午夜福利1000集合

AS THE mother of a child with severe allergies, Jana Robertson knows only too well that sometimes even constant vigilance isn鈥檛 enough. Recently her 16-year-old son Ian, who is allergic to several foods including dairy products and peanuts, was planning to go to a pizza restaurant with friends. A few days in advance, Jana tracked down ingredient lists for everything her son would be eating on his night out. She had been checking ingredients ever since he was rushed to hospital at 11 months of age after suffering a severe reaction to soy formula.

This time everything was fine 鈥� or so she thought. But on the way home from the pizza parlour Ian complained of itchiness. When his forehead and lips began to swell his parents rushed him to hospital where doctors pumped him with epinephrine and intravenous fluids. He was in the early stages of anaphylactic shock, a severe allergic reaction which if left untreated can lead to death.

A few days after this close call an allergy specialist gave Ian a skin-prick test using an extract from the leftovers of the (cheese-free) pizza he had eaten. It was positive. Jana now suspects the culprit may have been the bacterial 鈥渟tarter culture鈥� used to ferment the pepperoni for the topping. But she doesn鈥檛 know for sure. What she does know is that her son, who also has asthma and sometimes severe eczema, is suffering. 鈥淵ou can tell he鈥檚 really frustrated by it,鈥� she says. 鈥淗e鈥檚 always asking, 鈥榳hy is my body freaking out on me?'鈥�

Ian, of course, is not alone. Some 300 million people now suffer from asthma, and their ranks are expected to swell by another 100 million over the next 20 years, according to a 2004 report by the Global Initiative for Asthma, a programme launched in 1993 by US health agencies and the World 午夜福利1000集合 Organization. Some 40 per cent of American children have allergic rhinitis, which includes hay fever and perennial allergies to substances such as dust mites and cat dander. Eczema is thought to affect more than 15 per cent of children in Europe and the US and an even higher proportion in Japan. Food allergies appear to be on the rise as well. A UK study on the Isle of Wight found that the number of children with peanut allergy tripled between 1989 and 1996, while another study published a little over a year ago by researchers at Mount Sinai School of Medicine in New York city found that peanut allergies among American children nationwide doubled between 1997 and 2002. What is happening?

For decades scientists have been frustrated in their attempts to explain the increases. Recently, however, major breakthroughs in the field of immunology have enabled researchers to probe more deeply into the circuitry underlying the body鈥檚 defence mechanisms. They are finding evidence that the allergy epidemic may be due to a fundamental breakdown in the immune system鈥檚 ability to regulate its own strength. What鈥檚 more, this same malfunction may be behind the rise in a host of other immune-related diseases 鈥� a list that includes autoimmune diseases such as type 1 diabetes and multiple sclerosis, and inflammatory bowel diseases such as Crohn鈥檚 disease and ulcerative colitis.

These insights are forcing a rethink of the 鈥渉ygiene hypothesis鈥�, currently the most plausible explanation for an overactive immune system. Initially researchers suspected the rise in allergic diseases was a price the industrialised world was paying for the elimination of serious childhood infections, which occurred during the last century largely due to improved hygiene and the development of vaccines and antibiotics. By reducing our exposure to these long-time nemeses, we鈥檇 left the battle-ready immune system with no enemies to fight.

But now the evidence suggests that it鈥檚 not exposure to its old enemies that the immune system is missing, but exposure to certain old friends 鈥� the hordes of harmless microbes that come into contact with the body鈥檚 defences on a daily basis and that over the course of evolution may have played a key role in teaching the immune system how to keep its highly aggressive nature under control.

The good news is that recent breakthroughs offer hope of treatments that may eventually provide relief for the millions of people afflicted with these diseases. The bad news is the realisation that modern humans have fallen into what appears to be a dangerous biological trap 鈥� a trap from which there seems no easy way out.

鈥淲e have fallen into a dangerous biological trap from which there seems no easy way out鈥�

Throughout the 1980s and 1990s researchers disagreed over whether there was even a problem. Some argued that the rises in asthma (see Graph) and hay fever were simply due to patients and doctors becoming more aware of every little sniffle and wheeze. But more rigorous studies have now shown the increases to be real. 鈥淭he debate is virtually dead,鈥� says Bengt Bj枚rkst茅n, a leading allergy researcher at the Karolinska Institute in Stockholm, Sweden.

