Itchy, watery eyes, and a drippy nose. Constricted, swollen airways secreting thick mucus. Itchy, red, dry, cracked skin. These symptoms describe three conditions — allergies, asthma, and eczema, respectively — that are commonly found together in the same people. Yet, what causes these symptoms and why they are so closely associated with each other is still poorly understood.
People with allergies launch aggressive immune responses to a wide range of innocuous environmental triggers, such as cat hair or tree pollen. The immune system is the body’s way of blocking, recognizing, and fighting infectious agents like viruses, bacteria, and parasitic worms. T-helper 2 (TH2) cells are part of the body’s “adaptive” immune system. When parasitic threats manage to get into the body, TH2 cells are responsible for recognizing the new threats and activating other types of immune cells to detect, fight, and remember them for future attacks. In this way TH2 cells “adapt” to new threats, rather than forming a passive “innate” immune system barrier, like the skin. In allergic response the TH2 cells misinterpret harmless allergens as threats, and activate the immune system inappropriately.
Despite progress in fighting infectious diseases in developed countries with increased sanitation, antibiotics, and antiviral medications, allergies have become increasingly common in these regions. A few hypotheses have been put forth to explain this trend.
One explanation, called the “Hygiene Hypothesis,” proposes that underexposure to parasites in developed countries results in an under-stimulated immune system, which then overreacts to allergens. Helminth or parasitic worm infections have decreased drastically in countries that are experiencing a rise in allergies. Since helminth infections activate the same TH2 immune cells that are active in allergic reactions, perhaps the absence of worms in some people causes their TH2 immune systems to overreact to innocuous triggers like allergens [1]. In other words, instead of immune reactions to worms or other macroscopic parasites, some people living in developed countries have allergic reactions to harmless substances. However, many people living without worm infections in developed countries never get allergies! Pollution and dust have been cited as another factor strongly associated with asthma and allergies. As yet, no mechanism firmly explains this correlation [1]. So, who really gets allergies and why?
Leaky Skin Hypothesis
Recent research suggests that another cause of allergies may be skin deep. Developing eczema, or dry, irritable skin, within the first year of life is closely associated with developing allergies. Why should this be? One idea, called the “leaky skin” hypothesis, is that dry, cracked skin allows potential environmental allergens to get inside the body. The skin is part of the immune system’s first line of defense, and is supposed to protect the sensitive internal parts of the body from foreign particles and pathogens. If a “leaky” barrier allows potential allergens inside the body, the TH2 immune system puts up a second line of defense against the supposed threat. People with healthy, moist skin rarely allow allergens past the initial barrier, and so are less likely to develop adaptive immune sensitivity to them [2].
Figure 1. Allergens enter the body through a defective skin barrier, leading to activation of TH2 cells, which trigger the adaptive immune system. TH2 cells promote the activity of other cells and factors that circulate throughout the body and cause atopic eczema and allergies.
This leaky skin hypothesis is supported by three lines of research. First, people with genetic mutations that result in dry skin are at a higher risk for developing allergies. For example, ichthyosis vulgaris is a genetic disorder affecting 1 in 100 Europeans, which results from mutations in filaggrin, a gene responsible for maintaining skin integrity and moisture. People with ichthyosis vulgaris exhibit dry, scaly skin (ichthyosis comes from the Ancient Greek word for fish) and deeply lined palms, and are at high risk for developing eczema, allergies, and asthma [2].
Second, mutations in another gene called TSLP result in higher production of TSLP (thymic stromal lymphopoietin), and have been associated with the development of eczema, environmental allergies, asthma, and food allergies. Recent research demonstrates that TSLP, secreted from the skin, induces production of basophils, a type of immune cell involved in the allergic response [3]. TSLP is secreted at higher levels in response to trauma like skin lesions or infections. From experiments done in mice, researchers now understand that secretion of TSLP in one location can cause an allergic reaction all over the body, specifically via the action of basophils [3]. This research links dry, atopic skin, which may produce TSLP at higher levels since it is prone to breaking, to the development of systemic allergies [4]. In addition, TSLP secretion resulting from trauma to the linings of the lungs or gut provides a potential mechanism for development of asthma and food allergies among those already exhibiting allergies and eczema [4].
