultured mycelia of the mushroom Cordyceps sinensis, or a normal saline (control).⁵ CorImmune was administered beginning two hours after a lethal dose of TBI. There was a 55-percent improvement in survival in the treatment group vs. zero percent in the saline control (P<0.0001). The supplement increased normal leukocyte levels in a dose-dependent fashion. Animals treated with sub-lethal TBI and monitored for blood leukocyte recovery exhibited a return to normal baseline three weeks after TBI injury. In contrast, only 50 percent returned to normal baseline in the saline control group (P<0.01).

Yeast on the Rise

Yeast-based supplements have proven to be a strong weapon against attacks on the immune system. A 12-week experimental, double blind, placebo-controlled study randomized 116 healthy participants with up-to-date vaccination histories to receive 500 mg/d of EpiCor®, a dried Sacharomyces cerevisiae fermate, or a placebo.⁶ The EpiCor-treated group experienced a statistically significant reduction in the incidence (P=0.01) and duration (P=0.03) of colds or flu compared with the placebo. They also experienced a non-significant (P=0.23) reduction in adverse events compared with the placebo.

In an unpublished study, Wellmune WPG® (from Biothera), a yeast-based (beta-glucan) antioxidant supplement, decreased the amount of upper respiratory tract infections in firefighters. Supported by an unrestricted grant from Biothera, the single blind, randomized, crossover study administered Wellmune WPG or a placebo to 54 wildland firefighters for 14 days, followed by a three-day washout period and another 14-day treatment period. Thirty-seven percent of the treatment group experienced an upper respiratory tract infection; 48 percent of the placebo group experienced an infection. Additionally, Wellmune WPG alleviated duration, severity and down time due to cold symptoms in an unpublished, double blind, placebo-controlled study. Healthy subjects (n=40), aged 18 to 65, received either 250 mg/d of Wellmune WGP or placebo for 90 days during the cold season. In contrast with the placebo group, the treatment group reported no incidence of medically verified fever, an increase in general health markers and no need to take a “sick day” off work or school, compared with an average of 1.38 days of work/school missed for participants in the placebo group. There were no differences between groups in the number of colds; however, at the end of the 12-week test period, the Wellmune WGP-supplemented group exhibited significant improvements in physical component summary scores.

SOD

Superoxide Dismutase (SOD) is a biological active compound produced by most cells of the body and is an important antioxidant defense. P.L. Thomas supplies Glisodin®, a cantaloupe melon-based form of SOD with wheat gliadin, which protects SOD from stomach acid and enzymes found in the digestive system. A study published in Current Trends in Immunology evaluated the bioadhesive properties of the wheat gliadin in Glisodin to delay the release of SOD throughout the digestive system compared to a melon SOD extract without wheat.⁷ Glisodin was able to stimulate the host antioxidant system by inducing a Th-1-polarization of the immune response through the expression of IFN-gamma and an antibody response of IgG isotype. In a separate, unpublished double blind, clinical investigation, presented at the XVI International AIDS Conference in August 2006, Glisodin or a plant SOD extract without gliadin was administered to 35 patients with AIDS that did not receive any anti-retroviral therapy; the control group consisted of 30 non-HIV-1-infected patients. Compared to the control group, circulating erythrocytes Cu/Zn-SOD (SOD1) activity and total antioxidant status were significantly (P<0.01) decreased in AIDS patients and correlated with the increased plasmatic concentration of beta2-microglobulin that reflect the activation state of macrophages. Patients receiving Glisodin normalized their circulating SOD1 activity and total antioxidant status, and reduced their circulating levels in beta2-microglobulin indicating a correlation between the reduction of oxidative stress and the reduction of macrophage activation. The study demonstrated Glisodin could regulate the activation state of macrophages and down-regulate the oxidative stress caused by the infectious process.

Zinc, Vitamin C and Echinacea

Some of the more well-known immune boosters are zinc, vitamin C and Echinacea. In a 2008 study, lipopolysaccharide (LPS)-challenged adult male mice were fed a zinc-adequate (40 ppm) or a zinc-marginal (4 ppm) diet for four weeks, and then a bacterial challenge was simulated by intraperitoneal injection of LPS (10 mcg/g body weight) or saline (control).⁸ Diet did not affect body weight and feed intake. The LPS challenge led to decreased voluntary locomotor activity (P<0.05). Moderate zinc restriction led to greater leukocyte infiltration in the lamina propria after the LPS challenge (P<0.05) and higher plasma IL-6 and IL-10 levels 24 hours after the LPS challenge (P<0.01).

