Immune Threats

Dr Paul Clayton, Medical Pharmacologist, Former President of the Forum on Food and Health at the Royal Society of Medicine

Immune system threats

Each day you inhale millions of germs (bacteria and viruses) that are floating in the air. And there are millions more already in your body. Your immune system normally deals with all of them without a problem.

Occasionally, however, a germ or virus gets past the immune system and you catch a cold, the flu, or get food poisoning. A cold or flu is a visible sign that your immune system failed to stop the germ. If your immune system was not working, you would never recover from a cold – or anything else.

To understand the power of the immune system, all you have to do is look at what happens to an animal when it dies. On death, the immune system (along with everything else) shuts down. In a matter of hours, the body is assaulted by all sorts of bacteria, microbes, and parasites. Few of these are able to cause damage when the immune system is working properly, but the moment an immune system stops, the defences crumble and it only takes a few weeks for these organisms to completely dismantle the body.

So ensuring that your immune system is in optimum condition is a key element in ‘healthy longevity’. Especially in view of the increased threats we now face.

Real threat of a new flu pandemic

Newspapers like a good scare story and headlines of a potential global pandemic derived from some form of flu have become regular features.

The US Secretary of Health and Human Services Michael Leavitt has said, “The threat is both real and formidable.” The World Health Organisation has complained that failure of scientists from different countries to share research data on the flu virus is putting millions of lives at risk.

The UK’s Chief Medical Officer’s website currently states, “Wherever in the world a flu pandemic starts, perhaps with its epicentre in the Far East, we must assume we will be unable to prevent it reaching the UK. When it does, its impact will be severe in the number of illnesses and the disruption to everyday life.” Sir Liam Donaldson, Chief Medical Officer

Even the normally conservative Times newspaper is on record as saying that, “Public health officials in Britain are working on a new contingency plan. The fears are that when – rather than if – a pandemic emerges, hospitals will be overwhelmed, businesses will falter, public transport will be halted and facilities for burying the dead will prove inadequate.”

Asian avian flu – or strain H5N1 – has crossed over from birds to humans in only a few cases so far, in the Far East. But if the strain mutates human to human, transmission will become easier, the global pandemic will start, and the warnings will become reality.

Asian bird flu is a serious threat. But so are a host of bacterial infections that used to be, until recently, managed with antibiotics.

Antibiotic resistance

Increasingly hospital super-bugs like MRSA and community infections such as multi-drug resistant TB, are becoming genuine threats. For the last half century we have relied on antibiotics to protect ourselves (from bacterial infections) – but that defence is starting to fall apart.

The use of antibiotics leads eventually to bacterial resistance, and the more antibiotics that are prescribed the greater the problem of resistance becomes. Bacteria have a very much shorter life cycle than ours, and can adapt very quickly to hostile (to them) environmental factors such as antibiotics.

Antibiotic resistance is partly due to doctors who over-prescribe, combined with poor infection control in some hospitals – a problem that has been flagged up lately in the UK.

But drug resistance is by no means the sole fault of the medical profession. Indiscriminate use of antibiotics in less-well-regulated parts of the globe is a major issue, as is the uncontrolled grey market in veterinary antibiotics in certain countries. Patients who do not take their antibiotics as instructed (who discontinue before the course is complete) bear an equally heavy responsibility, as do parents who insist on antibiotics for their children’s minor infections.

For example, the vast majority of coughs and colds are not caused by bacteria at all but by viruses, which cannot be treated with antibiotics. Nevertheless, nearly a half of children with common colds are treated with antibiotics (Nyquist et al ’98).

Because children catch an average of three to eight colds each year they may be given many courses of unnecessary antibiotics. And although doctors know that antibiotics will not help, they often find themselves prescribing them for demanding parents if only to reassure them that something – anything – is being done (CDC ‘98).

In fact children with colds, ear infections, sinus infections, bronchitis and sore throats account for a staggering three-quarters of all antibiotic prescriptions!

