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 suppressing natural development of the immune system.^[1] The rise of autoimmune diseases and acute lymphoblastic leukemia in young people in the developed world has also been linked to the hygiene hypothesis.^[2][3] There is some evidence that autism may be caused by an immune disease;^{[4][5][6][7][8]} One study supports the hygiene hypothesis theory and cites the lack of early childhood exposure as a cause of autism.^[9]

History

Although the idea that exposure to certain infections may decrease the risk of an allergy is not new, David P. Strachan was the first scientist who gave the theory a scientific background in an article published in the British Medical Journal (now the BMJ), in 1989.^[10] In this article, the hygiene hypothesis was proposed 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.^[11]

Mechanism of action

Allergic diseases are caused by inappropriate immunological responses to harmless antigens driven by a T_h2-mediated immune response. Many bacteria and viruses elicit a T_h1-mediated immune response, which down-regulates T_h2 responses. The first proposed mechanism of action of the hygiene hypothesis stated that insufficient stimulation of the T_h1 arm, stimulating the cell defence of the immune system, leads to an overactive T_h2 arm, stimulating the antibody-mediated immunity of the immune systems, which in turn led to allergic disease.^[12]

The first proposed mechanistic explanation for the hygiene hypothesis cannot explain the rise in incidence (similar to the rise of allergic diseases) of several T_h1-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 T_h1 and T_h2 responses, respectively.^[13]

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.^[14] In recent times, the development of hygienic practices, elimination of childhood diseases, widespread use of antibiotics, and relative availability effective medical care 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.^[15]

Supporting evidence

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.^[16]

Studies in mice have shown that exposure of young mice to viruses can result in a decreased incidence of diabetes.^[17]

In Cell : Homeostatic Expansion of T Cells during Immune Insufficiency Generates Autoimmunity they showed that when short lived T cells were replaced during a state of too few long lived T-cells (Memory T cell), because of lack of infections, the risk of developing autoimmune diseases will increase. They showed that in a state of too few long lived T-cells, because of lack of infections, not enough short lived T-cells could be produced by long lived T-cells during homeostatic expansion. Therefore, more auto reactive T-cells will divide in such a state, causing multiplying auto reactive T-cells with a greater risk of causing autoimmune diseases like type I diabetes or MS.^[18]

One conclusion is that a clean environment, with lack of infections (like early life infections) increases the risk of an autoimmune disorder.

T_h2 immune disorders such as asthma and other allergic diseases are probably related to the hygiene hypothesis. A baby has many T_h2 cells, which stimulate the production of antibodies. When not sufficiently stimulated with early life diseases, the immune system will have too many T_h2 cells present, leading to a greater risk of T_h2 immune disorder. If a child is exposed to infection diseases then the cell defense will be stimulated via Th1 cells causing a reduction of Th2 cells and subsequently a reduction of antibody stimulation by Th2 and therefore a lower risk of developing an allergic disease such as asthma. Unfortunately, vaccination only uses the Th2 mechanism.

In developed countries where childhood diseases were 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.^[19] The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases.^[20] 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.^[21][22] However, the studies investigating these links showed only tenuous correlations between the factors described and the conditions they are hypothesized 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.^[23][24]

A double blind study performed on 2500 pregnant women in Uganda showed that infants of the women treated with anthelminthic medication for worm infections had double the rate of doctor-diagnosed infantile eczema.^[25]

Helminthic therapy

Main article: Helminthic therapy

See also: Effects of parasitic worms on the immune system

The use of parasitic worms (also known as 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 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,^{[26][27][28][29]} multiple sclerosis,^[30] asthma,^[31][32] and ulcerative colitis.^[33] Autoimmune liver disease has also been demonstrated to be modulated by active helminth infections.^[34]

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.^[35]

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.^{[32][36][36][37][38]} If helminthic therapy and other therapies using other types of infectious organisms, such as protozoa,^[39] 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 allergies 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 in occupational situations can cause allergic diseases, such as Laboratory animal allergy, bird lung, farmer's lung, and bakers lung (See Wheat allergy). 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, and much more so than in the bleak Dickensian years of the early 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 (includes more discussion of hygiene hypothesis)
• Diseases of affluence

References

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Further reading

• Hadley C (December 2004). "Should auld acquaintance be forgot.". EMBO Rep. 5 (12): 1122–4. doi:10.1038/sj.embor.7400308. PMC 1299202. PMID 15577925. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1299202. 
• Watts G (May 2004). "The defence of dirt". BMJ 328 (7450): 1226. doi:10.1136/bmj.38075.565822.55. PMC 416594. PMID 15121715. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=416594. 
• Rook GA, Brunet LR (March 2005). "Microbes, immunoregulation, and the gut". Gut 54 (3): 317–20. doi:10.1136/gut.2004.053785. PMC 1774411. PMID 15710972. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1774411. 
• 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/. 
• Camateros P, Moisan J, Hénault J, et al. (2006). "Toll-like receptors, cytokines and the immunotherapeutics of asthma". Curr Pharm Des 12 (19): 2365–74. doi:10.2174/138161206777698918. PMID 16842184. http://www.bentham-direct.org/pages/content.php?CPD/2006/00000012/00000019/0004B.SGM. 

External links

• Separating Friend From Foe Among the Body’s Invaders
• Hygiene Hypothesis: Are We Too "Clean" for Our Own Good?^{[dead link]}
• His Parasite Theory Stirs a Revolution