Third, a “leaky barrier” can be caused by more than just genetically inherited dry skin. External environmental factors, such as air pollution, and behavioral practices, such as excessive use of antibacterial soaps and smoking, can also dry or damage skin and the lining of the lungs and gut [5,6]. This may partially explain increasing incidence of allergies and asthma among those in developed countries.
Hygiene Hypothesis Extended
Finally, the development of allergies may be explained not only by the health of the skin and other body linings, but also by the bacteria that colonize those linings throughout the body. The Hygiene Hypothesis, proposed to explain the increase in allergies as a result of the decrease in parasitic worms, may have another dimension. Every surface of the human body exposed to the external environment, including the lungs and gut, are colonized by a diverse array of bacteria [7]. We have co-evolved with these bacteria since the inception of multi-cellular life to the extent that we need these bacteria to keep us healthy [8]. Unfortunately, these relationships are under attack from antibiotics and other modern “hygienic” practices.
Antibiotics and antibacterial soaps kill not just harmful pathogens, but also these beneficial bacteria [8, 9]. After antibiotic treatment, these populations never fully recover. Bacterial populations stabilize, but have fewer species than before the treatment [10]. Losses of beneficial bacteria have been linked to many modern diseases on the rise, including allergies and asthma [8]. Along similar lines, children growing up on farms experience higher exposure to bacterial diversity (from contact with animals and drinking unpasteurized milk) than urban children, and exhibit lower incidence of allergies [1]. Hygienic modern life reduces exposure to parasitic worms as well as naturally occurring intestinal and skin bacteria, all of which may interfere with proper function of the immune system and contribute to the rise of allergies.
Allergy-sufferers may be frustrated with the current understanding and treatment of allergies. However, recent research suggests a critical role for skin and human-dwelling bacterial health in protecting against the development and aggravation of allergies, eczema, and asthma. This new information helps explain why these conditions typically aggravate the same individuals, and suggests new modes of treatment for allergies that focus on the integrity of skin and the ecosystem of beneficial bacteria living on it.
Elizabeth Brown is a graduate student in the Human Evolutionary Biology program of the Graduate School of Arts and Sciences at Harvard University.
References:
1. Duncan Graham-Rowe, “Lifestyle: When allergies go west,” Nature, November 24 2011, Vol 479, pgs S2-S4
2. Claire Ainsworth, “Skin: Into the breach,” Nature, November 24 2011, Vol 479, pgs S12-S13
3. Mark C. Siracusa et al, “TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation,” Nature, September 8 2011, Vol 477, pgs 229-233
4. Paige Brown, “Atopy: Marching with allergies” Nature, November 24 2011, Vol 479, pgs S14-S15
5. Reviewed by: James E. Gerace, “Asthma Risk Factors,” WebMD, June 21 2009 <http://www.webmd.com/asthma/guide/asthma-risk-factors>
6. R. Morgan Griffin, “What’s Causing Your Dry Skin?” WebMD <http://www.webmd.com/healthy-beauty/features/dry-skin-causes>
7. Cassandra Willyard, “Microbiome: Gut reaction,” Nature, November 24 2011, Vol 479, pgs S5-S7
8. Martin Blaser, “Antibiotic overuse: Stop the killing of beneficial bacteria,” Nature, August 25 2011, Vol 476, pgs 393-394.
9. Jennifer Welsh, “Are Antibiotic-Infused Products Causing Allergies in Kids?” Discover Magazine, November 30 2010 <http://blogs.discovermagazine.com/80beats/2010/11/30/are-antibiotic-infused-products-causing-allergies-in-kids/>
10. Les Dethlefsen and David A. Relman, “Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation” Proceedings of the National Academy of Sciences of the United States of America, March 15 2011, Vol 108, pgs 4554-4561
11. Andrew Moseman, “Study: C-Section Babies Miss Out on a Dose of Beneficial Bacteria,” Discover Magazine, June 22 2010 <http://blogs.discovermagazine.com/80beats/2010/06/22/study-c-section-babies-miss-out-on-a-dose-of-beneficial-bacteria/>