Theanine & Isoleucine Can Help Strengthen Your Immune System

Can You Afford to Be Sick?
With the worst recession in fifty years,
it is especially important to be on guard against the flu
By Will Block

ith the worst recession in fifty years ongoing, now is not a good time to be sick. So be on guard, especially against the flu. Influenza outbreaks in temperate zones—such as most of the United States, except for Southern California and Florida—typically occur in winter and last 2 to 3 months. Outbreak contagiousness directly correlates with low temperature and low relative humidity.1 In other words, cold and dry conditions favor transmission. When you combine the predictions of an exceedingly cold winter and below normal precipitation for a sizable portion of the country,2 the powder keg of the annual flu epidemic could explode and become far worse than usual.

The Elderly Suffer the Most

Powder keg indeed! Flu epidemics are a major health hazard, worldwide. According to the World Health Organization, these yearly epidemics are believed to cause between three and five million cases of severe illness and between 250,000 and 500,000 deaths every year around the world. Unfortunately, in industrialized countries, it is the elderly—those over 65 years of age—who suffer the greatest number of deaths associated with influenza. Then there is always the possibility that an unknown strain of influenza could catch the world by surprise, and plummet into a pandemic. This has happened before in 1510, 1889–1890 (the “Asiatic Flu”), 1918–1919 (the “Spanish Flu”), 1957–1958 (the “Asian Flu”), and 1968–1969 (the “Hong Kong” Flu). It is thought that the Spanish Flu may have killed as many as 50 million people worldwide, and some estimates place the figure at twice that number.

The Virus is Coming

Fundamentally, there are two ways that an influenza virus can spread: by aerosol and by contact. Hence news of where the outbreaks are occurring and their level of intensity can be quite valuable. Google has recently published a letter in Nature, showing that Google’s search engine can predict the progress of the flu—when and where the influenza will hit—with far greater accuracy and speed than the Centers for Disease Control and Prevention (from one to two weeks earlier).3 So following those trends can give us advanced notice, and that’s good, because early detection can reduce the impact, by allowing us to take precautionary measures, to help avoid and prepare to defend against the annual virus.

The bad news is that influenza vaccines as well as antibiotics (for illnesses driven by bacteria, fungi, and protozoa) have been hobbled, to say the least. Our government’s attempt to prevent profit in each of these areas—because their political importance is too great to be left to “greedy” competition—has resulted in the virtual termination of any development that might be successful. This is really bad news, and depressing. Be careful! Depressed states increase viral vulnerability by lowering immunity.

How Can One Defend Oneself?

What’s the alternative, you may ask? By all means, use the Google system (www.google.org/flutrends).* As of the date of this writing (December 31, 2008), there are, or already have been, moderate outbreaks in Alabama, Florida, Hawaii, Idaho, Maine, Maryland, New Hampshire, North Carolina, South Carolina, Texas, Virginia, and Wyoming. While the status is just moderate at this time, and status fluctuates, these are the first outbreaks in the country, so you might shun visiting your relatives if they happen to live in any of those States, or don’t fly into them if you can avoid it. News Flash: one of the common strains of influenza that is already circulating in the United States is resistant to Tamiflu®, according to federal health officials.4 Tamiflu is the most popular drug used to treat this strain.


*Not to be paranoid, but such data collection systems have been referred to as surveillance engines, and could represent a privacy infringement. Google continues to work closely with the CDC (a government agency), claiming it will keep individual user data confidential: “Google Flu Trends can never be used to identify individual users because we rely on anonymized, aggregated counts of how often certain search queries occur each week.” See http://www.google.org/about/flutrends/how.html.


Contrary to the poor progress in the drug arena, on the supplement front there is a lot of excitement, and the basis for a great deal of advancement.