We are running out of pharmaceutical solutions

The result of all the above problems is that leading bacteriologists now believe that the world may already be running out of effective antibiotics, with a gap of five years or more before new drugs can be developed to combat the so-called ‘superbugs.’

The warning that the age of infectious disease control is coming to an end was issued in early 2005 by one of the world’s most influential scientists, Professor George Poste, an advisor to the US president. “Frankly, most governments are asleep at the switch,” he said in a recent interview, “even though we are facing a relentless increase in antibiotic resistance across all classes of drug.”

In UK clinical circles the bacteria causing most concern are MRSA (Methycillin-Resistant Staph Aureus), bacteria which are resistant not only to methycillin but to many other antibiotics besides. Some strains are now resistant to all commonly used antibiotics.

Other organisms, however, are potentially even more serious. Multidrug-resistant Mycobacterium tuberculosis (MDR-TB), which is resistant to the most powerful anti-tuberculous drugs, is one of these. Viruses such as HIV are showing even more rapid increases in drug resistance, for the same reasons.

Flu scares

At the end of 2005 the WHO issued a stark warning of a pending flu global epidemic (or pandemic). Said spokesperson Klaus Stohr, of the World Health Organisation’s Global Influenza Programme: ‘There will be another pandemic. In the best case we expect billions to fall ill, with 2 to 7 million deaths – but it could be far worse.’

Why are people like Stohr so convinced that there will be a global spread? Because history shows that flu pandemics occur every 30 years or so. After this time, the genetic makeup of a flu virus has changed so much that the human population has little or no immunity built up from previous strains. ‘Herd immunity’, as it is known, has become compromised.

There were three pandemics in the 20th century; all spread worldwide within a year of being detected. The Spanish flu in 1918-19 killed up to 50 million people. In the ’50s the Asian flu pandemic killed a million, and in ’68 Hong Kong flu killed another million or so.

That was over 40 years ago – so we’re overdue for the next one.

How a virus multiplies

Antibiotics are no use in treating viral infections, and the right vaccines to protect us against any particular strain of flu take 5-10 years to develop.

Our ability to deal with the fall-out of a contagious and highly lethal viral epidemic is, realistically, inadequate. And the efficacy of the anti-virals, which was never very high, is being seriously undermined by government-backed schemes in China to give amantadine, a human anti-viral drug, to infected flocks of poultry. Nothing is more likely to breed new drug-resistant viruses, and the WHO has asked for urgent ‘clarification’.

Let us assume, however, that the anti-viral drugs are still at least partially effective when the time comes, and the emergency plans actually work. One in four people deemed sufficiently important (the army, police, medical personnel and the political classes) may be protected. What should the rest of us, the expendable folk, do?

And, even if we escape bird flu, what should we do to protect ourselves against the pending bacterial epidemics which, once the antibiotics finally run out of road, will become the main causes of disease and death as they were in the pre-antibiotic era?

To understand what we can do to best defend ourselves, we need to explore a little biology.

The two immune systems

The immune system can be divided into two distinct sub-systems: the innate and the acquired immune systems.

The acquired immune system is the one with the ‘memory function’, and is involved in immunisation, allergy and auto-immunity. Once the acquired immune system has learned to recognise an enemy (after an initial infection or after vaccination), it remembers the enemy’s characteristics. On second exposure to the threat the memory cells recognise it, and generate an immune response involving highly specific weapons such as antibodies.

It is the acquired immune system which is stimulated by injections – against, for example, measles or whooping cough. Giving a small amount of a safe version of the pathogen (ie. infectious agent) creates an immunological ‘memory’ so that when faced with a ‘real’ attack, the body can quickly mobilise a specific defence.

This is a powerful, sophisticated and highly specific system, but it is slow to mount and often insufficient to protect the host against the first onslaught of a virulent bacterium or virus. And, of course it only works against a threat that it has experienced before. In the case of bird flu, for example, the more a virus has mutated, the less effective the vaccination.

The innate immune system is rather more basic. In evolutionary terms it is much older than the more sophisticated acquired immune system. It is less specific; and its key components are macrophages and Natural Killer (NK) cells.