In another study published in Vaccine, researchers immunized a sub-cohort of 241 Bangladeshi infants who had previously received three doses of a Hib (Haemophilus influenzae) conjugate vaccine with three doses of the heptavalent pneumococcal protein conjugate (PNC) vaccine at four-weeks intervals beginning at 18 ± one weeks of age.⁹ The infants were supplemented with 5 mg/d of zinc or a placebo from 4 to 33 weeks of age. After three doses of PNC, at 29 weeks of age, geometric mean titres for the pneumococcal serotypes ranged from 3.68 to 13.34 μg/ml. Titres were significantly higher for infants who had received PNC compared to infants who had only received DTP-Hib. Zinc supplementation resulted in higher titres for serotype 9V and 3.33 μg/ml for the zinc and placebo group, respectively, (P<0.05) after three doses, but had no effect on other serotypes. Zinc supplementation enhanced the immune response to only one of the serotypes (9V); however, there was no effect on other serotypes.

A study at the University of Michigan, Ann Arbor found zinc supplementation lowered the incidence of infections, increased plasma zinc, and significantly lowered the generation of tumor necrosis factor alpha (TNF-a) and oxidative stress markers in healthy elderly subjects.¹⁰

Contrary to previous findings, a study published in The Journals of Gerontology Series A: Biological Sciences and Medical Sciences found an intake (diet plus supplementation) of up to 40 mg/d of zinc did not have significant long-term effects on immune status in apparently healthy persons aged 55 to 70 years.¹¹ For six months, 15 mg/d or 30 mg/d of zinc were examined on immune status in healthy individuals. At baseline, zinc concentration was positively associated with lymphocyte subpopulation counts and T-lymphocyte activation. Zinc supplementation of 30 mg/d significantly lowered B-lymphocyte count, at month three only. Lower doses of 15 mg/d of zinc significantly increased the ratio of CD4 to CD8 T lymphocytes at month six.

Vitamin C offers protection against free radicals in addition to enhance immune functions, including interferon activities. Vitamin C was found to suppress proliferation of the human melanoma cell line SK-MEL2 via the down-regulation of insulin-like growth factor (IGF)-II production and IGF-IR expression, which is followed by the activation of p38 MAPK and the inhibition of COX-2 expression.¹²

A separate double blind, randomized, placebo-controlled study confirmed vitamin C’s ability to assist immune health, noting the vitamin C from an encapsulated fruit and vegetable juice powder concentrate may have been responsible for a 30-percent increase in circulating gamma delta-T cells and a 40-percent reduction in DNA damage in lymphocytes, as well as significantly increased plasma levels of vitamin C beta-carotene, lycopene and lutein.¹³

In contrast, a 2007 study found an antioxidant supplement comprising of beta-carotene (9 mg/d), vitamin C (1,500 mg/d), vitamin E (130 mg/d), zinc (45 mg/d), selenium (76 mcg/d) and garlic (150 mg/d) “significantly increased levels of vitamin C, vitamin E, beta-carotene and selenium, but no change in immune responses, serum AC or plasma F(2)-isoprostanes.”¹⁴

Echinacea is a flower widely used as a supplement for immune health. In a randomized, double blind, placebo-controlled, prospective four-week clinical trial, 48 healthy female volunteers, 22 to 51 years old, were randomly assigned to one of six groups: standardized extract of E. purpurea (EP); ultra-refined E. purpurea/E. angustifolia (urEPA); E. purpurea/E. angustifolia (EPA); E. purpurea/E. angustifolia plus larch arabinogalactan (EPALA); larch arabinogalactan (LA); or placebo.¹⁵ Complement properdin increased by 21 percent in the EPA group (P<0.05) and by 18 percent in the EPALA group (P<0.05), compared to the placebo group (P>0.05). SF-36 showed improvements in overall physical health, vitality and emotional health in the same two groups (EPA and EPALA). Researchers concluded an increased complement properdin may be an indication of one aspect of immune system stimulation in patients treated with either E. purpurea/E. angustifolia or E. purpurea/E. angustifolia plus larch arabinogalactan.