Isoleucine Induces Beta Defensin, the Front Line of Microbial Defense

A largely ignored or forgotten study, dating from 2000, reported that the essential amino acid isoleucine induced beta-defensin in a wide variety of tissues. Defensins are a subclass of antimicrobial peptides that are essential components of the innate immune system that provide the first line of defense against invading pathogens. As the most important antibacterial defensin, beta-defensin affords important protection against microbes by—catch this!—drilling holes in their membranes.5 Given their broad spectrum, surface-active antimicrobial activities, beta-defensin plays a crucial role in the integration of the innate and acquired immune responses. They are produced at virtually all mammalian epithelial surfaces, including those of the skin, airway, gut, and urogenital tracts. Other amino acids tested, including valine and leucine, did not promote the activation of the defensin gene and had little of no effect on defensin antimicrobial activity.

At the time of the study, antimicrobial peptides—including the defensins—had only recently been recognized to play an important role in mucosal host defense. Interestingly, their induction is controlled by “pattern recognition” receptors that signal the presence of microbes that are potentially harmful. The hypothesis preferred by the researchers is that isoleucine (or a similar metabolite) is produced by invading bacteria and operates as a intercellular communication messenger, and that defensins pick this up as early warning detection system. Thus, they get the jump.

Arginine Also Upregulates Beta Defensin

In a more recent paper, researchers set out to determine if the ingredients of immune-enhancing formulas, such as Abbott Nutrition’s enteral product Perative®, derive their power from the ability to upregulate hBD-1, the most important of the defensins (also known as beta defensin).6 Investigating arginine, isoleucine, and polyunsaturated fatty acids (PFA), they found that both arginine and isoleucine upregulate beta defensin, on a dose-dependent basis. The amounts in the immune-enhancing formulas are small, but nevertheless, they do induce the release of beta defensin. Although PFAs have been found to be beneficial for the immune system, they were not found to induce beta defensin. Nutritional bolstering of the immune system with isoleucine and arginine could result in fewer complications, reduced antibiotic use, and briefer hospital stay, as indeed has been shown in patients fed immune-enhancing formulas. Of course, it seems reasonable to say that if stronger concentrations are used, the outcomes could be superior.

Isoleucine Prevents Liver Metastases of Colon Cancer

Beta-defensin molecule
In a departure from what was anticipated, isoleucine has been found to prevent liver metastases of colon cancer by inducing antiangiogenesis.1 This came as a surprise. The authors expected to find that the mechanism involved beta-defensin, following an earlier paper showing that isoleucine induces beta-defensin, which play an important antimicrobial role.

The treatment of colon cancer has recently made progress, yet liver metastases of colon cancer are still difficult to treat, and there are high risks of side effects associated with advanced treatments. So it is exciting that new research shows that isoleucine prevents liver metastases, in an animal model. These are remarkable results. But the benefit wasn’t the result of up-regulation of beta defensin, but through a novel mechanism of isoleucine: down-regulation of angiogenesis via inhibition of vascular endothelial growth factor (VEGF). Importantly, the researchers confirmed that isoleucine is safe for administration to humans because it does not affect cell viability. They conclude that isoleucine is novel as a prophylactic agent for the prevention of liver metastases of colon cancer.

Reference

  1. Murata K, Moriyama M. Isoleucine, an essential amino acid, prevents liver metastases of colon cancer by antiangiogenesis. Cancer Res 2007 Apr 1;67(7):3263-8.

Theanine Enhances Immune Function

Recent research reports that theanine, a distinctive amino acid found in very small amounts in tea (Camellia sinensis) exerts a remarkable effect on the immune system.7 In the event of bacterial infection, theanine has been found to activate a state of preparedness in what are known as gammadelta T cells. These cells comprise a significant portion of total peripheral blood T cells and are mobilized by up to 50-times in response to bacteria. Theanine is the precursor to the ankylamine ethylamine, an antigen that primes gammadelta T cells in a manner that is like cocking a gun, pulling its trigger back. This doesn’t directly result in firing, but it is necessary to invoke gammadelta T killer activity against bacteria, and it increases the speed within which they can act. Interestingly, isoleucine is also an ankylamine; it also probably primes the gammadelta T cells in the same way as theanine.

The researchers found that primed gammadelta T cells protected immune-deficient mice against death from bacteria that normally would kill them. Also, in the same type of mice, adoptive transfer of gammadelta T enhanced survival against a variety of cancers including myelomas, carcinomas, and lymphomas.