Broadly, these patrol the body and look out for anything that doesn’t belong there. If macrophages spot a bacterium, they swallow it whole and try to digest it.

If NK cells recognise a virally infected cell or a cancer cell in the body they will kill it so that it cannot produce more viruses, or replicate.

Unlike the acquired immune system, the innate immune system is on constant alert. It springs into action the moment it recognises the presence of a pathogen. It is our first line of defence, while the acquired immune system is the second line.

As the numbers of antibiotic resistant bacteria in our environment continue to increase, and the flu pandemic approaches, it makes good sense to ensure that your innate immune system is working as effectively as possible.

Unfortunately there is increasing evidence that both lines of defence – the acquired and the innate immune systems – are often below par due to Type B malnutrition: a pattern of multiple micronutrient depletion, caused by our modern lifestyles, which degrades the ability of our immune systems to protect us against infection.

Why our innate immune systems may be weaker than before

The best defence against infection of any sort is, as Louis Pasteur realised, a healthy host defence or immune system. This means that our best hope of remaining uninfected by infection, seasonal flu, bird flu or a super-bug is to ensure that our own immune systems are in good condition. Sadly, the evidence shows that in many cases our immune systems are well below par.

This is well documented, and the reasons are clearly understood. They include …

1. Immunosuppressant medications – such as oral steroids, and most anti-cancer drugs.
2. HIV infection
3. Chronic stress, which drives up levels of natural steroids in the body
4. Chronic depression – which has a similar impact on steroid levels
5. Over-exercise (although this probably only affects marathon runners and other serious athletes)
6. Under-exercise (far more common!)
7. Diabetes (rapidly becoming an epidemic of its own)
8. Nutritional depletion – sub-optimal intake of vitamins, minerals, trace elements and other nutrients, sometimes called Type B Malnutrition.
9. The success of our own health and safety standards!

It is difficult to rank these factors accurately, but last three are probably the most important in the developed nations. In particular:

Type B malnutrition (multiple micronutrient depletion) is probably the most prevalent cause of impaired immunity. Recent studies of hospital patients found that that a staggering 60% of them were malnourished on admission (Gallagher-Allred et al ‘96). Malnourished in this case means depleted in several essential vitamins and minerals.

In 30 to 40% of patients, the malnutrition was sufficiently severe to cause lymphopenia (Bistrian et al ’76, Naber et al ‘97) a condition in which numbers of white blood cells are significantly sub-normal. This indicates substantial immuno-suppression, and a significantly increased risk of acquiring an infection while in hospital.

Hospital admissions are by definition unhealthy people, and the criticism has been raised that the findings of malnutrition in this group do not reflect the situation in the community. However, similar findings have been reported in the wider community.

Sub-optimal immune function is now common in elderly (Chandra ’97, Edington et al ’99) and in middle-aged subjects (Chandra ‘02). As with the hospital patients, however, their impaired immune systems can be improved and brought back to normal with well designed supplement programmes; both the elderly (Chandra ’92, Bogden ’94, Chandra ’97, Meydani ’97, Jain ’02) and middle-aged subjects (Chandra ‘02) respond positively to supplementation. (See my book Health Defence and/or www.healthdefence.com)

Another reason for our generally sub-optimal immune systems is rather counter-intuitive. Over the last 50 years every home has acquired a fridge and deep freezer and although our supermarket-bought ready-meals may sometimes contain excessive fat, sugar and salt, they are produced, transported and distributed in exceptionally clean environments.

Compared to the old days when we ate many foods that were on the cusp of ‘going off’, there is relatively little in our food now to challenge our immune systems.

For this reason, it has been suggested that our innate immune systems are less active than they were designed to be; which has lead some to use immuno-stimulants such as echinacea to try to ward off colds and other infections.

How can we boost our immune systems?

So far it has been doom and gloom. But there is something we can do.

A well-designed comprehensive supplement is a good foundation. It should include optimum levels of all the classical vitamins and minerals which are important in supporting the immune system generally; and the newer micro- and phyto-nutrients such as betaine, Q10, beta carotene, lycopene, lutein and the flavonoids.

