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Authors: Randolph M. Nesse

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Genes are not the whole story, though. Studies of identical twin pairs show that in half the cases, one twin has allergies while the other twin is unaffected. So factors other than genes must be important as well. And even among atopic individuals, one may be allergic to ragweed while the other is allergic to shrimp. Why? As a start toward answering this question, we will invoke two ideas, one being the tendency, discussed above, for defensive adaptations to make many of the cheap kind of mistake in preference to the expensive kind (the smoke-detector principle). The other derives from the phenomenon of enzymatic variability, which has gotten considerable recognition in the recent biological literature.

Specimens of the same species, human or otherwise, can be immensely variable. Their genetic codes may be 99 percent identical, but tiny differences in genetic code can result in strikingly different
structures and body chemistry. The parts of the code that are the same can also code for differences, if they include instructions of the form “if A then X, else Y.” In retrospect we see that the evidence for wide variation among individuals has always been there. Just consider how different males and females of many species can be in size and anatomy, reproductive processes, behavior, and often in diet, habitat, and other features. These differences may result from genes that are expressed only if testosterone above some threshold concentration is present. The best examples of human variations are differences in reactions to drugs. Some individuals may take ten times as long as others to reduce a drug concentration to half its initial value. To put this into perspective, suppose you and your friend each get the same injection of quinine; it takes you an hour to detoxify half of it, and his system does this ten times as fast. At the end of the hour, when your concentration is still half what it was initially, his is down to less than a thousandth of its starting value. If the enzyme is cholinesterase and the drug is a cholinesterase inhibitor, often used to relax muscles during surgery, such slow metabolism might leave you still paralyzed and unable to breathe hours after other patients have been up and around. Anesthesiologists are, thankfully, on the lookout for individuals with this idiosyncrasy.

If Profet’s theory is right, people may develop allergies to the specific toxins to which they are especially vulnerable. Consider President Clinton, who is allergic to cats. Could it be that this allergy protects him from some dangerous toxin? Remember that the pito-hui bird (
Chapter 6
) has toxic feathers. It seems unlikely that cats have a comparable adaptation, but let’s consider the possibility. Why should Bill Clinton be vulnerable when none
of
his relatives are? Perhaps merely because he inherited defective forms of some gene that makes an enzyme important in denaturing some cat toxin. If he touches cat fur or inhales macroscopic particles of it, the toxin would enter his cells and reach harmful concentrations, instead of being quickly destroyed by the enzymes normally present. Fortunately, the president has mast cells and IgE-producing T cells that react to the toxin by triggering defensive reactions, such as sneezing. This might mean that he has to interrupt important negotiations to yank a handkerchief out of his pocket, but the sneeze, as a backup defense, might save him from some serious malady. Do you believe this explanation for Bill Clinton’s allergy to cats? We don’t, but we have a good excuse
for telling it. At the moment, there is no evidence that it is wrong. As long as we do not know what the IgE system is for, we will have great difficulty distinguishing its accomplishments from its mistakes.

We can alter the story to make the cat allergy a nuisance without value, while still basing the explanation on Profet’s theory of allergy as a backup defense against toxins. Perhaps Bill Clinton’s allergy is just another example of the smoke-detector principle. Perhaps as a child he encountered bacterial toxins during a respiratory infection, and his IgE system went into action and reacted, not only to the dangerous material, but also to some innocent “bystander” molecules (Profet’s term). Perhaps some harmless component of cat fur was mistakenly perceived, by a few IgE-producing cells, to be a troublesome toxin, or at least a reliable sign of the toxin’s presence. Immune cells that react to a foreign substance multiply and become far more numerous. So after this first episode, large numbers of anti-cat cells were poised to go into action on the next exposure. Do you prefer this explanation for Bill Clinton’s allergy? We do, but we are not inclined to bet on it. There is just not enough information for an informed decision.