Echinacea contains arabinogalactan, a phytochemical that can also be extracted from the timber of the larch tree. A study published in International Immunopharmacology used an arabinogalactan polysaccharide, G1-4A, from the stem of Tinospora cordifolia, for protection against endotoxin-induced sepsis.¹⁶ There was 100-percent protection against LPS-induced mortality in mice pretreated with G1-4A. G1-4A was shown to bind to the murine macrophages leading to their activation and reciprocally inhibited binding of LPS to macrophages. Following treatment with G1-4A, there was a small increase in serum TNF-alpha and IL-1beta levels. However, challenge with LPS elicited significantly reduced levels of TNF-alpha in G1-4A pretreated mice as compared to the controls while the level of soluble TNFR was enhanced. An increase in serum IL-1beta, IL-6, IFN-gamma levels and decrease in that of IL-10 was observed following challenge with LPS in mice pretreated with G1-4A as compared to the controls. In addition, G1-4A also modulated the release of nitric oxide (NO) by murine macrophages. A similar phenomenon was observed in a human monocytic cell line, U937. G1-4A appeared to induce tolerance against endotoxic shock by modulation of cytokines and NO.

Vitamin D also plays a large role in immune health. In a review out of UCLA, researchers said: “It is becoming increasingly clear that vitamin D can exert effects on human physiology beyond its long-standing association with skeletal homeostasis. In particular, the ability of active 1,25-dihydroxyvitamin D (1,25(OH)2D) to function as a potent modulator of human immune responses has attracted much attention. Over the last 10 years, most studies on the relationship between vitamin D and immunity have focused on the effects of 1,25(OH)2D on lymphocytes and adaptive immunity; however, studies have shown that local macrophage synthesis of 1,25(OH)2D in response to toll-like receptor (TLR) signaling is also a key feature of innate immunity.”¹⁷

A German study investigated if TLR function and antimicrobial peptide (AMP) expression were controlled by active vitamin D3 - 1,25-dihydroxyvitamin D3 (1,25D3) in keratinocytes.¹⁸ The AMP cathelicidin and TLR cofactor CD14 were known to be induced by 1,25D3, and analysis of TLR2 expression revealed this also was increased by 1,25D3. Topical 1,25D3 application to human skin confirmed these results, showing increased cathelicidin, CD14 and TLR2 by immunostaining. The presence of 1,25D3 enabled human keratinocytes to respond to Malp2 (a TLR2/6 ligand) with increased cathelicidin production which was inhibited by neutralizing antibody to TLR2. 1,25D3 also increased the ability of keratinocytes to kill Staphylococcus aureus. Keratinocytes surrounding human skin wounds increased expression of CD14 and showed a previously known increase in cathelicidin AMP. Researchers also found CYP27B1, the enzyme that converts 25-hydroxy vitamin D3 (25D3) to active 1,25D3, was significantly increased in wounds and induced in response to factors in the wound micromilieu such as TGFbeta(1) or TLR stimulation. Blocking the vitamin D receptor, inhibiting CYP27B1 enzymatic activity or limiting 25D3 in culture each prevented TGFbeta(1) from inducing cathelicidin, CD14 or TLR2. Furthermore, mice deficient in CYP27B1 failed to increase CD14 in vivo following injury.

Probiotics containing beneficial bacteria are gaining momentum with growing research pointing to their positive impact on immune and digestive health. Mice were given 50 μl/d of either L. acidophilus L10 or L. paracasei L26 (10⁸ CFU) during a 14-day feeding trial in New South Wales, Australia.¹⁹ The proliferative responses of splenocytes to concanavalin A (sparks lymphocyte mitosis, or cell division) and LPS were significantly higher in mice fed L. acidophilus. Concanavalin A-induced splenocyte proliferative responses increased significantly in mice fed L. paracasei. Interleukin 10 and interferon γ production from the splenocytes stimulated with concanavalin A were enhanced in mice fed L. acidophilus or L. paracasei. The phagocytic activity of the peritoneal macrophages was significantly higher in mice fed either L. acidophilus or L. paracasei compared with control mice. In mice fed L. acidophilus or L. paracasei, the bacterial translocation of Lactobacillus spp. and total anaerobes to Peyer’s patches and mesenteric lymph nodes was modulated compared with that in the control mice. Furthermore, there was no indication of disruption of intestinal mucosal integrity and thus no bacterial translocation to spleen, liver or blood in mice fed either L. acidophilus or L. paracasei.