Onto that foundation you can add a second layer of very specific innate immune support agents. Chief amongst these in my opinion should be the plant extract beta-sitosterol, and especially the 1-3, 1-6 beta glucans derived in the main from yeast.

Beta sitosterol

Beta sitosterol is one example of a group of molecules called sterols, which can be regarded as the plant kingdom’s equivalent of cholesterol. Present in a large number of plant foods, dietary intakes of sterols have fallen due to changes in the way we eat. As beta sitosterol is an immuno-modulator (it up-regulates certain aspects of immune function while down-regulating others), the removal of this and the other sterols from our diets and hence our bodies has had profound consequences on our health.

One effect of lower intakes of beta sitosterol appears to be to make us more prone to allergy and auto-immune disorders; replacing it in the diet can ‘quieten’ auto-immune responses, and recently beta sitosterol has become popular as the anti-asthma supplement Moducare.

As beta sitosterol increases Natural Killer (NK) cell activity (Bouic et al ’96), beta sitosterol depletion presumably leaves NK cells under-active, thus contributing to an overall degradation of the innate immune system.

1,3 1,6 Beta glucans

Of all the natural compounds known to activate the innate immune system, the best documented and most effective are the 1-3, 1-6 beta glucans, generally derived from baker’s or brewer’s yeast (Kernodle et al ’98, Wakshull et al ‘99). These molecules activate the innate immune system very strongly indeed; in humans and other mammals, and in birds and fish. (Mansell et al ’75, Hahn & Albersheim ’78, Robertsen et al ’94, Song & Hsieh ‘94).

Macrophages have receptors which specifically recognise 1-3, 1-6 beta glucans (Czop & Austen ’85), because they occur in the cell walls of many bacteria and fungi. This means that when you ingest beta glucans, your innate immune system thinks, not unreasonably, that an enemy has arrived and it rises to the challenge.

Here is the main sequence showing how 1-3 1-6 beta glucans work.

[with thanks to Biothera – a company which has spent years researching beta glucans and is the manufacturer of a patented source of 1-3, 1-6 beta glucans (WGP 3-6) which has in turn been subjected to a significant number of clinical trials]

1. Once swallowed, the whole 1-3, 1-6 beta glucans pass through the stomach into the small intestine where they are taken up by specialised regions called the Peyer’s Patches.

2. Specialised cells called M cells transport the whole beta-glucans particles to macrophages.

3. These whole beta glucans are then transported by the macrophages to immune organs throughout the body.

4. The macrophages break down the beta glucans 1-3, 1-6 into smaller particles. These active fragments then bind or lock onto the surface of neutrophils – which are the most abundant immune cells in the body. They lock on to a receptor called CR3 – (Complement Receptor 3). The neutrophil is now activated or ‘primed’ and ready to seek out foreign challengers or pathogens.

5. For a neutrophil to kill a foreign challenger – pathogen – the CR3 receptor (Complement Receptor 3) must be “occupied” by both complement – a blood protein – and beta glucan. This ‘occupancy’ occurs naturally in the presence of some pathogens – eg fungal infections. But in other challenges, including many infectious disease and cancer, beta glucan is not present.

6. A fully primed neutrophil can now migrate to the site of a pathogen (virus or bacterium) through a process called chemotaxis. The neutrophil binds to the surface of the pathogen and recognises it as ‘non-self’ ie foreign. It is now able to destroy that pathogen by releasing toxic chemicals.

7. At the same time, other killer cells retain fragments of the pathogens (ie. foreign invaders) that they have destroyed and ‘present’ them on their surface. These send signals to other members of the immune system family, which become memory cells.

Next time the same virus or pathogen is encountered, these newly programmed memory cells will recognise the virus and produce antibodies. These antibodies stick to the surface of the virus and prevent it from infecting healthy cells.

Therefore by initiating this sequence, beta glucans may also indirectly assist the functioning of the Acquired Immune System.

Beta glucans can boost the body’s defences against cancer
Of particular interest is the potential use of 1-3, 1-6 beta glucans in cancer treatment. Innate immune cells do not always recognise cancer cells as non-self and therefore do not attack the cancer cells – because they see them as ‘self’.

