BRAIN INJURY RESEARCH
Emory research offers new hope to those with brain injuries
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HEALTH AND MEDICINE / INFECTIOUS DISEASES OF PARASITES AND POLLEN
Why do so many of us suffer from useless allergies? The answers may lie in our body's efforts to protect us from unseen invasions by worms.
by Peter Radetsky
From the September 1993 issue; published online September 1, 1993
The tiny tropical island of Mauke is about as far as you can get from the rest of the world and about as close as you can get to paradise. It is a speck in the South Pacific, four miles long by two miles wide, fringed with windswept palms and ancient coral limestone reefs. Mauke is one of the Cook Islands, named for James Cook, the eighteenth-century British navigator who explored them. Its only connection to the outside world is a thrice-weekly plane from Rarotonga, the largest island of the group,
100 miles away. Almost all of Mauke’s 600 inhabitants are Polynesian. They fish the local waters, cultivate taro, banana, and breadfruit, and grow cash crops such as mango for export to New Zealand. On Sundays they congregate in their missionary-built churches for exuberant Maori celebrations of singing.
But there are less friendly residents on the island. One is a threadlike parasitic roundworm--a filarial worm--that is transferred from person to person by a mosquito, another of the island’s less pleasant occupants. The worms, in a tiny larval stage, crawl into their victim’s skin through the puncture made by the mosquito, migrate into the lymph nodes, then mate and produce more tiny offspring, which find their way into the bloodstream. In the process, the worms wreck the lymph system, which drains fluid from the body’s tissues, causing the massive fluid buildup that produces the painfully bloated limbs of elephantiasis.
It’s not just on Mauke that parasitic worms are unwelcome neighbors. Filarial worms of one sort or another, and their various cousins--hookworms, whipworms, pinworms, and flatworms--cause an immense amount of grief throughout the world. They affect more than 2 billion people, causing afflictions from elephantiasis to blindness to serious intestinal problems. At least 40 percent of the world’s population is infected by worms, says Eric Ottesen.
Ottesen ought to know--he is head of the Clinical Parasitology Section at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. But Ottesen is not just a parasitologist; he’s also an allergist. And that confluence of disciplines is what makes his involvement with the inhabitants of Mauke downright intriguing. Nineteen years ago, when he was 31 and at the start of his dual career, Ottesen made a visit to Mauke to study the prevalence of filarial worms and to begin treating the islanders for infection. Last summer he returned to the island. But this time he didn’t just look for parasites; he found himself on the trail of what he suspects may be the source of allergies as well.
It’s an interesting thing, he says. When we made our first trip to Mauke to check for filarial worms, we also checked for allergies. But it was hard to find anyone who had allergic complaints. Now, almost two decades later, there’s much less parasite infection on the island, but the fascinating thing is--he leans forward and speaks in an insistent stage whisper--there’s so much more allergy. This observation, and similar disclosures from elsewhere in the world, have persuaded Ottesen to consider a provocative possibility--that there’s an inverse relationship between allergies and the presence of parasites.
Ottesen isn’t the first to suspect such a link, though his combined expertise in parasitology and allergy may make him the best qualified to do so. It’s not as odd an idea as it first seems. Both our allergies and our response to parasites are immune system reactions, and both rely on the same rather unusual immune mechanism. Could allergies result when the body’s mechanism for getting rid of worms becomes somehow misdirected? There must be a reason for having the allergic mechanism, Ottesen says. It probably evolved first to fight parasite infections. But when there are no parasites around, you’re left with a honed immune system looking for something to attack. So people who would have been protected against parasites in the jungle are now stuck in New York or someplace where parasites are scarce, and they’re wheezing and coughing because of pollen blowing down the street.
If so, it’s news to most allergy sufferers, who number approximately 50 million--that’s one in five people--in this country alone. Americans spend at least $5 billion a year in an attempt to cope with the seemingly useless affliction. Allergy, as far as most researchers are concerned, is a pointless marshaling of the body’s defenses against usually benign intruders. Allergy-causing substances such as pollen surely pose no great threat to our well-being; neither do cat dander and dust mites. Yet contact with such allergens causes millions of us to swell, wheeze, scratch, and sneeze as though under siege. In extreme cases, in reaction to insect stings and certain foods such as peanuts, an overwhelming allergic response, called anaphylactic shock, can even kill the body our immune system is ostensibly protecting.
Why does the immune system carry on in this misguided fashion? Allergists don’t really know; the field is as replete with controversy as it is with solid science. But one thing is certain: allergy is caused by an immune reaction unlike any other--with the exception of the antiparasite response.