Similarly, a randomized, controlled, double blind nutritional intervention study with parallel groups with a sample size of 104 women, found intake of milk fermented with L. casei during the lactation period modestly contributed to the modulation of the mother’s immunological response after delivery and decreased the incidence of gastrointestinal episodes in the breast-fed child.²⁰ After consuming the L. casei milk, reseachers observed a non-significant increase in T and B lymphocytes and a significant increase in NK cells. A decrease in the pro-inflammatory cytokine TNF-alpha in maternal milk and fewer gastrointestinal disturbances were also observed in the breast-fed child of the mothers who consumed L. casei. Additionally, the probiotic strain L. casei CRL 431 demonstrated great activity on the immune cells and the enriched population in intestinal epithelial cells, activating mainly cells of the innate immune system in an Argentine study.²¹

Lipoic acid, also known as alpha-lipoic acid, is an antioxidant found in every cell in the body. Unlike other antioxidants, lipoic acid functions in both water and fat. A study out of New York Medical College, Vilhalla, provided evidence that lipoic acid (LA) induces multiple cell cycle checkpoint arrest and caspase-independent cell death in HL-60 leukemia cells, supporting its efficacious potential as a chemopreventive agent.²² Another study out of Portland, Ore., found LA stimulated cAMP production in human cells in a dose-dependent manner.²³ In addition, LA suppressed interleukin (IL)-12/IL-18 induced IFNgamma secretion and cytotoxicity in NK cells.

In a randomized, double blind, placebo-controlled trial, 33 HIV-infected men and women with a viral load greater than 10,000 copies/cm³, despite highly active antiretroviral treatment (HAART), aged 44 to 47 years old, were assigned to receive either 300 mg of LA, three times a day, or a matching placebo for six months.²⁴ The mean blood total glutathione level in LA-supplemented subjects was significantly elevated after six months compared to an insignificant change in the placebo group (LA vs. placebo: P=0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after six months of LA supplementation compared to progressive decline in the placebo group (LA vs. placebo: P<0.001 with phytohemagglutinin; P=0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R2=0.889). There was no significant change in either HIV RNA level or CD4 count over six months in the LA-supplemented group compared to the control group.

Colostrum

Colostrum is the first milk substance produced immediately after the birth of a baby. Bovine colostrum contains many immunological factors. A review published in the British Journal of Nutrition stated: “Bovine colostrum-based immune milk products have proven effective in prophylaxis against various infectious diseases in humans. Good results have been obtained with products targeted against rotavirus, Shigella flexneri, Escherichia coli, Clostridium difficile, Streptococcus mutans, Cryptosporidium parvum and Helicobacter pylori. Some successful attempts have been made to use immune milk in balancing gastrointestinal microbial flora. Immune milk products are promising examples of health-promoting functional foods, or nutraceuticals.”²⁵

An Argentine study found antibodies against proteins implicated in Enterohemorrhagic E. coli’s (EHEC) ability to form attaching and effacing lesions were identified in bovine colostrum by Western blot analysis.²⁶ Twenty-seven (77 percent) out of the 35 samples examined contained IgG antibodies against the three proteins assayed in the study. Every colostrum sample was able to inhibit, in a range between 45.9 and 96.7 percent, the type three secretion system (TTSS)-mediated hemolytic activity of attaching and effacing E. coli. The inhibitory effect was partially mediated by IgG and lactoferrin. Researchers concluded that early colostra from cows contains antibodies, lactoferrin and other unidentified substances that impair TTSS function in attaching and effacing E. coli strains. “Bovine colostrum might act by reducing EHEC colonization in newborn calves and could be used as a prophylactic measure to protect non-breastfed children against EHEC infection in an endemic area.”

A separate study investigated whether bovine colostrum had any immunomodulatory effect on human peripheral blood mononuclear cells (PBMC) from healthy donors.²⁷ Bovine colostrum induced a dose-dependent production of IL-12 by CD14+ monocytes, but was unable to induce IFN-gamma production. It differentially affected (not dose-dependent) stimuli-induced IFN-gamma production. PBMC proliferation was substantially unaffected by bovine colostrum.

Ai/E¹⁰® is a refined lacteal complex that is sourced from an isolate from lactate. In an unpublished study, an evaluation of the NK cell activity of peripheral blood lymphocytes was performed in 107 patients with chronic illness and a mean NK cell activity of 18 lytic units. Subjects were followed for a mean period of 13.2 months and treated with a medical regimen that included 200 to 800 mg/d of Ai/E¹⁰ (from Dietary Ingredient Solutions). NK cell activity rose significantly (P=<0.001) to a mean of 246 lytic units placing them at the high end of the recognized range for people in a healthy population. Age and months of treatment, which varied among the study group, did not present a linear relationship and accordingly suggests the NK levels to be independent of these factors.

Supplementing with natural ingredients increases the body’s ability to fight off foreign bodies, keeping it healthy and strong. As more research is conducted, more nutraceutical opportunities will arise creating an even larger market for immune health.

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References for "Strengthening the Immune System"