What do clean houses have in common with childhood infections?
One of the many explanations for asthma being the most common chronic disease in the developed world is the “hygiene hypothesis.” This hypothesis suggests that the critical post-natal period of immune response is derailed by the extremely clean household environments often found in the developed world. In other words, the young child’s environment can be “too clean” to pose an effective challenge to a maturing immune system.
According to the “hygiene hypothesis,” the problem with extremely clean environments is that they fail to provide the necessary exposure to germs required to “educate” the immune system so it can learn to launch its defense responses to infectious organisms. Instead, its defense responses end up being so inadequate that they actually contribute to the development of asthma.
Scientists based this hypothesis in part on the observation that, before birth, the fetal immune system’s “default setting” is suppressed to prevent it from rejecting maternal tissue. Such a low default setting is necessary before birth—when the mother is providing the fetus with her own antibodies. But in the period immediately after birth the child’s own immune system must take over and learn how to fend for itself.
The “hygiene hypothesis” is supported by epidemiologic studies demonstrating that allergic diseases and asthma are more likely to occur when the incidence and levels of endotoxin (bacterial lipopolysaccharide, or LPS) in the home are low. LPS is a bacterial molecule that stimulates and educates the immune system by triggering signals through a molecular “switch” called TLR4, which is found on certain immune system cells.
The science behind the hygiene hypothesis
The Inflammatory Mechanisms Section of the Laboratory of Immunobiochemistry is working to better understand the hygiene hypothesis, by looking at the relationship between respiratory viruses and allergic diseases and asthma, and by studying the respiratory syncytial virus (RSV) in particular.
What does RSV have to do with the hygiene hypothesis?
- RSV is often the first viral pathogen encountered by infants.
- RSV pneumonia puts infants at higher risk for developing childhood asthma. (Although children may outgrow this type of asthma, it can account for clinic visits and missed school days.)
- RSV carries a molecule on its surface called the F protein, which flips the same immune system “switch” (TLR4) as do bacterial endotoxins.
It may seem obvious that, since both the RSV F protein and LPS signal through the same TLR4 “switch,” they both would educate the infant’s immune system in the same beneficial way. But that may not be the case.
The large population of bacteria that normally lives inside humans educates the growing immune system to respond using the TLR4 switch. When this education is lacking or weak, the response to RSV by some critical cells in the immune system’s defense against infections—called “T-cells”—might inadvertently trigger asthma instead of protecting the infant and clearing the infection. How this happens is a mystery that we are trying to solve.
In order to determine RSV’s role in triggering asthma, our laboratory studied how RSV blocks T-cell proliferation.
Studying the effect of RSV on T-cells in the laboratory, however, has been very difficult. That’s because when RSV is put into the same culture as T-cells, it blocks them from multiplying as they would naturally do when they are stimulated. To get past this problem, most researchers kill RSV with ultraviolet light before adding the virus to T-cell cultures. However we did not have the option of killing the RSV because that would have prevented us from determining the virus’s role in triggering asthma.
Our first major discovery was that RSV causes the release from certain immune system cells of signaling molecules called Type I and Type III interferons that can suppress T-cell proliferation (Journal of Virology 80:5032-5040; 2006).
The hygiene hypothesis suggests that a newborn baby’s immune system must be educated so it will function properly during infancy and the rest of life. One of the key elements of this education is a switch on T cells called TLR4. The bacterial protein LPS normally plays a key role by flipping that switch into the “on” position.
Prior research suggested that since RSV flips the TLR4 switch, RSV should “educate” the child’s immune system to defend against infections just like LPS does.
But it turns out that RSV does not flip the TLR switch in the same way as LPS. This difference in switching on TLR, combined with other characteristics of RSV, can prevent proper education of the immune system.
One difference in the way that RSV flips the TLR4 switch may be through the release of interferons, which suppresses the proliferation of T-cells. We still do not know whether these interferons are part of the reason the immune system is not properly educated or simply an indicator of the problem. Therefore, we plan to continue our studies about how RSV can contribute to the development of asthma according to the hygiene hypothesis.
This finding that Type I and Type III interferons can mediate the suppression of T-cells caused by RSV generated two significant questions that our laboratory is now addressing:
- Interferons are important molecules that enhance inflammation, so why--in the context of RSV--do they suppress T-cells?
- Interferons are clearly not the only way RSV suppresses T-cells. What are the other mechanisms that may depend upon T-cells coming in direct contact and communicating with other immune cells?