As a general rule, when the body is faced with an invasion of foreign viruses or bacteria, it responds by producing billions of Y-shaped antibodies. These antimicrobial bits of protein belong to the family of antibodies called IgG, which is short for immunoglobulin G. IgG antibodies float freely in the bloodstream looking for distinctive proteins on the surfaces of microbes that label them as foreign; when they encounter the intruders, the Y-shaped molecules seize them and hold them down for the immune system’s killing cells. The antibodies act like a bridge between the foreign particles and the killer cells, bringing them together, says Ottesen.
But as researchers found out in the late 1960s, a different mechanism is activated when we’re invaded by a parasite--say, by a worm burrowing into the skin. Once again the immune system churns out Y-shaped antibodies to foreign proteins shed by the worm, but this time the antibodies are of a type called IgE. Rather than going directly after the foreign intruder, IgE lodges tail-first on the surface of specialized cells called mast cells. These cells are found wherever the body comes into contact with the outside world and therefore with parasites (or, for that matter, allergens)--in the skin, in the mucous membranes of the eyes, nose, and throat, and in the lining of the lungs and gut. By the time the initial IgE response is complete, each mast cell has between 100,000 and 500,000 Y- shaped antibodies protruding from its surface with outstretched arms, like a forest of diminutive trees.
At this point, usually within 14 days of the initial worm invasion, the immune system is primed. Each mast cell contains an arsenal of a thousand or more large, globular granules. Now, when a worm protein sticks to the arms of two adjacent IgE antibodies (a likely occurrence considering the sheer density of antibodies on the mast cell surface), it’s as if a biochemical circuit is closed. An explosive chain of events is set into motion that ends with the mast cell bursting open and spewing forth its bellyful of granules.
IgE is very different from other antibodies, says Ottesen. You take these little molecules, stick them on mast cells, give them a signal, and they initiate a big blast--the balloon explodes and all its granules tumble out.
The granules, in turn, contain a pharmacopoeia of histamines and other chemicals that infiltrate the skin and other tissues close to the activated mast cells. These chemicals cause all the symptoms of inflammation--itching, dilated and leaky blood vessels, swelling, excess mucus secretion. While no one knows exactly how this IgE response defends against parasites, Ottesen has some good hunches, based on experiments in his lab and elsewhere. Take, for example, filarial worms and hookworms, which enter the body through the skin. An immune response that causes the area to become inflamed and swollen may wall off the worms and prevent them from burrowing farther. What’s more, the mast cell response attracts other cells to the scene that spill their own toxic chemicals onto the cornered worms. You want to have an inflammatory response to parasites to protect yourself from penetration, Ottesen asserts.
Intestinal worms such as pinworms, on the other hand, enter through the mouth--often traveling in food or water contaminated with fecal matter-- then make their way to the gut. Diarrhea, which results when the inflamed gut pours out fluid and mucus, might flush out worms before they can infiltrate the intestinal wall. A number of these worms, including those that cause the prevalent tropical disease schistosomiasis (sometimes called snail fever because the schistosome worm is spread by water snails), also spend part of their elaborate life cycle in the human lung. The coughing and sneezing triggered by inflammation in the airways might be the immune system’s attempt to dislodge worms that have found their way into the respiratory tract. These inflammatory responses tend to be more pronounced in newcomers to the parasite-filled tropics than in those who have encountered the worms before. And they are by no means foolproof--some worms still manage to make themselves at home in the human body, establishing a chronic infection. But on the whole, the IgE response seems to do a fine job of keeping the world of worms at bay.
All well and good. But it’s also this immune process that gives us utterly useless allergies. When we first encounter an allergen--say, an airborne grain of ragweed pollen--its foreign proteins also activate the IgE branch of the immune system, and IgE antibodies are quickly posted on mast cells in vulnerable pollen-exposed areas, such as the nose, respiratory tract, and eyes. Unfortunately, when we later encounter ragweed proteins again, our mast cells are all too ready for them. IgE antibodies on the cells snare the foreign proteins, the cells spew forth histamine, histamine causes inflammation, and we suffer the familiar torture of hay fever--streaming nose, sneezing, coughing, and itchy, watery eyes. Similarly, if the invaders are dust mites that find their way to the lungs, the allergic reaction can trigger the wheezing and shortness of breath associated with asthma. And a meal of shellfish can produce the upset stomach and diarrhea of food allergy.
As Ottesen points out, however, it’s not like nature to waste energy on a completely pointless process. Evolutionary theory suggests that animals retain those traits that are useful for survival and jettison those that aren’t. The response that produces allergy is so common that it’s bound to be doing something useful, Ottesen says. The only way it would have gotten here is because it’s better to have it than not. And in Ottesen’s view it’s better to have it because it defends us against infiltration by wormy parasites. That’s what it’s there for.