However when beta glucan is present – (together with complement) – on the CR3 receptor sites of a neutrophil, that neutrophil is then primed and can recognise the cancer cell as non-self and attack it.

In this way beta glucans may well enhance the effect of cancer drugs, especially monoclonal antibody drugs. This a prime objective of Biothera’s research which already shows encouraging results.

More about beta glucan 1,3 1,6

Sources
Beta glucans and similar molecules occur in several plants with a history of medicinal use such as aloe vera, Echinacea and fungi such as the shiitake mushrooms; but these are not as good or as consistent sources as brewer’s yeast (Goldman ’88).

The molecular size of the beta glucans also appears to be important. Particles of 2-6 microns in size appear to be most effective in binding to macrophage beta glucan receptors, and ‘waking up’ the innate immune system.

Non-allergenic
Many people have concerns about yeast. They were told by well-meaning therapists to avoid brewer’s yeast because it increases the risk of candida infections. Others believe, rightly or wrongly, that they are allergic to it.

These concerns are baseless. The candida story was popularised by untrained therapists who mistakenly believed that brewer’s yeast and candida were related species – whereas in fact they are totally unrelated! And although allergy to yeast can occur, correctly purified beta glucan preparations are free of yeast mannoprotein – which is the part that can cause an allergenic reaction – and are hypo-allergenic.

Beta glucans do not trigger allergic and auto-immune symptoms because they do not stimulate the acquired (or ‘learned’) immune system, our second line of immune defence, which is involved in those types of problems (Washburn et al ‘96). And perhaps because they have always been in our environment, these valuable compounds are completely non-toxic (Williams et al ’88, Acute Oral Toxicity Study ‘90). This was accepted by the FDA, which designates Baker’s Yeast as GRAS (Generally Recognised As Safe).

Impossible to take too much
And finally, beta glucans WGP 3-6 mode of action makes over-use almost impossible. It primes neutrophils to make them more effective and the average life of a neutrophil is not much more than 1-3 days. On the other hand, products like echinacea work by stimulating the whole immune system and should only be taken for limited periods – otherwise they can create what has been termed cytokine inflammation, which can be counter-productive. Although the distinction between priming and stimulating may seem to be minor – it is in fact important.

Extensively tested – and rated top
Infection: The beta glucans’ ability to activate macrophages and prime neutrophils has been extensively tested (Rasmussen et al ’85, ’87, ’89, ’90, ’91, ‘92); and has been shown to protect animals such as mice against otherwise fatal infections (Williams & Deluzio ’78, ’79, ’80, Leibovich & Danon ’80, Lahnborg et al ’82, Deluzio & Williams ’83, Rasmussen & Seljelid ’91, Tzianabos & Cisneros ’96).

In fact in a pre-clinical trial conducted by Patchen – now at Biothera – 90% of mice exposed to very high levels of E-coli survived when their innate immune systems were primed by 1-3, 1-6 beta-glucans. 0% survived in the control group.

In a further test 80% survived exposure to high levels of Staphylococcus aureus as opposed to 0% in the control group.

Yet further studies on influenza showed the same pattern – ie a high proportion of test subjects who received beta glucan prophylactically 7 days before exposure survived, and none of untreated animals survived. (R Mandeville Biophage Pharma Inc.)

Trials have also shown the same protective effects in human infections. (de Felipe ’93, Babineau & Hackford ‘94, Barbineau & Marcello ‘94, Dellinger et al ’99). In fact when beta glucans was administered in combination with anti-biotics after exposure to bacteria, the number of bacteria needed to actually create infection was increased 10 – 2,000 fold.

Bacterial exposure: A particularly interesting experiment was conducted by the Department of Defence of a major NATO country. Mice were given a daily dose of WGP 1-3, 1-6 beta glucans seven days before being exposed to a lethal dose of anthrax. About half of the untreated control subjects died after 7 days, whilst 100% of the beta glucans sample survived. In a further study over 80% survived (as opposed to 30%) even when the beta glucans was only taken after exposure to anthrax.

