In medicine, the hygiene hypothesis is a hypothesis that states a lack of early childhood exposure to infectious agents, symbiotic microorganisms (such as the gut flora or probiotics), and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system. In particular, the lack of exposure is thought to lead to defects in the establishment of immune tolerance.
- 1 Overview
- 2 History
- 3 Evolution of the adaptive immune system
- 4 Biological basis
- 5 Epidemiological evidence
- 6 Experimental evidence
- 7 Public health trends
- 8 Treatment
- 9 Cleanliness
- 10 Alternative hypotheses
- 11 See also
- 12 References
- 13 Further reading
- 14 External links
The original formulation of the hygiene hypothesis dates from 1989 when David Strachan proposed that lower incidence of infection in early childhood could be an explanation for the rapid 20th century rise in allergic diseases such as asthma and hay fever.
It is now also recognised that the "reduced microbial exposure" concept applies to a much broader range of chronic inflammatory diseases than asthma and hay fever, which includes diseases such as type 1 diabetes and multiple sclerosis, and also some types of depression and cancer.[specify]
In 2003 Graham Rook proposed the "old friends hypothesis" which some claim offers a more rational explanation for the link between microbial exposure and inflammatory disorders. He argues that the vital microbial exposures are not colds, influenza, measles and other common childhood infections which have evolved relatively recently over the last 10,000 years, but rather the microbes already present during mammalian and human evolution, that could persist in small hunter gatherer groups as microbiota, tolerated latent infections or carrier states. He proposes that humans have become so dependent on these "old friends" that their immune systems neither develop properly nor function properly without them.
Strachan's original formulation of the hygiene hypothesis also centred around the idea that smaller families provided insufficient microbial exposure partly because of less person-to-person spread of infections, but also because of "improved household amenities and higher standards of personal cleanliness". It seems likely that this was the reason he named it the "hygiene hypothesis". Although the "hygiene revolution" of the nineteenth and twentieth centuries may have been a major factor, it now seems more likely that, although public health measures such as sanitation, potable water and garbage collection were instrumental in reducing our exposure to cholera, typhoid and so on, they also deprived people of their exposure to the "old friends" that occupy the same environmental habitats.
Some evidence indicates that autism is correlated to factors (such as certain cytokines) that are indicative of an immune disease. One publication speculated that the lack of early childhood exposure could be a cause of autism.
The risk of chronic inflammatory diseases also depends on factors such as diet, pollution, physical activity, obesity, socio-economic factors and stress. Genetic predisposition is also a factor.
Although the idea that exposure to certain infections may decrease the risk of allergy is not new, Strachan was one of the first to formally propose it, in an article published in the British Medical Journal in 1989. This article 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 hypothesis was extensively investigated by immunologists and epidemiologists and has become an important theoretical framework for the study of chronic inflammatory disorders. It explains the increase in allergic diseases that has been seen since industrialization and the higher incidence of allergic diseases in more developed countries. Epidemiological studies continue to confirm the protective effect of large family size and of growing up on a farm. However, exposure to common childhood infections such as chickenpox or measles is not thought to be protective.
The "old friends hypothesis" proposed in 2003 may offer a better explanation for the link between microbial exposure and inflammatory diseases. This hypothesis argues that the vital exposures are not common childhood and other recently evolved infections, which are no older than 10,000 years, but rather microbes already present in hunter-gatherer times when the human immune system was evolving. Conventional childhood infections are mostly "crowd infections" that kill or immunise and thus cannot persist in isolated hunter-gatherer groups. Crowd infections started to appear after the neolithic agricultural revolution, when human populations increased in size and proximity. The microbes that co-evolved with mammalian immune systems are much more ancient. According to this hypothesis, humans became so dependent on them that their immune systems can neither develop nor function properly without them.
Rook proposed that these microbes most likely include:
- Ambient species that exist in the same environments as humans
- Species that inhabit human skin, gut and respiratory tract, and that of the animals we live with
- Organisms such as viruses and helminths (worms) that establish chronic infections or carrier states that humans can tolerate and so could co-evolve a specific immunoregulatory relationship with the immune system.
"Evolution turns the inevitable into a necessity." This means that the majority of mammalian evolution took place in mud and rotting vegetation and more than 90 percent of human evolution took place in isolated hunter-gatherer communities and farming communities. Therefore, the human immune systems have evolved to anticipate certain types of microbial input, making the inevitable exposure into a necessity. The organisms that are implicated in the hygiene hypothesis are not proven to cause the disease prevalence, however there are sufficient data on lactobacilli, saprophytic environment mycobacteria, and helminths and their association. These bacteria and parasites have commonly been found in vegetation, mud, and water throughout evolution.