If you were the president’s physician, what would you recommend? Would you prescribe a drug to inhibit the allergic reaction? The answer should depend on whether the allergy is useful or not. Is it an effective defense against an otherwise dangerous toxin, or is it a false alarm? How do you decide? At the moment, you have no solid basis for deciding. You might want to use antihistaminic drugs to suppress the allergic reaction, since they have no known dangers, but there are no adequate antihistamine studies that would detect the kinds of dangers implied by Profet’s theory.

The possibility of harm resulting from suppressing the symptoms of allergy is of special concern because of data suggesting that allergy may protect against cancer. Profet reports that sixteen out of twenty-two epidemiological studies found that people with allergies are less likely to have cancers, especially of tissues that show allergic reactions. On the other hand, three of the studies found no clear relationship, and three others, including one large, well-controlled investigation, found that some allergies are associated with an increased likelihood of developing some cancers. What are we to make of this? It would certainly be premature to conclude that allergies protect against cancer, but it is not premature to begin looking at the possible risks of long-term use of medications that suppress
allergic responses. Unfortunately, the nonmedication treatments are mainly inconvenient or not very effective. If you’ve got hay fever, you may be hard put to follow your doctor’s advice to stay indoors in closed rooms as much as possible, wear a pollen mask when you must be outdoors, or go somewhere else for the bad season. Taking a pill is much more convenient.

If the antitoxin theory of allergy is correct, it has clear implications for medical research. A Utopian recommendation is simple: find out just what the toxins are in pollen, cats, seafood, and so on, that induce allergy and devise techniques for their denaturation. These toxins may be different from the antigens that stimulate the allergy. If we knew just what was dangerous about ragweed pollen, we could perhaps equip people with nose drops or inhalants that would chemically inactivate both the toxin and the antigen. We could treat allergenic foods in similar ways. If we knew which patients don’t need their allergies to compensate for some deficiency in their ability to detoxify, we could suppress their symptoms without concern.

Such studies will be inconclusive unless they can distinguish useful allergies from useless ones. If Prof et is correct in reasoning that an allergy to eggs is consistently maladaptive, this allergy should not protect against cancers of the digestive tract, and the inflammation caused by the allergy might even increase the risk of cancer. An allergy to shrimp, however, would be expected to decrease the cancer risk for anyone who is unable to detoxify one of the many noxious compounds that shrimp get from their phytoplankton diets. Profet’s theory provides a basis for predicting when allergy will protect against cancer and when it might be irrelevant or actually increase the risk. We should emphasize that her theory is novel. Few allergists have even heard about it; far more believe the antiworm theory. But either theory may be better than no theory at all. As Thomas Huxley once observed, truth is more likely to emerge from error than from vagueness.

Still another possible function of the IgE system may be to defend against ectoparasites such as ticks, chiggers, scabies, lice, fleas, and bedbugs. A small problem for most people in modern societies, ectoparasites have been, throughout most of human evolution, not only a constant nuisance but vectors for many diseases. Slapping, scratching, and mutual grooming are only partially effective defenses. When cows are prevented from grooming by a thick collar, their burden
of ticks and lice increases steadily and then suddenly crashes when the cow’s immune systems begin responding to a bite with an inflammatory response that makes it impossible for the parasites to get a blood meal. Prevention of ectoparasite infestation might explain many aspects of the IgE system, especially the concentration of mast cells on the body’s surfaces, the immediate massive response, and the stimulation of itching. This theory could be tested by looking to see if the immune response that counters ticks on cows is indeed based on IgE and by looking at the IgE responses of people who are infested with ectoparasites.

As with other traits, the IgE system may well have more than one function. Some combination of the above and other explanations may be correct. One of the best ways to determine the function of a trait is to observe the problems of those who lack it. The deficits of a person who lacks eyes are obvious, and those of a person without kidneys soon become apparent, but the functions of many traits are more subtle. The spleen, for instance, is usually surgically removed if it ruptures, as it sometimes does in automobile accidents. Such patients have no apparent disability, but if they are stricken with pneumonia, the infection may quickly kill them because the spleen is not there to filter infectious particles out of the blood.

