Allergy – The Mystery of the IgE system

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 posts on signs and symptoms and on toxins. Profet proposes that the IgE system evolved as a backup defense against toxins. As we argued in this post 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.