Hygiene hypothesis

In medicine, the hygiene hypothesis states that a lack of early childhood exposure to infectious agents, symbiotic microorganisms (e.g., gut flora or probiotics), and parasites increases susceptibility to allergic diseases by modulating immune system development.^[1]

History

First proposed by David P. Strachan in an article published in the British Medical Journal (now the BMJ), in 1989,^[2] the hygiene hypothesis was developed to explain the observation that hay fever and eczema, both allergic diseases, were less common in children from larger families, which were presumably exposed to more infectious agents through their siblings, than in children from families with only one child. The hygiene hypothesis has been extensively investigated by immunologists and epidemiologists and has become an important theoretical framework for the study of allergic disorders. It is used to explain the increase in allergic diseases that has been seen since industrialization, and the higher incidence of allergic diseases in more developed countries. The hygiene hypothesis has now expanded to include exposure to symbiotic bacteria and parasites as important modulators of immune system development, along with infectious agents.^[3]

Mechanism of action

Allergic diseases are caused by inappropriate immunological responses to harmless antigens driven by a TH2-mediated immune response. Many bacteria and viruses elicit a TH1-mediated immune response, which down-regulates TH2 responses. The first proposed mechanism of action of the hygiene hypothesis stated that insufficient stimulation of the TH1 arm of the immune system lead to an overactive TH2 arm, which in turn led to allergic disease.^[4]

The first proposed mechanistic explanation for the hygiene hypothesis cannot explain the rise in incidence (similar to the rise of allergic diseases) of several TH1-mediated autoimmune diseases, including inflammatory bowel disease (IBD), multiple sclerosis (MS), and type I diabetes. The major proposed alternative mechanistic explanation is that the developing immune system must receive stimuli (from infectious agents, symbiotic bacteria, or parasites) in order to adequately develop regulatory T cells, or it will be more susceptible to autoimmune diseases and allergic diseases, because of insufficiently repressed TH1 and TH2 responses, respectively.^[5]

Breadth of the hypothesis

The hygiene hypothesis has expanded from eczema and hay fever to include exposure to several varieties of microorganisms and parasites, with which humans coexisted throughout much of our evolutionary history, as necessary for balanced and regulated immune system development.^[6] In recent times, the development of hygienic practices and effective medical care, like vaccines, have diminished or eliminated exposure to these microorganisms and parasites during development. Examples of organisms that may be important for proper development of T regulatory cells include lactobacilli, various mycobacteria, and certain helminths.^[7]

Evidence for the hypothesis

The hygiene hypothesis is supported by epidemiological data. Studies have shown that various immunological and autoimmune diseases are much less common in the developing world than the industrialized world and that immigrants to the industrialized world from the developing world increasingly develop immunological disorders in relation to the length of time since arrival in the industrialized world.^[8]

Studies in mice have shown that exposure of young mice to viruses can result in a decreased incidence of diabetes.^[9]

In Cell : Homeostatic Expansion of T Cells during Immune Insufficiency Generates Autoimmunity they showed that when lymphocytes are replaced, but there are too few memory cells (because of lack of infections) the chance for autoreactive T-cells grows, causing autoimmune diseases like MS.^[10] One conclusion is that a clean environment, with lack of infections (like early life infections) increases the chance of an autoimmune disorder.

TH2 immune disorders such as asthma and other allergic diseases are probably related to the hygiene hypothesis. A baby has many TH2 cells, which stimulates producing antibodies. When not sufficiently stimulated with early life diseases, the immune system will have too many TH2 cells present, leading to a greater chance of TH2 immune disorder. In developed countries where childhood diseases are eliminated, the asthma rate for youth is approximately 10%. In the 19th century, asthma was a very rare disease.

Longitudinal studies in the third world demonstrate an increase in immunological disorders as a country grows more affluent and, presumably, cleaner.^[11] The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases.^[12] The use of antibacterial cleaning products has also been associated with higher incidence of asthma, as has birth by Caesarean section rather than vaginal birth.^[13][14] However, the studies investigating these links showed only tenuous correlations between the factors described and the conditions they are hypothesised to cause.^{[citation needed]}

Several pieces of experimental evidence also support the hygiene hypothesis. Work performed in the laboratory of Professor Anne Cooke at the University of Cambridge showed that mice of the NOD strain (which spontaneously develop type 1 diabetes mellitus) had a significantly reduced incidence of this disease when infected with the helminth parasite Schistosoma mansoni.