A recently published double-blind, placebo-controlled, trial using theanine along with catechins found that healthy human subjects (aged 18–70 years) taking a proprietary formulation for three months had a 32% reduction in the incidence of cold and flu symptoms.8 They also had 23% fewer overall illnesses of at least 2 days duration, and nearly 36% fewer symptom days, compared to subjects taking placebo. These results were attributed to enhancement of the activity of gammadelta T cells.

While we’re on the subject of tea, Durk Pearson & Sandy Shaw point out that certain teas that inhibit fatty acid synthase also serve to reduce the ability of a couple of viruses to replicate, including the influenza A virus. (See page 10.)

L-Cysteine Helps Inhibit Influenza

In a study done several years ago, the effects of long-term treatment with N-acetylcysteine (NAC) on influenza and influenza-like episodes were investigated in a randomized, double-blind trial.9 NAC is an analogue and precursor of reduced glutathione, an endogenous antioxidant. Using 262 male and female subjects (78% > or = 65 yrs), 62% of whom were suffering from non-respiratory chronic degenerative diseases, the researchers gave each subject either placebo or 600 mg of NAC twice daily for 6 months.

Those receiving NAC treatment were found to have a significant decrease in the frequency of influenza-like episodes, as well as the severity, and length of time confined to bed. Local and systemic symptoms were also sharply and significantly reduced. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease. The researchers suggest that glutathione “provides an alternate [to antiviral drugs] strategy to limiting influenza infection.”

A more recent study reports that influenza infections are characterized by low levels of intracellular glutathione.10 Many viruses cause oxidative stress, which tends to lower intracellular glutathione. What the researchers found was that glutathione significantly inhibits production of active influenza virus, both in cell cultures and in a normal human respiratory-epithelial cell line. Also, upon adding supplemental glutathione to the drinking water of mice inoculated with a non-lethal dose of influenza they found that it inhibited viral presence in trachea and lung. This was probably due to an increased presence of glutathione in oral, nasal, or upper-airway epithelium, rather than in lung tissue.

With aging, total glutathione levels normally decrease. However, a recent study has found this not to be true with centenarians, who were found to have similar levels to those of young adults.11 The better preservation of antioxidant systems in centenarians could play a key role in the longevity of these subjects.

Glutathione is made in the body from the amino acid L-cysteine. The way that NAC is used by the body to make glutathione requires that it be deacetylated to cysteine. Durk Pearson & Sandy Shaw take L-cysteine supplements rather than NAC as part of their daily personal regimen. See Life Extension News ( Vol. 5 No. 5, Oct. 2002) explaining why they use cysteine rather than NAC. It is important to take vitamin C to help prevent cysteine from being oxidized to insoluble cystine in your kidneys and urinary bladder.

Vitamin D Fights Infections and Operates to Strengthen Immunity

Researchers have found that the innate immune response to injury—the recognition of bacterial invasion and the production of antimicrobial peptides—operates through a vitamin D-dependent mechanism.12 The discovery was made when the scientists investigated which genes are influenced by vitamin D3 during wound repair. When injury occurs, there is a local increase in vitamin D3-signaling in skin.

An earlier paper had investigated pattern-recognition receptor activation in human macrophages, the white-blood cells that engulf and digest cellular debris and pathogens, stimulating immune cells to respond to the pathogen.13 The researchers found that Toll-like receptor activation up-regulated the expression of the vitamin D receptor and the vitamin D1-hydroxylase genes, resulting in the induction of the antimicrobial peptide cathelicidin. The cathelicidin killed intracellular Mycobacterium tuberculosis.*


*It has long been known that tuberculosis patients do better when exposed to sunlight, which increases the production of vitamin D. Here, at last is proof of the mechanism.


The Immune System of Self Defense

The best offense is a good defense. How many times have you heard that? Well it’s true, especially when it comes to infectious agents. During our lives, we are constantly exposed to invading pathogens and, in most cases, we successfully resist and destroy them before significant injury is done to us (we are the unwilling hosts). However, when we don’t beat them down at the gates, the result can be extended bouts of misery and serious downtime. Fortunately, we are bestowed with an immune system that enables each of us to overpower those nasty aggressors, and stay healthy or recover rapidly.

