Why We Get Sick

by Randolph M. Nesse

  Before we discuss possible explanations for the IgE system and the allergies it causes, we need to describe the proximate mechanisms of allergy. When a foreign substance enters the body, it is taken into cells called macrophages (macro means “big” and phage means “to eat”), which process the proteins from the substance and then pass them on to white blood cells called helper T cells, which take the proteins to another kind of white cell called B cells. If the B cell happens to make antibodies to that foreign protein, it is stimulated by the T cell to divide and make those antibodies. Most often that antibody is the familiar immunoglobulin G (IgG), but, for certain substances, the B cell is instead induced to make IgE antibody, the substances that mediate allergic reactions.

  There is remarkably little IgE, compared to other antibodies. It makes up only one hundred-thousandth of the total amount of antibody. The IgE antibody circulates in the blood, where about one out of one hundred to one out of four thousand molecules attaches to the membranes of still other cells called basophils (if they are in the circulation) or mast cells (if they are localized). When attached to these cells, the IgE remains for about six weeks. Despite the small amount of IgE, there will still be between 100,000 and 500,000 IgE molecules on each basophil, and, in an individual allergic to ragweed, about 10 percent of IgE may be specific to ragweed antigens.

  These mast cells are primed, like mines floating in a harbor, waiting for reexposure to the allergen. When it does return and is bound by two or more IgE molecules on the surface of the mast cell, the cell pours out a cocktail of at least ten chemicals in the space of eight minutes. Some are enzymes that attack any nearby cells, some activate platelets, some attract other white cells to the site, while others may stimulate smooth muscle (causing asthma). One, histamine, causes itching and increased permeability of membranes, unpleasant effects that can be blocked by antihistaminic drugs. While the details are still being worked out, the general operations of this proximate mechanism have been known for about twenty-five years and are essentially the same in all mammals.

  At this point you may be thinking: surely by now someone must have figured out what all that IgE machinery is there for! People have tried, but so far there has not been enough serious research to arrive at a generally accepted explanation. Many thoughtful researchers are well aware that a system this sophisticated must have some useful function. “These cells are not simply troublemakers devoid of redeeming biological value,” says Stephen Galli from Harvard, who notes that the distribution of mast cells adjacent to blood vessels in the skin and respiratory tract places them “near parasites and other pathogens as well as near environmental antigens that come in contact with the skin or mucosal surfaces.” Galli does not, however, review evidence about the possible functions of the system. A new nine-hundred-page textbook on allergy devotes only one page to the problem. It notes that “Several roles for the possible beneficial effect of IgE antibody have been postulated,” including regulation of microcirculation or as a “sentinel first line of defense” against “bacterial and viral invasion” and attacking parasitic worms. It concludes, “With 25% of the population having significant allergic disease mediated by the IgE antibody, an offsetting survival advantage for the presence of IgE has been suggested.” But, like other textbooks, it never seriously tries to explain the adaptive significance of allergy.

  The most widely accepted view is that the IgE system is there to fight parasitic worms. Evidence for this idea comes from the observation that substances released by worms may stimulate local IgE production and the resulting inflammation, which are interpreted as defensive activities against the worms. Further evidence comes from experimental studies of rats that developed strong IgE responses to Schistosoma mansoni infections. Transfer of IgE from one rat to another transfered protection against infection, while blocking the ability of IgE to recruit other cells made the rat more vulnerable to the worms. In people infected with schistosomes, 8 to 20 percent of their IgE may attack these worms, and those with a decreased ability to make IgE have more severe infections.

  Worms such as schistosomes, which cause liver and kidney failure, and filaria, which cause blindness, were all substantially greater problems before the introduction of modern sanitation and vector control. If attacking worms is the only function of the IgE system, this supports the current practice of treating allergies in developed countries by inhibiting allergic symptoms because an allergic reaction to anything but a worm would be maladaptive. However, the evidence that attacking worms is the only or even a major function of the IgE system remains inconclusive, and some of it may be flawed by attempts to interpret the data in terms of the only available hypothesis. Alternative explanations for the association of IgE phenomena with worms, such as the possibility that worms arouse IgE responses for their own benefit (by increasing the local blood supply), have been insufficiently considered.

  There is, however, another possible function for the IgE system, one recently championed by Margie Profet, whom we met in our chapters on signs and symptoms and on toxins. Profet proposes that the IgE system evolved as a backup defense against toxins. As we argued in Chapter 6, our environment is and always has been full of toxins. Inhaled pollen, contacted leaves, and ingested plant and animal products all contain potentially harmful substances. Most of these toxins are formed by plants to protect themselves against parasites and insects or other plant-eating animals.

  We have several kinds of defenses against these chemicals. First, we avoid them when we can. Also, the linings of our respiratory and digestive systems are equipped with toxin-fixing antibodies of the IgA group and with detoxification enzymes that collectively decompose broad categories of chemical structures. Mechanical defenses provided by mucous secretions and by the structure of our skin and absorptive surfaces also play a role. Toxins that bypass these initial defenses are attacked by concentrated batteries of enzymes in our liver and kidneys.

  But suppose all these defenses fail, as all adaptations must sometimes. Then, according to Profet, comes the backup defense, allergy, which gets toxins out of you in a hurry. Shedding tears gets them out of the eyes. Mucous secretions and sneezing and coughing get them out of the respiratory tract. Vomiting gets them out of the stomach. Diarrhea gets them out of parts of the digestive system beyond the stomach. Allergic reactions act quickly to expel offending materials. This fits with the rapidity with which toxins can cause harm. A few mouthfuls of those beautiful foxgloves in your garden can kill you a lot faster than a phone call can summon first aid. Appropriately for Profet’s theory, the only part of our immunological system that seems to be in a great hurry is that which mediates allergy. Other aspects of allergy that she mentions in support of her theory include the propensity to be triggered by venoms and by toxins that bind permanently to body tissues, the release of anticoagulants during allergic inflammation to counteract coagulant venoms, and the apparently erratic distribution of allergies to specific substances.

  At this point we pause to line up our ducks in a row so we can aim at them, even though we don’t yet have a way to shoot them. As we have already noted, the first and most important question is, What are the normal functions of the IgE system? The second question is why some people are especially susceptible to allergies while others are not. The third question is why a susceptible person develops an allergy to one substance and not another, say, milk instead of pollen. The fourth question is why allergy rates seem to be rapidly increasing in recent years.

  ATOPY

  People who are especially susceptible to allergies are said to be “atopic.” Atopy runs strongly in families. While the risk of clinically significant allergy in the general population is about 10 percent, the risk is closer to 25 percent if you have one atopic parent and 50 percent if both your parents are atopic. The responsible genes remain elusive, but a dominant gene on chromosome 11 may play a key role. If the genes that predispose to allergy are found, we will still need to find out why they exist. Do they, like the sickle-cell g
ene, give an advantage in certain environments or protection against certain infections? Or do they give an advantage when combined with certain other genes but a disadvantage otherwise? Or might they be “quirks” that did not cause disease until they interacted with modern environments?

  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?