In November 2009 a group of researchers at the School of Medicine at University of California, San Diego, found that Staphylococci helped reduce inflammation.^[15]

Therapies arising out of the hygiene hypothesis

The use of infectious organisms, specifically helminths, to treat the types of disease described by the hygiene hypothesis is being studied in the UK, USA and Australia.

Because of the promise shown by this research two versions of what is now commonly referred to as Helminthic therapy, using Trichuris suis ova or Necator americanus larvae, have become available.

Helminthic therapy is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth or with the ova of a helminth. Helminthic therapy is currently being studied as a promising treatment for several (non-viral) autoimmune diseases including Crohn's disease,^{[16][17][18][19]} multiple sclerosis,^[20] asthma,^[21][22] and ulcerative colitis.^[23] Autoimmune liver disease has also been demonstrated to be modulated by active helminth infections.^[24]

In addition to the treatment of immune disorders the anti-inflammatory effects of helminth infection are prompting interest and research into diseases that involve inflammation but that are not currently considered to include autoimmunity or immune dysregulation as a causative factor. Heart disease and arteriosclerosis both have similar epidemiological profiles as autoimmune diseases and both involve inflammation. Nor can their increase be solely attributed to environmental factors. Recent research has focused on the eradication of helminths to explain this discrepancy.^[25]

As a result of the hygiene hypothesis helminthic therapy emerged from the extensive research into why the incidence of immunological disorders and autoimmune diseases is relatively low in less developed countries, while there has been a significant and sustained increase in immunological disorders and autoimmune diseases in the industrialized countries.^{[22][26][27][28]} If helminthic therapy and other therapies using other types of infectious organisms, such as protozoa,^[29] to treat disease are proven successful and safe the hygiene hypothesis has potentially large implications for the practice of medicine in the future.

Alternative hypotheses

There are many other hypotheses which aim to explain the increase in allergic disease in developed nations, many of which are also related to the other. A few other major areas of focus in the literature include infant feeding, over-exposure to certain allergens and exposure to certain pollutants. Infant feeding covers a range of topics which include whether babies are breast fed or not and for how long, when they are introduced to solid foods and the type of these foods, whether they are given cow's milk and even the types of processing that the milk undergoes. Numerous articles have reported that over-exposure to certain allergens can cause allergic diseases, most obviously Laboratory Animal Allergy, farmer's lung and baker's lung. The third of these theories suggests that pollution (such as diesel exhaust) might be responsible for the increase of these diseases, however some also claim that developed nations have also been becoming cleaner (especially in comparison to the industrial revolution).

For immunological conditions related to Strachan's original version of the hygiene hypothesis, such as atopy and asthma, the pool chlorine hypothesis was proposed by Albert Bernard and his colleagues as an alternative hypothesis based on epidemiological evidence in 2003.

See also

• Hookworm in therapy
• Antibacterial soap
• Helminthic therapy
• Diseases of affluence

References

Additional references

External links

• Hadley C (December 2004). "Should auld acquaintance be forgot..". EMBO Rep. 5 (12): 1122–4. doi:10.1038/sj.embor.7400308. PMID 15577925. 
• Watts G (May 2004). "The defence of dirt". BMJ 328 (7450): 1226. doi:10.1136/bmj.38075.565822.55. PMID 15121715. 
• Rook GA, Brunet LR (March 2005). "Microbes, immunoregulation, and the gut". Gut 54 (3): 317–20. doi:10.1136/gut.2004.053785. PMID 15710972. 
• Rook GA, Adams V, Hunt J, Palmer R, Martinelli R, Brunet LR (February 2004). "Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders". Springer Semin. Immunopathol. 25 (3-4): 237–55. doi:10.1007/s00281-003-0148-9. PMID 15007629. http://www.springerlink.com/content/0byj25luk2l8e6f8/. 
• Separating Friend From Foe Among the Body’s Invaders
• Hygiene Hypothesis: Are We Too "Clean" for Our Own Good?
• His Parasite Theory Stirs a Revolution