Some researchers believe allergies have also become more severe. 鈥淲hat we鈥檙e seeing now is an increase in more complex allergy,鈥� says Stephen Holgate, a respiratory disease specialist from the University of Southampton in the UK, who has been studying allergies for nearly 25 years. He says combinations of food allergies, asthma and rhinitis are increasingly being seen in the same patient. 鈥淲e鈥檙e also seeing some unusual allergies coming through where people who become sensitised to birch pollen are also becoming sensitised to closely related proteins that are in certain foods, like apples and pears and potatoes and carrots,鈥� he says. 鈥淎bout five or six years ago this was unheard of. And yet it鈥檚 quite frequent now.鈥�

Although allergic diseases clearly have a genetic component, their rapid rise and peculiar distribution strongly suggest that environmental factors play a major role. Allergies are far more common in most western countries than in the developing world (see Map), and are more common in cities than in rural areas. Studies also show that allergies increase among immigrants who move to the west. In 2003, for example, Italian researchers at the Fatebenefratelli Hospital in Milan reported that among non-European immigrants treated at the hospital between 1994 and 2000, 84 per cent had never had symptoms before arriving in Europe (Clinical and Experimental Allergy vol 33, p 449). Asthma rates are also extremely high among African Americans, but low among Africans living in Africa.

And where western-style modernisation takes place, increases in allergies may not be far behind. In the early 1990s, a team led by Erika von Mutius at the University Children鈥檚 Hospital in Munich showed that allergy rates were much higher in what was then West Germany, than in East Germany. In 1997, however, von Mutius and her team reported that in the four years after reunification in 1990, hay fever rates in the former East German city of Leipzig more than doubled.

What was to blame? One explanation that gained currency in the 1980s was that people were simply being exposed to more dust mites and other allergy triggers with the increase in plush furniture and carpeting, coupled with the reduced air flow that results from double-glazed windows and proper insulation.

This idea has recently lost support, however, partly because the incidence of allergies has continued to rise in areas where such luxuries became common long ago, and partly because attempts to reduce children鈥檚 exposure to allergens have failed to prevent the disease. Other suspects, including increased exposure to air pollution, greater maternal stress, changes in diet, obesity, tobacco smoke and changes in breastfeeding patterns have also come under scrutiny. And while evidence suggests that such factors do have secondary roles in allergy, particularly in making sick people sicker, none appears to adequately explain the global trends associated with the diseases.

Protection by infection?

The possibility that high allergy rates have something to do with micro-organisms, meanwhile, has been around for decades. In the mid-1970s it was observed that allergies were lower among the Metis people of northern Saskatchewan, Canada, than among whites living in the central part of the province. The Metis also suffered from much greater rates of bacterial and viral infections, leading one local team of researchers to contemplate whether this high degree of illness offered some sort of protection. A series of studies during the 1980s suggested that allergies were less frequent among people who caught measles or other serious illnesses during childhood. In 1989, David Strachan, an epidemiologist at the London School of Hygiene and Tropical Medicine, coined the term 鈥渉ygiene hypothesis鈥�, arguing that modern immune systems were somehow under-primed because of the dramatic reduction in serious childhood infections.

Existing knowledge about the immune system seemed initially to support this idea. In the mid-1980s researchers identified a specialised subset of T-cells, known as helper T-cells, whose job it is to direct different types of immune responses. When they encounter a particular foreign molecule, T-helper-2 (Th2) cells send out signals that generate a class of antibodies that can bind to other immune cells and lead to the release of chemicals such as histamine. These potent molecules in turn trigger muscle contraction, mucus release and other tissue responses associated with diarrhoea or sneezing. It鈥檚 a strategy used against parasitic worms and also the immune response triggered during an allergy attack. Th1 cells, on the other hand, send out different signals that help the body to locate and destroy microbes that have invaded cells 鈥� including viruses and bacteria. The key, however, was the finding that Th2 signals have the ability to suppress Th1-type responses and vice versa. This led to suspicions that the human immune system, missing the stimulation of serious childhood bacterial and viral infections, becomes too ready to launch a Th2 response 鈥� and thus more prone to allergies.