What happens to people who lack the ability to make normal IgE? While some people with very low levels of IgE are healthy, others are plagued with recurrent infections of the lungs and sinuses as well as fibrosis of the lungs. While these findings could be a result of exposure to toxins or a secondary result of whatever factor caused the IgE deficiency, there is also evidence for specific IgE antibodies directed against
Staphylococcus aureus
in people who cannot make other immunoglobulins. In a study of 190 patients with bronchial asthma, 55 had IgE antibodies to substances in the bacteria
Streptococcus pneumoniae
and/or
Haemophilus influenzae
. Furthermore, one effect of the substances released by mast cells is to attract other immune defense cells to the area, where they are available to fight any invader. All this suggests that the IgE system may directly or indirectly defend us against ordinary bacteria and viruses. The complexity of the immune systems, with functions that overlap and back one another up, makes it difficult to identify the benefits of the IgE system. It will take patient, well-designed research to answer the important but unanswered question,
What is the IgE system for?

T
HE
M
OST
W
ORRISOME
Q
UESTION

A
nother puzzling aspect of allergy, at least respiratory allergy, is the apparent recency of its appearance as a major medical problem. John Bostock originally described his own symptoms of hay fever for the Royal Society in 1819 and later reported that he could find only twenty-eight cases after investigating five thousand patients in all of England. Records imply that hay fever was essentially unknown before 1830 in Britain and 1850 in North America. In Japan its incidence was negligible in 1950, but it now affects about a tenth of the population. If the increase is real and not just an artifact of inadequate records, what novel environmental factor of the last century or two can account for this alarming phenomenon?

One clue comes from studies of the factors that seem to sensitize predisposed individuals, mainly exposure to antigens in the first two years of life. In one study of 120 infants with high susceptibility to allergy on the basis of their IgE levels at birth, 62 were raised as a control group without any intervention, while the mothers of 58 in the experimental group were taught how to keep their homes relatively clean of allergens, prevent mites, and avoid giving potentially allergenic foods to their infants. At age ten months, 40 percent of the control group had developed allergies compared to only 13 percent of the experimental group. Perhaps part of the increasing rate of allergy results from living indoors with drapes and wall-to-wall carpets, which provide breeding places for dust mites.

When Eric Ottesen, head of the Clinical Parasitology Section at the National Institute of Allergy and Infectious Disease, studied the six hundred people who live on Mauke, an atoll in the South Pacific in 1973, only 3 percent of them had allergies. By 1992, the rate was up to 15 percent. He suggests that institution of treatment for worm infestations during the intervening years left the IgE system with no natural target, so that the usual mechanisms that downregulate the system are inactive and the IgE begins to attack harmless antigens.

Breast-feeding decreases the incidence of allergies, so bottle-feeding may also contribute to the rise in allergies. Perhaps babies deprived of maternal antibodies make more immunological mistakes in coping with antigens on their own. Or perhaps crowded, mobile modern
societies expose infants to a greater diversity of viral respiratory diseases and thereby greater exposure to miscellaneous allergens. The increased quantity and variety of atmospheric pollutants may foster increases in both helpful allergies (if such there be) and harmful ones, perhaps because chemical damage to the respiratory mucosa may admit antigens that would otherwise be kept out. Food allergies, although perhaps not as clearly on the increase, may have become more troublesome because we now have so little control over what we are really eating. Eggs, wheat, soybeans, and other possible allergens may be present in a great variety of commercially prepared foods and be extremely difficult to avoid, even by people who know they are allergic to them.

What are we doing today that is different from what we did just a century ago and that makes us so much more vulnerable to so many diverse allergies? We desperately need real answers. Respiratory allergies affected less than 1 percent of people in industrial societies in 1840. Now, a hundred and fifty years later, it afflicts 10 percent. What might the future hold if we remain as ignorant as we are now?

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