Radiation hazards: Finally 1-3, 16 beta glucans have been shown to stimulate the replenishment of white blood cells after exposure to radiation – which of course happens to patients undergoing radiation therapy, who often have a lower white blood cell count than normal. Less obviously it also happens to air travellers – who are exposed to much higher levels of cosmic radiation than at sea level, because much of the radiation is absorbed by the atmosphere before it reaches the ground.

Again animal studies showed that when 1-3, 1-6 beta glucans was given at the same time as a normally lethal dose of radiation, over 50% of the sample survived in contrast to 100% mortality amongst mice within 15 days, who were not given beta glucans. The deaths were due to the fact that radiation normally sharply reduces white blood cell count and leaves the patient vulnerable to infection. (Patchen, ABTI) (University of Louisville 2005)

The army, however, was taking careful note. Starting in the late ’80s, they ran an exhaustive test programme to measure the immuno-protective effects of beta glucans and over 100 other immuno-stimulants. As recently as 2004 they reported that the purified beta glucans were the most effective of them all. Not only did they protect against infection with bacteria, viruses and fungi, they also conferred protection against radiation injury (Patchen et al ’87, Patchen & McVittie ’85).

Given that soldiers may at any time face an unpredictable range of biological weapons and even, in the worst case, radiation, I understand the US army is planning to stock-pile beta glucans.

Safe for widespread use in adults and children
I personally think that these valuable compounds are too good to be left to the armed forces. As the age of antibiotics wanes and specific threats continue to advance, I have put up a store of purified beta glucans on the top kitchen shelf. When the time comes I will take them and give them to my children, at a dose of 250 mg of per day.

For some people and for some occasions, I would not even wait. Athletes engaged in high intensity training, people under significant stress and probably night workers with interrupted sleep patterns would benefit. There is also a good case for prophylactic use before a hospital visit, before airline travel and before the flu season in any year.

The safety of any nutrient is paramount. Food derived nutrients are, in principle, normally safer than artificially created pharmaceutical molecules, precisely because they are natural and have mostly been consumed for centuries. You will also notice that I have almost always worked with, and/or recommended food derived nutrients rather than herbs, because the latter are generally subjected to less tests and are not always standardised.

Since 1-3, 1-6 beta glucans is derived from Brewer’s or Baker’s Yeast it is, prima facie, safe. It has also been taken in human trials at both twice the recommended dose of 250 mg a day for 20 days and also at 30 times the same recommended dose – with no adverse effects. Animal experiments have shown no adverse effects at 50 times the recommended dose for over 90 days.

Beta glucans do not trigger allergic and auto-immune symptoms because they do not stimulate the acquired (or ‘learned’) immune system, our second line of immune defence, which is involved in those types of problems (Washburn et al ‘96). And perhaps because they have always been in our environment, these valuable compounds are completely non-toxic (Williams et al ’88, Acute Oral Toxicity Study ‘90).

There are several suppliers mentioned on the internet, but I have chosen the supplier who I have chosen to consult for, because they have combined their 1-3, 1-6 beta-glucans with beta-sitosterol. Their source of beta-glucans is also patented (Biothera’s WGP) and has been the most extensively tested – some 200 clinical trials in total.

A less technical alternative is dried brewer’s yeast, which can be eaten sprinkled over breakfast cereal or mixed into soups or stews. The therapeutic dose is around one tablespoonful per day. However it is a distinctly acquired taste! And sadly for beer aficionados, levels of beta glucans in most brews are far too low to provide any benefit!

NB. If you intend to eat brewer’s yeast, it should be microwaved before use, as it may otherwise ferment in your stomach! And it will contain the allergenic part i.e mannoprotein.

The beta-glucans/beta sitosterol combination is available from Uni-Vite Healthcare Ltd at www.immunoshield.com.

Finally I need to point out that 1-3, 1-6 beta glucans purified from yeast is completely different from oat beta glucans. Oat beta glucans can help, at certain levels, to lower cholesterol.