But certain aspects of this idea didn鈥檛 quite fit. For one thing it made little sense from an evolutionary perspective that proper functioning of the immune system would depend on contact with micro-organisms that were potentially so dangerous. Another problem was the fact that autoimmune diseases involve a Th1 response. If the rise in allergies were the result of immune systems skewed towards Th2 responses, then one would expect to see a corresponding drop in autoimmune diseases as that branch of the immune system was suppressed. In fact, just the opposite is true. Similarly, since parasitic worms tend to boost the Th2 response, one might expect to see high rates of allergic diseases in areas where worms are a problem. But again, the reality is just the opposite.

A revised version of the hygiene hypothesis is now emerging, partly thanks to a discovery in 1995 by scientists at Kyoto University in Japan. Immunologist Shimon Sakaguchi and his team isolated a new subset of T-cells that appear to function exclusively as a brake on the immune system. Dubbed regulatory T-cells and now the focus of intense interest, these cells secrete chemical signals that stop both Th1 and Th2 responses in their tracks.

Not only that, but the failure of proper regulatory T-cell function now appears to play a major role in immune-related diseases. Last year, a team of European researchers led by Cezmi Akdis at the Swiss Institute of Allergy and Asthma Research in Davos reported a study in which they removed T-cells capable of recognising birch pollen, house dust mites, pear and hazelnuts from the blood of both healthy and allergic individuals. In the blood of allergic donors, the majority of these cells were shown to be Th2 cells. In the healthy blood, the majority were regulatory T-cells.

Another team of researchers led by Douglas Robinson, an immunologist at Imperial College in London, has demonstrated that regulatory T-cells seem to be less effective in people with allergies. The researchers removed regulatory T-cells from both allergic and non-allergic human blood. Without these cells, both samples exhibited an allergic-type response when presented with an allergen. When regulatory T-cells from the healthy blood were added to either mix, the response was toned down. But when the same experiment was done using regulatory T-cells from allergy sufferers, this braking effect was not detected.

An even more direct glimpse into the importance of regulatory T-cells has come from investigations into a human genetic disorder known as X-linked autoimmunity-allergic disregulation syndrome (XLAAD). The mutated gene responsible for this disease, plays a key role in the production of regulatory T-cells. Babies born with XLAAD rarely survive their first year. Among other problems they suffer from severe eczema, food allergies, intestinal inflammation and type 1 diabetes.

Holding fire

According to Graham Rook, an immunologist at Royal Free and University College Medical School in London, the discovery of regulatory T-cells is causing a fundamental shift in the way researchers view the body鈥檚 defences. 鈥淥ne tends to think of the immune system as doing nothing until provoked into action,鈥� says Rook. 鈥淚n fact, people are beginning to think just the opposite. The immune system is constantly having to be held back.鈥�

Work being done by several labs is now demonstrating that exposure to harmless micro-organisms can have a direct impact on how well the immune system is able to regulate itself. Rook and his colleagues had previously shown that mice with respiratory allergies get better when treated with dead Mycobacterium vaccae, a harmless bacterium commonly found in mud. Last year they reported that this effect is due to interactions between the M. vaccae and branched immune cells known as dendritic cells in the lungs of the mice, resulting in signals that boost the production of regulatory T-cells. Another group of researchers led by Eyal Raz at the University of California in San Diego showed last year how dendritic cells are able to recognise DNA from harmless bacteria such as the lactobacilli found in live yogurt, triggering an anti-inflammatory response that reduces symptoms in mice stricken with colitis.

These and other results now suggest that contact with the hordes of benign microbes encountered by the body on a daily basis 鈥� deemed largely irrelevant by immunologists in the past 鈥� may be an essential step on the infant immune system鈥檚 road to healthy maturity. Likewise they suggest that the shift to a western lifestyle may have short-circuited this development by cutting off the body鈥檚 contact with certain microbes. The key question now is which ones.

One focus of attention is the microbes that humans would have regularly encountered when they drank from streams and other untreated sources of water and came into regular contact with soil and animals. Indeed, studies in Europe, Australia and the US have consistently shown that children who grow up on a farm have a much smaller chance of developing allergies than kids growing up in a city, or even than those raised in a rural home that isn鈥檛 a farm. More recently a team of American and European scientists found that, compared with cribs in non-farm homes, the cribs of infants on farms contain greater quantities of endotoxin, a potent immune stimulatory molecule associated with many bacteria commonly found in dirt and in animal faeces. Similarly, endotoxin is also more common in the homes of healthy children than in the homes of children with allergies. Work is now focusing on why the risk of developing allergies seems to be particularly low among children fed unpasteurised milk and who were in frequent contact with cow sheds during their first year of life.