The immune system is comprised of innumerable biological defenses designed by evolution to distinguish between pathogens or abnormal cells and healthy host cells, and to avoid or diminish infection, disease, and other consequences of invasion by bacteria, fungi, protozoa, and viruses. It does this by generating an unimaginably large number of cells and molecules to attack, defend, and dismantle what appears to be a limitless variety of foreign invaders, all without damaging the host. Furthermore, these internally generated cells and molecules work closely together dynamically in a mind-boggling ballet of intricacy.

All immune activities can be thought of as involving recognition and response. They are two major subdivisions, the innate immune system and the adaptive immune system. The innate immune system is nonspecific regarding the type of organism it fights; it mobilizes readily at the first signs of infection. Its reactions are given. The adaptive immune system is specific to the invading pathogen and is slower to respond because it must first custom-tailor its response. Also setting it apart, the adaptive system “remembers” antigens through its encounters; it acquires immunity that is not given. This enables it to react more quickly and efficiently when next time that antigen is met. Thus the adaptive system protects against re-exposure to the same pathogen. You can think of the innate immune system as our first line of defense against invading organisms, and the adaptive immune system, as our second line of defense.

While the two branches of the immune system have separate functions, there are many interactions between them. Mechanisms of the innate system influence the adaptive system and vice versa. The nonspecific mechanisms act both as barriers to and eliminators of a large range of pathogens, without regard to antigenic specificity. The specific mechanisms of the immune system adapt themselves to each new disease encountered and are able to generate pathogen-specific immunity. Specific immune response mechanisms supplement and enhance the nonspecific defense mechanisms, producing a more robust total response.

Naturally acquired immunity occurs through contact with a disease causing agent—when the contact was not deliberate—whereas artificially acquired immunity develops only through deliberate actions such as vaccination. Both naturally and artificially acquired immunity can be further subdivided depending on whether immunity is induced in the host or passively transferred from an immune host. Passive immunity is acquired through the transfer of antibodies or activated T-cells from an immune host, and is short lived, usually lasting only a few months. Whereas active immunity is induced in the host itself by an antigen, and lasts much longer; it is sometimes life-long.

Each of the two major subdivisions of the immune system possesses humoral and cellular components by which they carry out their protective function. Humoral immunity is mediated by secreted antibodies which bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), flagging them for destruction. Cellular immunity involves T lymphocytes, which are produced in the B cells, and protects against intracellular bacteria, viruses and cancer. It is also responsible for graft rejection.

Furthermore, this demonstrated that pattern-recognition receptor stimulation induces: 1) the enzyme that catalyzes conversion of vitamin D to its active form; 2) the expression of the vitamin D receptor; and 3) the relevant downstream targets of the vitamin D receptor (including cathelicidin). These results explain “the action of vitamin D as a key link between [pattern-recognition receptor activation] and certain antibacterial responses in innate immunity.” Tipping their hats to the importance of vitamin D levels, the authors suggest that the innate differences in the efficiency with which human populations produce vitamin D may increase susceptibility to microbial infections.

In another report,14 the vitamin D receptor was found to be required for the development of natural killer T cells, which are important cells in immune regulation, tumor surveillance, and host defense against pathogens.

Finally, in a human study, a single dose of vitamin D was found to enhance immunity to tuberculosis.15 This double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks. Based on the immune enhancement findings, the authors suggested that clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent tuberculosis infection.

Seasonal Flu Shots May Protect Against Bird Flu

One of the really scary influenzas still in the news is the bird flu. While this deadly virus can currently be transmitted to humans, it is not currently contagious. Perhaps it will never cross over to humans, but if it does, we will need every level of defense obtainable. A recent paper found that there may be increased immune response to bird flu in people who received seasonal flu shots.16 This is because of what is known as cross-reactivity.


Street car conductor in Seattle not allowing passengers aboard without a mask during the Spanish flu pandemic.

Obey the laws/And wear the gauze.
Protect your jaws/From septic paws.