Hence Ottesen’s contention that fighting parasites must be the real purpose of the IgE response, and that superfluous allergies occur when it gets misdirected. That led him to the next step in his hypothesis. If he was right, then it would follow that the more parasites in an environment, the fewer allergies people would suffer, as it was unlikely that this unique arm of the immune system could go after pollen and dust mites when its IgE antibodies were busy fighting off disease-causing worms. Similarly, the fewer parasites to contend with, the more likely that unemployed IgE would target pollen and other allergens instead.
That was the link Ottesen wanted to explore on Mauke last summer. In May 1992 Ottesen and his team of immunologists, parasitologists, and physicians landed on the island for a three-month stay, equipped with two tons of lab equipment, their own electricity generators, and a Polaroid camera. Just like last time, we took pictures of all our patients, says Ottesen. There are hardly any photos on the island. Many of the people had the original pictures we took of them years ago. They treasure them. They were happy to see us again.
With the help of the local doctor, a venerable Scotsman named Archie Guinea, they set out to examine every single inhabitant of the island. They drew blood, inserted tongue depressors, shone lights into ears and eyes, and took detailed personal histories. It was amazing, recalls Ottesen. There wasn’t a refusal on the island. It became a community thing--nobody wanted to let anybody down.
Compared with 19 years ago, Ottesen found, there was much less filarial infection on Mauke. Only 16 percent of the population harbored the microscopic worms, as opposed to 35 percent on his first visit. The reduction resulted primarily from treating the islanders with the antiparasite drug diethylcarbamazine, which Ottesen had initiated during his earlier visit. And what about allergies? There’s no question that there was a heck of a lot more allergy out there this time, says Ottesen. Nineteen years ago barely 3 percent of the people had allergies. This time it was at least 15 percent. The complaints ranged from eczema to hay fever and asthma to food allergies. What’s more, the dominant problem was one nobody had even heard of 19 years earlier: octopus allergy. It’s the number one offender, says Ottesen. People are breaking out in rashes, hives, swelling of the throat. Yet octopus is nothing new to them--they were eating it when we were there before. What’s different now? Ottesen answers his own rhetorical question: perhaps the IgE defense mechanism, no longer occupied with attacking worms, is now going after octopus protein and other new targets.
The trouble is, it’s awfully hard to prove one way or the other. The scope and effectiveness of our immune defenses are genetically determined; they vary from person to person. Allergies are a prime example. While one person may mount a debilitating IgE response to octopus, another may react mildly, and another not at all. (Not everyone reacts to the same worms with equal intensity, either.) That makes it tough to pin down the exact relationship between parasites and allergies. It’s extraordinarily difficult to design the experiment that would confirm the inverse relationship, Ottesen says. There are too many variables. No two people have precisely the same immune responses, and no two people have the same exposure to allergens or to parasites. So it’s not an easy question to answer. It’s not simply a matter of curing a few people of their parasites and then seeing if they develop allergies. To get anything approaching meaningful results, you’d have to follow large populations over long periods of time, or somehow simulate the human situation in animals.
Nevertheless, researchers have been trying. Within the last decade, experiments with rats have shown that worm-infested animals have weak allergic reactions, as though their battle with parasites leaves the IgE response with little ammunition to spare for allergens. In humans, studies of immigrants from the Philippines, China, and the West Indies, where parasite infestation is high, revealed that these people have virtually no allergies--while their parasite-free offspring born in the United States and England are miserable with them.
Still, not all studies point in the same direction. In rural New Guinea, for example, persistent parasite infection seems to have no effect on the prevalence of at least one allergic condition, asthma. Nor is it easy to explain why the immune system, no matter how unemployed and misdirected, should target invaders as inoffensive as dust mites and pollens. Perhaps allergens, like parasites, present the immune system with some characteristic molecular component or shape that induces an IgE response, says Ottesen. Or perhaps the way the allergen is processed by the immune system drives the system into an IgE as opposed to an IgG mode. But nobody really has a handle on that yet.
Such uncertainties are enough to persuade Margie Profet, a theoretical biologist at the University of California at Berkeley, to dismiss the parasite connection out of hand. It would be ludicrous if allergies were here because of parasites, she asserts. Natural selection just doesn’t come up with such a faulty design. In fact, Profet proposes that allergies aren’t nearly as useless as they’re made out to be. In her unconventional view, they defend us against toxins often transmitted by allergy-causing substances. For example, certain allergenic foods like peanuts may contain noxious molds, such as aflatoxin. The way Profet sees it, the explosive nature of the allergic reaction--all that swelling, sneezing, coughing, diarrhea, and vomiting--could serve to block or flush toxins from the system.
