Allergies, asthma and the environment. (by Diego Fdez-Sevilla)
In 1989 a scientists named Strachan proposed a novel but speculative explanation for the principal epidemiological features of hay fever and the apparent rise in the prevalence of allergic diseases. Colloquially named the “hygiene hypothesis”, this stated, in summary: “These observations . . . could be explained if allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings, or acquired prenatally . . . Over the 21st century declining family size, improved household amenities and higher standards of personal cleanliness have reduced opportunities for cross- infection in young families. This may have resulted in more widespread clinical expression of atopic disease.”
At first this hypothesis was received with scepticism because the prevailing immunological thinking considered infection as a potential trigger of allergic sensitisation rather than as a protective influence. However, during the early 1990s a plausible mechanism arose from the distinction of Th1 and Th2 lymphocyte populations in laboratory animals and the recognition that “natural immunity” to bacterial and viral infections induces a Th1 pattern of cytokine release, potentially suppressing the Th2 immune responses involved in IgE mediated allergy. Although the Th1/Th2 paradigm may not be as clear in humans as it first appeared in rodents, the “hygiene hypothesis” has remained of interest to both immunologists and epidemiologists until today and has been the subject of a number of editorials and review articles.
Allergic diseases are partly genetically determined, but environmental factors have a strong influence on the expression of allergic symptoms in genetically predisposed subjects. In particular, outdoor air pollution has received widespread attention as a potential manifestation factor. The unification of Germany provided a unique opportunity to study the impact of radically different environmental and social conditions on the development of allergies in two genetically homogeneous populations.
In the late 1980s, a German doctor, Erika von Mutius, compared the incidence of allergies and asthma in children from East Berlin and West Berlin. She expected to find that children living in unhygienic, polluted, and economically disadvantaged East Berlin had higher rates than the children from the same genetic background who lived in clean, prosperous West Berlin. She found just the opposite.
Two scientists, Nicolai and Mutius, back in 1997 assessed the prevalence of asthma and allergic disorders in 9-11 year old children in in East Germany (Leipzig and Halle) and in West Germany (Munich). A high car density and NO2 exposure were typical for many West German cities. Severe pollution due to heavy industrialization and private coal burning for heating purposes were the main sources of air pollution in East German cities. All fourth grade pupils in Munich (n = 7,445) were compared with those in Leipzig and Halle 1991 (n = 3,105). Hay fever, skin test reactivity to common aeroallergens and asthma were considerably more prevalent in West Germany as compared to East Germany.
The “Farm Effect”
In 2001, Mutious, Riedler and colleagues pointed out that a farming environment protects against development of asthma, hay fever, and atopic sensitisation in children. They performed a study aimed to establish whether increased exposure to microbial compounds has to occur early in life to affect maturation of the immune system and thereby reduces risk for development of allergic diseases. Their results suggested that Long-term and early-life exposure to stables and farm milk induces a strong protective effect against development of asthma, hay fever, and atopic sensitisation.
In 2012, Mark Holbreich, an allergist in Indianapolis, has recently discovered that the Amish people who lived in the northern part of the state were remarkably free of allergies and asthma.
About half of Americans have evidence of allergic sensitization, which increases the risk of allergic disease. But judging from skin-prick tests, just 7.2 percent of the 138 Amish children who Dr. Holbreich tested were sensitized to tree pollens and other allergens. That yawning difference positions the Indiana Amish among the least allergic populations ever described in the developed world.
This invulnerability isn’t likely to be genetic. The Amish originally came to the United States from the German-speaking part of Switzerland, and these days Swiss children, a genetically similar population, are about as allergic as Americans.
The working hypothesis is that innocuous cowshed microbes, plant material and raw milk protect farming children by favorably stimulating their immune systems throughout life, particularly early on.
In 2012, Torsten Olszak and colleagues published a study in which they claim that exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. In this study they show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal—but not adult—GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.
However, regarding the therapeutic effect of consuming raw milk, Böcking C and colleagues have published this year 2014 a work focusing on this subject:
“Cross-sectional epidemiological studies have demonstrated that farm milk from traditional farm settings possesses allergoprotective properties. Up to now, it has not been clarified which milk ingredient is responsible for protection against allergic diseases. As farm milk is rich in conjugated linoleic acids (CLA), it is hypothesized that this n-3 polyunsaturated fatty acid family contributes to the allergoprotective capacity of farm milk. We aim to prove this hypothesis in a murine model of allergic airway inflammation.”
Their results showed that, in animals, supplementation with a diet rich in milk CLA resulted in elevated CLA levels in plasma and erythrocyte membranes, indicating bioavailability of milk fatty acids. Though membrane-associated phospholipid patterns were affected by supplementation with milk CLA, this application neither reduced the hallmarks of allergic airway inflammation in sensitized and OVA-challenged mice nor modified the eiconsanoid pattern in the bronchoalveolar lavage fluid of these animals.
They concluded that milk-associated CLA was not capable of preventing murine allergic airway inflammation in an animal model of OVA-induced allergic airway inflammation.
The research of Mutius and others interested in the “hygiene hypothesis” has begun to fill in a picture of those who were most and least at risk. Children who had lots of siblings, who lived on farms, had cats, or went to daycare in their first year were discovered to do best at avoiding allergic diseases. Even children whose mothers had lived on farms during their pregnancies were less likely to become allergic. The children most likely to develop allergies and asthma were children who lived in cities, did not go to daycare, had no pets, washed their hands more than five times a day, and bathed more than once a day.
According to the ‘hygiene hypothesis’, the decreasing incidence of infections in western countries and more recently in developing countries is at the origin of the increasing incidence of both autoimmune and allergic diseases. The hygiene hypothesis is based upon epidemiological data, particularly migration studies, showing that subjects migrating from a low-incidence to a high-incidence country acquire the immune disorders with a high incidence at the first generation. However, these data and others showing a correlation between high disease incidence and high socio-economic level do not prove a causal link between infections and immune disorders. Proof of principle of the hygiene hypothesis is brought by animal models and to a lesser degree by intervention trials in humans. Underlying mechanisms are multiple and complex. They include decreased consumption of homeostatic factors and immunoregulation, involving various regulatory T cell subsets and Toll-like receptor stimulation. These mechanisms could originate, to some extent, from changes in microbiota caused by changes in lifestyle, particularly in inflammatory bowel diseases. Taken together, these data open new therapeutic perspectives in the prevention of autoimmune and allergic diseases.
So far, no one has suggested feeding children actual dirt or relaxing hygienic standards to any great extent. Eventually, asthmatic and allergic children may take some kind of bacterial medication, but for the rest of us, Tore Midtvedt, a microbiologist at the Karolinska Institute in Sweden, advises a more moderate approach. He wants to see an end to “war on germs” thinking and a new understanding that reflects our often fruitful coexistence with germs. Midtvedt isn’t advocating that we live close to rats or fleas or drink polluted water, just that we stop trying to live in sanitized houses and bodies. “I’m not saying that we should be more dirty,” he says. “I’m saying we should be less clean.”
Before you rush to the nearest farm, however, a word of caution. Some studies indicate that if you grow up in an urban environment, occasional visits to the farm may exacerbate allergic propensities. If you haven’t matured with abundant microbial stimulation, the thinking goes, encountering it intermittently may push you into overdrive, prompting the misery you seek to avoid.