Self & Other · Allergies: When the Guards Panic
Why Does Any of This Exist?
This is what Richet discovered in his dogs. It is what the EpiPen is designed to interrupt: epinephrine reverses many of the effects of mass mast-cell discharge, buying time for the person to get to a hospital. Without it, anaphylaxis can be fatal in minutes.
Why Does Any of This Exist?
Here is the question that has bothered immunologists for a hundred years. Why does the body have IgE at all?
Most of the immune system, when you think hard about it, is doing something useful even when it goes wrong. The autoimmune-prone variations we met in the last few chapters are real liabilities, but they exist because they also confer real protection against certain infections. The cost of having an immune system is balanced, evolutionarily, by the benefit.
But IgE seems different. The diseases of IgE — hay fever, asthma, eczema, food allergies, anaphylaxis — cause enormous suffering and very little obvious benefit. Why would evolution maintain a system whose main effect, in most modern people, is to make them miserable when they encounter pollen?
The traditional answer, and probably part of the truth, is that IgE evolved to fight parasitic worms.
In the world of our ancestors — and in much of the world today — parasitic worms were and are a major problem. Hookworm, roundworm, schistosomiasis, tapeworm. These parasites are too large for normal antibody responses to handle. You cannot kill a tapeworm with IgG, the way you can kill a virus. Worms are multicellular, mobile, often well-armored. The immune system needs different tools for them.
IgE, with its rapid mast-cell-dumping response, turns out to be reasonably good against worms. The histamine and other chemicals released make local tissue inhospitable. The contraction of smooth muscle helps to expel worms from the gut. The recruitment of specialized cells called eosinophils — which we haven’t met before in this book, but which are part of the worm-fighting machinery — brings additional firepower. In a person harboring intestinal worms, the IgE system is doing real work.
Most modern people in wealthy countries do not have parasitic worms. They have not had them in generations. The IgE system, evolved for a problem that most of its hosts no longer have, is sitting around with nothing to do — and, it turns out, a system with nothing to do can find other things to react to.
This is part of the story, and probably true. But it is not the whole story, because if it were, you would expect that adding worms back into people’s lives would calm down their allergies. There have been a few small studies that hint at exactly this, with cautious volunteers swallowing capsules of harmless hookworm larvae and reporting some improvement in their allergic symptoms. The results are interesting. They are not yet a treatment.
The fuller picture, which we started to introduce in Chapter 5, has more layers.
The Old Friends, Returning
Recall the hygiene hypothesis from Chapter 5, and its more careful descendant, the old friends hypothesis. The basic idea: the human immune system evolved over millions of years in the constant presence of certain microbes — ordinary soil bacteria, harmless gut companions, the parasites and microbes our ancestors lived with on farms and in dirt-floored homes. The immune system, especially the developing immune system in early childhood, may need exposure to these old friends in order to learn the right calibration. Without them, the system seems to come up miscalibrated.
In the case of allergies, the miscalibration appears to be specific. The immune system has, broadly, two main modes of response. One mode — sometimes called Type 1 or Th1 — is the mode you use against viruses and bacteria that get inside cells. The other mode — Type 2 or Th2 — is the mode you use against parasites, and it is also the mode that produces IgE.
These two modes are normally kept in balance by the regulatory cells we met in Chapter 7, especially the Tregs. When the system is well-calibrated, each mode is used for the right kind of threat, and the Tregs keep both modes appropriately quiet when nothing is happening.
In children who grow up with little exposure to ordinary microbial life — in clean homes, in cities, with limited contact with farms or animals or other children — the developing immune system seems to come up imbalanced. The Tregs may be less robust. The Type 2 mode may be over-represented. The result, at the population level, is more allergies.
The evidence for this is now substantial, though no single study is conclusive. Children raised on traditional dairy farms, with regular exposure to barn dust and unpasteurized milk, have markedly lower rates of asthma and allergy than children raised in nearby suburban homes. The Amish, who farm traditionally and live in close contact with animals, have allergy rates dramatically lower than the genetically similar Hutterites, who farm with modern industrial methods. Children in large families have fewer allergies than children in small families. Children who attend day care young have fewer allergies than children who don’t. Children with dogs in the home have fewer allergies than children without. None of these findings is definitive on its own. Together, they form a consistent picture.
So allergies appear to be, in part, a disease of immune systems that grew up too quiet. Not too clean in a moral sense — hand-washing during a flu outbreak is still important; vaccinating against deadly diseases is still important; chlorinated drinking water has saved hundreds of millions of lives. The kind of cleanliness that matters is not the kind a careful family eliminates. The kind that matters is the lifelong absence of background microbial chaos that all of human history, until about a century ago, took for granted.