While raising barricades against deadly scourges, however, the industrialized world has also shielded people from the microbes and parasites that do no harm. Does it matter?

A growing number of scientists now suspect that stamping out these innocuous organisms is weakening some parts of children's immune systems, allowing other parts to grow unchecked. Such an imbalance, they theorize, triggers a host of illnesses, including asthma, allergies, and even such autoimmune diseases as rheumatoid arthritis and the most severe type of diabetes.

This notion, called the hygiene hypothesis, arose from scientists' inability to explain the rising prevalence of asthma and allergies in many developed nations. The National Heart, Lung, and Blood Institute estimates that in the United States, for example, the incidence of asthma is now 1.75 times what it was in 1980, and for children less than 4 years old, 2.60 times the earlier incidence. Pollution and allergens—such as mold and pollen—can take some of the blame, but not all of it. "One needs an explanation" for these trends, says Graham A.W. Rook of the University College London Medical School, who is one of the chief advocates of the hygiene hypothesis. "People should be getting healthier, not less healthy.

"For several years, investigators have been uncovering signs that illness can result when the immune system lacks practice fighting bacteria and viruses. This evidence, however, has been circumstantial and too sparse to convince most scientists. "It's greeted with some skepticism, and quite rightly, because we need more evidence," says Richard Beasley of the University of Otago's Wellington (New Zealand) School of Medicine. "In many respects, it's still early days, but the evidence is starting to build.

"Recently, several epidemiological and experimental studies have converged to put the hygiene hypothesis on firmer ground. Some researchers are already trying to create vaccines that mimic potentially crucial immune effects of the microbes that society has banished. According to the hygiene hypothesis, the immune system is like a set of scales that sometimes tips sharply enough to send a person's health tumbling. One arm of the immune system deploys specialized white blood cells, called Th1 lymphocytes, that direct an assault on infected cells throughout the body. Counterbalancing this, another arm of the immune system tries to hit the intruders even earlier. It produces antibodies that block dangerous microbes from invading the body's cells in the first place. This latter strategy exploits a different variety of white blood cells, called Th2 lymphocytes. The Th2 system also happens to drive allergic responses to foreign organisms.

At birth, an infant's immune system appears to rely primarily on the Th2 system. According to the hygiene hypothesis, the Th1 system can grow stronger only if it gets exercise, either through fighting infections or through encounters with certain harmless microbes. Without such stimulation—and ordinary colds and flu don't seem to do the trick—the Th2 system flourishes and the immune system teeters toward allergic responses.

Early support for this view came from Julian M. Hopkin, now at the University of Wales Swansea, and his colleagues. In 1997, they reported on a study of 867 Japanese children given a vaccine against tuberculosis. Those who showed a strong Th1 response—indicating previous exposure to the bacterium that causes the disease—had far fewer allergies and asthma than did those who didn't show a Th1 response. Furthermore, among the children who had allergies, some showed a decrease in allergy symptoms after receiving the vaccine. The ones with a strong Th1 response to the tuberculosis vaccine were six to nine times as likely to benefit as were children who did not have such a response. In the past, some scientists speculated that the Th1 system required periodic infections, particularly in childhood, in order to develop properly, but most researchers now dispute that idea.

Rook argues that the main problem may be that kids have become too squeaky clean. He suspects that children need contact not with disease-causing agents but with innocuous microbes in soil and untreated water—particularly organisms called mycobacteria—to give the Th1 system enough of a workout. "The [lymphocytes] have got to be kind of marinated in this stuff in the early years of life," he says. If they aren't, he says, the Th2 system grows ever stronger, priming the immune system to overreact to allergens. Mycobacteria (red) found in dirt and untreated water may help people cultivate a well-balanced immune system. (Hopkin)

Recent epidemiological research has further hinted that the cleanest environments may be the best breeding grounds for allergies and asthma. In the January Journal of Clinical and Experimental Allergy, Swiss researchers reported that hay fever was less common for farm children than for urban children or for rural children who didn't live on farms. Several years ago, scientists found that children in large families—particularly the younger siblings of brothers—had fewer allergies than children in small families did. Researchers speculated that exposure to the germs brought home by older siblings protected the younger children from allergies. Bolstering that idea, a study in the Feb. 6 Lancet found that children from small families who entered day care before age 1 were less likely to develop allergies than those who entered day care later. No such difference emerged for children from larger families, suggesting that early day care may have stood in for the protection provided by dirty older siblings.