In response to Profet’s theory, Ottesen shrugs. Though a few observations might seem to support her view, there’s less biological evidence for it than there is for his, he maintains. In any case he has little time or inclination to debate the theoretical merits of the two ideas. What interests him far more is the potential for exploiting the one incontrovertible piece of evidence in favor of his own hypothesis: the similarity between allergy and our parasite defense. For if it’s true that the allergic response is a parasite response gone awry, then Ottesen may be onto something of more than academic interest. He might just have hit on a way to stop allergy in its tracks.
Compared with elusive allergy-causing substances, parasites are an open book--easy to identify and, in much of the world, almost ubiquitous. Similarly, the IgE response to parasites is more obvious and amenable to study than the response to allergies. In filarial infections, the worms crawl into the body and circulate through the blood, explains Ottesen. You can actually see them wiggling under the microscope, thousands of them per cubic centimeter of blood. You have enormous amounts of IgE directed against the parasites, ten times as much as in allergies, so you have the ingredients for a huge inflammatory response.
But as Ottesen and others have found out, you don’t necessarily get a huge response at all: it is often moderated. In fact, when parasitic worm infections become chronic, as they eventually do in many people living in the tropics, the infections are quite low-key--they depend on mutual tolerance, a manageable laissez-faire between guest and host. There are billions of people in the world affected with parasites, but they walk around with them for decades, says Ottesen. After all, if a worm succeeds in getting inside you--if it gets past your initial immune defense--then you want to be at peace with your parasite. You don’t want your whole body swelling up all the time. There must be something that has evolved naturally to control the severity of the response. Could that something, Ottesen wonders, provide the key to taming allergies as well?
At the moment, to the misery of millions, there’s no reliable method to quell them. Antihistamines and decongestants work for some people but often cause unpleasant side effects such as drowsiness. Allergy shots are effective only about half the time. The idea behind them is to induce the body to build up tolerance to allergens through regular injections of minute bits of the offending substances. But what actually happens, no one knows. In the scientific community they’re not highly regarded, says Ottesen. They’re based on almost no science, like witchcraft. Sometimes they work and sometimes they don’t work, and what the hell’s going on?
But when it comes to moderating the reaction to parasites, Ottesen thinks he knows exactly what’s going on. Indeed, he’s devoted many lab hours over the past decade to piecing the process together. It turns out, he explains, that there’s an IgG antibody that competes with IgE. The G antibody grabs onto the worm protein before it encounters the E antibody fixed on the mast cells, preventing it from triggering the inflammatory response.
This blocking antibody, called IgG4, is the rarest of the IgG family. Normally most of the IgG antibodies we make are those garden- variety killers of viruses and microbes, officially known as IgG1; IgG4 accounts for only 1 to 2 percent of the total. But intriguingly, in people with parasites, the blocking antibody jumps to 10 percent of the total, a fivefold to tenfold increase. The parasitized people we’ve studied have enormous G4 responses, says Ottesen. So even though they churn out plenty of IgE antibodies to attack the parasites’ proteins, many attacking antibodies are prevented from reaching their targets by blocking antibodies. The blockade results in a subdued inflammatory reaction that makes it possible for human and worm to live together. It’s the other side of the coin--the control side, he concludes. Even if you have a strong IgE response, if you know how to make a lot of G4 you can control the reaction.
This blockade appears to be an unusual feature of parasitic infections. It doesn’t normally occur in people suffering from allergies. But wouldn’t it be a boon if we could tame our ridiculously inappropriate allergic reactions in the same way? The challenge in controlling allergies, Ottesen is convinced, is to learn how to stimulate blocking responses. That is precisely what he’s now urging his allergist colleagues to do.
Of course, not everyone agrees that this is the way to conquer allergy. Some researchers think it would be preferable to eliminate the IgE response altogether or to disrupt the allergic mechanism in some other way. But then, those allergy researchers probably haven’t been to Mauke and don’t share Ottesen’s passion for worms. Ottesen realizes that he’s looking at the problem from a unique vantage point. If you talk to other allergists, you might not come up with the same approach. But, he says, leaning forward and speaking in a stage whisper, that’s because they haven’t seen the whole story.
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BUILDING UP THE IMMUNE SYSTEM IS IMPORTANT!!
CLEANSING ON A REGULAR BASIS HELPS THE BODY RID ITSELF OF TOXINS. THEN THE GOD GIVEN BODY THAT WE HAVE CAN HELP FREE UP THE DEBRIS AND GET AT THE HEALING!