— Public service poem, ca. 1918

The researchers evaluated cell-mediated immunity in 42 Roman healthcare workers, who had received seasonal flu shots. When their peripheral blood cells were isolated and then stimulated with a synthetic influenza of the bird flu variety, a large number of the subjects were significantly more able to deactivate the influenza. The authors concluded that “Our findings indicate that seasonal vaccination can raise neutralizing immunity against [bird] influenza (H5N1) which shows the existence of an antibody-dependent cross-type immunity.”

Other Ways to Minimize Vulnerability to the Flu

As a final word of caution, avoid public places as the epidemic heats up and wash your hands often and use disinfectant wipes on commonly used telephones, remote controls, computer keyboards, and the like. During the Spanish Flu of 1918, when advanced notice was given and parades and other public gatherings were canceled, contagion went down by as much as 50% and there were far fewer deaths. It is also a good idea to avoid close contact with sick people, get plenty of sleep, eat well, and exercise regularly (but wipe down equipment with disinfectant wipes if you use a public gym). Reducing stress may also bolster immunity. Furthermore, don’t smoke; smokers are more vulnerable to the flu. And take the supplements recommended in this article.

References

  1. Lowen AC, Mubareka S, Steel J, Palese P. Influenza virus transmission is dependent on relative humidity and temperature. PLoS Pathog 2007 Oct 19;3(10):1470-6.
  2. Is global warming on the wane? The Old Farmer’s Almanac—National Edition 2009;217:68-79.
  3. Ginsberg J, Mohebbi MH, Patel RS, Brammer L, Smolinski MS, Brilliant L. Detecting influenza epidemics using search engine query data. Nature 2008 Nov 19. [Epub ahead of print]
  4. Fox M. U.S. flu shows resistance to flu drug, CDC says. Reuters Health report, December 19, 2008.
  5. Fehlbaum P, Rao M, Zasloff M, Anderson GM. An essential amino acid induces epithelial beta-defensin expression. Proc Natl Acad Sci USA 2000 Nov 7;97(23):12723-8.
  6. Sherman H, Chapnik N, Froy O. Albumin and amino acids upregulate the expression of human beta-defensin 1. Mol Immunol 2006 Apr;43(10):1617-23.
  7. Bukowski JF, Percival SS. L-theanine intervention enhances human gammadeltaT lymphocyte function. Nutr Rev 2008 Feb;66(2):96-102.
  8. Rowe CA, Nantz MP, Bukowski JF, Percival SS. Specific formulation of Camellia sinensis prevents cold and flu symptoms and enhances gamma delta T cell function: a randomized, double-blind, placebo-controlled study. J Am Coll Nutr 2007 Oct;26(5):445-52.
  9. De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997 Jul;10(7):1535-41.
  10. Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. Inhibition of influenza infection by glutathione. Free Radic Biol Med 2003 Apr 1;34(7):928-36.
  11. Alonso-Fernández P, Puerto M, Maté I, Ribera JM, de la Fuente M. Neutrophils of centenarians show function levels similar to those of young adults. J Am Geriatr Soc 2008 Dec;56(12):2244-51.
  12. Schauber J, Dorschner RA, Coda AB, Büchau AS, Liu PT, Kiken D, Helfrich YR, Kang S, Elalieh HZ, Steinmeyer A, Zügel U, Bikle DD, Modlin RL, Gallo RL. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 2007; 117(3):803-11.
  13. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311(5768):1770-3.
  14. Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci USA 2008;105(13):5207-12.
  15. Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, Packe GE, Davidson RN, Eldridge SM, Maunsell ZJ, Rainbow SJ, Berry JL, Griffiths CJ. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 2007 Jul 15;176(2):208-13.
  16. Gioia C, Castilletti C, Tempestilli M, Piacentini P, Bordi L, Chiappini R, Agrati C, Squarcione S, Ippolito G, Puro V, Capobianchi MR, Poccia F. Cross-subtype immunity against avian influenza in persons recently vaccinated for influenza. Emerg Infect Dis 2008 Jan;14(1):121-8.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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