Excessive cleanliness, city living might be leaving us susceptible to allergies
By Steve Sternberg
Until 200 years ago, hay fever was unheard of. When London doctor John Bostock described the first cases in 1828, he made a curious observation: "I have not heard of a single unequivocal case among the poor."
By 1871, Londoner Charles Blackley had proved hay fever is triggered by pollen. Why then, he wondered, do farmers and their families have "the fewest cases of the disorder"?
The two men had instinctively stumbled upon what is one of the hottest questions in allergy research: Can too much clean living make people sick? Or put another way, is a little bit of dirt a healthy thing?
Known as the hygiene hypothesis, this notion holds that growing up in cities, insulated from nature, makes people more susceptible to allergies, asthma, certain autoimmune diseases and perhaps even diabetes.
Why? Because good hygiene leaves the body's immune system underemployed and looking for something to do. Soon, the immune system begins overreacting to pollen, animal dander and other ordinarily harmless substances.
"The immune system learns from experience," says Irun Cohen, an immunologist at the Weizmann Institute of Science in Rehovot, Israel. "If it doesn't get the right kind of practice, it develops imperfectly."
The hygiene hypothesis implies what many historians have come to believe: that our problems with allergies began not when mankind entered the garden but when mankind was banished from it. And this exile began, not in biblical times, but in the 1800s during the Industrial Revolution.
The hypothesis represents an attempt to explain a troubling increase in allergy and asthma in developed nations. The federal Centers for Disease Control and Prevention in Atlanta has reported that asthma rates in the USA have increased by 75% since 1980, with cases in children during the same period mushrooming by as much as 160%.
No one knows why, but scores of researchers are vying to find out. "It's a fashionable subject," says Philippa Marrack of the National Jewish Medical and Research Center in Denver.
Marrack, one of the world's leading immunologists, illustrates her point with an impromptu search of recent medical literature. In the past three years, she says, scientists have published more than 6,000 research reports examining the apparent links between civilized living and allergies and asthma.
Is house dust good for you?
Although many doctors suspect that excessive cleanliness might play a role in the upsurge of allergies, they don't recommend that people throw away the soap or dump the vacuum cleaner bag on the carpet -- at least, not yet. "We don't quite have the smoking gun," Marrack says. "But we're close."
For parents wondering whether they should let their kids romp in a barnyard or hide them from germs, Marrack says: "There's probably a middle way, but we don't know what it is, a middle way between locking a child in an aluminum shed and exposing the child to lots of germs. There's some reasonable middle ground here, which is what people do anyway."
Driving the research explosion is an even more basic question: How does the immune system distinguish "self," the proteins that are made in the body, from "non-self," the proteins that are not? How does it learn which ones represent a threat to survival and which do not?
If researchers can answer these questions, they could learn not only to prevent allergic disease, they could begin to harness the immune system to fight a host of diseases, including cancer.
A study led by one of Marrack's colleagues, Andy Liu, offers the most intriguing evidence yet that the best protection against allergy or asthma might be exposure to a bacterial molecule in house dust.
The molecule, known as endotoxin, occurs naturally in every bacterium's outer envelope. Thus, endotoxin is released into the environment any time bacteria die.
"Early childhood exposure to endotoxin may be the common thread in communities where asthma and allergies are uncommon," says Liu, whose study appeared in the May 11 issue of the journal Lancet.
Endotoxin somehow protects
Liu's team studied the homes of 61 infants from9 months to 2 years old. All the children were tested for sensitivity to dust mite, cat, dog, cockroach, mouse, milk, egg and soy. Doctors also determined the endotoxin concentrations in each house by testing house dust collected from the child's bed, a couch, and floors in the living room, kitchen and bedroom.
Of these children, 51 tested negative for sensitivity to those irritants. Moreover, they had the highest concentrations of endotoxin in their homes, suggesting that exposure to endotoxin somehow protects against allergic disease.
"The study supports the thesis that exposure to endotoxin early on has an impact on the subsequent development of the immune system," says David Sacks, a parasitologist at the National Institutes of Health in Bethesda, Md.
Marrack asserts, however, that it will take many more studies to furnish proof. "Studies of this type are usually done multiple times before the medical establishment makes up its mind," she says. "It's a beginning."
A matter of immunity
Liu says he decided to test for endotoxin because a flurry of recent
studies suggested that people in rural areas are less likely to develop
allergies or asthma than people living in cities. Those studies included:
Although endotoxin is found in high concentrations in nature, Liu says, it's also found in urban settings because bacteria are everywhere. Moreover, researchers had previously demonstrated that endotoxin can prime the immune system to respond to allergy-causing substances.
To understand how this occurs, consider the workings of the immune system.
More than just the sum of its parts, the immune system is a highly coordinated network of millions of white blood cells that attack and kill invading microbes. At the top of the heap are T cells, specialized white blood cells that are capable of distinguishing self from non-self and coordinating the human immune response.
T cells come in many varieties. Some act as dispatchers, squirting out potent signaling molecules that can activate and deactivate other immune cells. Some T cells are capable of killing virus-infected cells. Without T cells, no one could survive for very long. Witness the effect of AIDS, caused by a virus that kills T cells.
Allergy, too, is a T-cell disorder, but it is very different from AIDS. Allergy might best be thought of as a case of arrested T-cell development.
At birth, the immune system relies on T cells to block deadly germs from so much as entering the body's cells -- by generating a set of immune responses that also happens to drive allergic responses to foreign proteins.
Later in life, the immune response changes dramatically, and T cells develop the ability to attack cells even after they have been infected. This set of responses depends on practice, which comes from exposure to the proper foreign proteins at the appropriate stage of immune development.
"It's like the brain," says Cohen of the Weizmann Institute. "If a child doesn't get the proper visual or auditory input at the proper time of life, he'll have a speech or hearing problem, even if the brain is normal."
'Being protective' has saved lives
Cohen has become one of the more outspoken advocates of a radical notion that immune deprivation might also lead to autoimmune diseases, such as multiple sclerosis or early-onset diabetes.
Although many researchers dispute this, arguing that infections can tilt the immune system toward self-destructive, autoimmune responses, Cohen says his evidence suggests the opposite.
"The more mice are protected from (microbial) contamination, the higher their incidence of autoimmune diabetes," he says.
Most privileged children nowadays get far fewer serious infections than they did two centuries ago. Vaccinations, antibiotics and better sanitation have virtually done away with plague, typhoid fever, cholera, diphtheria and polio. Smallpox, once a harrowing rite of passage for almost everyone, has been eradicated.
That's a good thing, doctors say, even if it leaves people susceptible
to immune imbalances later in life. "What we're seeing now may be a consequence
of being too protective," Marrack says. "But being protective has kept
a lot of children alive."Cover story