At the same time, Bj枚rkst茅n and his colleagues in Sweden have been investigating the microbes that normally live in or on the body, particularly those living in the gut. This is a huge site of contact with the microbial world 鈥� in an adult there is enough intestinal surface area to wallpaper a small room, every square micrometre a teeming microscopic zoo. In comparisons of gut microbes in babies from Sweden, where allergy rates are high, and those from neighbouring Estonia, where the rates are low, Bj枚rkst茅n has discovered that Estonian babies are normally colonised more rapidly and by a greater range of microbes. In addition, the mix of microbes changes more frequently over time. 鈥淪wedish babies tend to keep the same strains,鈥� says Bj枚rkst茅n. 鈥淭hat shows there is less exchange with the environment.鈥� This is particularly true of Lactobacillus and Bifidobacterium, two genera of lactic acid-producing bacteria long thought to be vital members of a healthy gut flora. In studies of Swedes, people with allergies tended to have a reduced variety of these types of bacteria.

鈥淭he shift to a western lifestyle may have short-circuited the infant immune system鈥檚 development鈥�

Even harmless microscopic worms may be important. In 2003, a multinational team headed by parasitologist Thomas Nutman of the US National Institutes of 午夜福利1000集合 reported a study of more than 2800 schoolchildren in Ecuador. It showed that allergies were less prevalent among the children infected with worms than among those who were parasite-free. Last year, researchers in the Netherlands reported a study from Gabon in which allergy rates rose among a group of children who were given worm-killing medication.

Many scientists are now convinced that better treatments for immune-related diseases lie just around the corner. In London, Rook鈥檚 group has already developed a vaccine from dead M. vaccae for treating eczema and asthma. The vaccine is now showing encouraging results in clinical trials. Other researchers are studying the effects of using live lactobacilli to treat children with eczema, allergic rhinitis, food allergies and inflammatory bowel diseases. There is even growing interest in using the eggs of worms such as the pig whipworm Trichuris suis 鈥� which cannot survive in humans as adult worms 鈥� to treat patients with colitis, type 1 diabetes and multiple sclerosis. In January, Joel Weinstock and his team at the University of Iowa in Iowa City reported that drinking a sports drink containing 2500 T. suis eggs once every three weeks for 24 weeks resulted in the disappearance of symptoms in 21 of 29 patients with Crohn鈥檚 disease.

An intricate trap

Prevention, however, is proving trickier. Despite recent attempts to manipulate the diets of mothers and infants, researchers still have no proven strategies for averting immune-related diseases. Feeding infants safe strains of lactobacilli has yielded mixed results. To find other microbes that may have a more dramatic effect, researchers would first have to test them on infants, which would be ethically unacceptable.

Another hurdle is the fact that how each human immune system gets programmed may depend not only on a vast array of external stimuli, but also on variation among a potentially large number of genes. Last year a team of American and European researchers headed by Fernando Martinez at the University of Arizona in Tucson reported a subtle variation in the gene for toll-like receptor 2 (TLR-2), a cell surface receptor on dendritic cells (see 鈥淎nswers from the front line鈥�). TLR-2 recognises endotoxin and other components of bacteria, parasites and yeast, and the variation identified by the team provides added protection from allergies for children living on farms. The same mutation, which the researchers speculate may result in more TLR-2 production and therefore enhanced immune regulation, had no effect in children who lived nearby but not on a farm. The team will report the discovery of a second mutation with a similar effect later this year.

鈥淚n the end it鈥檚 going to be a relatively complex but fascinating gene-environment interaction,鈥� says Martinez. A one-size-fits-all solution seems unlikely.

Despite these obstacles, Martinez and others remain confident that science will one day uncover a way to provide future generations with the immunological elixir that lurks in the cow sheds of Europe and America. 鈥淧eople on farms do live a completely different lifestyle,鈥� he says. 鈥淏ut they don鈥檛 live in caves, either.鈥� The mystery, he says, is that their lifestyle exposes them to something that leads to a five to tenfold decrease in their chances of getting asthma and allergies, but doesn鈥檛 increase their mortality or risk of sepsis or other severe infections.

And while such a discovery would be too late for Ian Robertson and the millions of other children struggling with allergies, it may not be too late for the millions to come. 鈥淲e can鈥檛 give up,鈥� says Martinez. 鈥淚f we do we鈥檙e simply condemning a whole generation.鈥