Multiple possible mechanisms have been proposed for how the 'Old Friends' microorganisms prevent autoimmune diseases and asthma. They include:
- Reciprocal inhibition between immune responses directed against distinct antigens of the Old Friends microbes which elicit stronger immune responses than the weaker autoantigens and allergens of autoimmune disease and allergy respectively.
- Competition for cytokines, MHC receptors and growth factors needed by the immune system to mount an immune response.
- Immunoregulatory interactions with host TLRs.
The "microbial diversity" hypothesis, proposed by Paolo Matricardi and developed by von Hertzen, holds that diversity and turnover of bacterial species in the gut mucosa and other sites is a key factor for priming and regulating the immune system, rather than stable colonization with a particular species. It is not clear whether diversity per se, or that a diverse population will include certain organisms without which the immune system fails to develop. Rook likened the embryonic immune system to a computer that contains programmes but little data. During gestation and infancy exposure to diverse organisms builds a "database" that allows the immune system to identify and respond to harmful agents and normalize once the danger is eliminated.
For allergic disease, the most important times for exposure are: early in development; later during pregnancy; and the first few days or months of infancy. Exposure needs to be maintained over a significant period. This fits with evidence that delivery by Caesarean section may be associated with increased allergies, whilst breastfeeding can be protective. The extent to which exposures need to be maintained after infancy and whether these conditions could be managed by on-going exposure is as yet unknown.
Evolution of the adaptive immune system
Humans and the microbes they harbor have co-evolved for thousands of centuries; however, it is thought that the human species has gone through numerous phases in history characterized by different pathogen exposures. For instance, in very early human societies, small interaction between its members has given particular selection to a relatively limited group of pathogens that had high transmission rates. When societies became larger, the introduction of agriculture some 10,000 years ago made the spreading of new pathogens more likely, and thus exposures to pathogens that favored high population densities to thrive. Furthermore, pastoralism has made zoonotic pathogen transmissions even more favorable. It is considered that the human immune system is likely subjected to a selective pressure from pathogens that are responsible for down regulating certain alleles and therefore phenotypes in humans, the thalassemia genes that are shaped by the Plasmodium species expressing the selection pressure being a model for this theory.
Recent comparative genomic studies have shown that immune response genes (protein coding and non-coding regulatory genes) have less evolutionary constraint, and are rather more frequently targeted by positive selection from pathogens that coevolve with the human subject. Of all the various types of pathogens known to cause disease in humans, helminths warrant special attention, because of their ability to modify the prevalence or severity of certain immune-related responses in human and mouse models. In fact recent research has shown that parasitic worms have served as a stronger selective pressure on select human genes encoding interleukins and interleukin receptors when compared to viral and bacterial pathogens. Helminths are thought to have been as old as the adaptive immune system, suggesting that they may have co-evolved, also implying that our immune system has been strongly focused on fighting off helminthic infections, insofar as to potentially interact with them early in infancy. The host-pathogen interaction is a very important relationship that serves to shape the immune system development early on in life.
Allergic conditions are caused by inappropriate immunological responses to harmless antigens driven by a TH2-mediated immune response, TH2 cells produce interleukin 4, interleukin 5, interleukin 6, interleukin 13 and predominantly immunoglobulin E. Many bacteria and viruses elicit a TH1-mediated immune response, which down-regulates TH2 responses. TH1 immune responses are characterized by the secretion of pro-inflammatory cytokines such as interleukin 2, IFNγ, and TNFα. Factors that favor a predominantly TH1 phenotype include: older siblings, large family size, early day care attendance, infection (TB, measles, or hepatitis), rural living, or contact with animals. A TH2-dominated phenotype is associated with high antibiotic use, western lifestyle, urban environment, diet, and sensitivity to dust mites and cockroaches. TH1 and TH2 responses are reciprocally inhibitory, so when one is active, the other is suppressed.  
The mechanism of action of the hygiene hypothesis was insufficient stimulation of the TH1 arm, stimulating the cell defence of the immune system and leading to an overactive mother TH2 arm, stimulating the antibody-mediated immunity of the immune systems, which in turn led to allergic disease.
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This explanation however, cannot explain the rise in incidence (similar to the rise of allergic diseases) of several TH1-mediated autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and type I diabetes. [Figure 1Bach] However, the North South Gradient seen in the prevalence of multiple sclerosis has been found to be inversely related to the global distribution of parasitic infection.[Figure 2Bach] Additionally, research has shown that MS patients infected with parasites displayed TH2 type immune responses as opposed to the proinflammatory TH1 immune phenotype seen in non-infected multiple sclerosis patients.[Fleming] Parasite infection has also been shown to improve inflammatory bowel disease and may act in a similar fashion as it does in multiple sclerosis.[Lee]
An alternative explanation is that the developing immune system must receive stimuli (from infectious agents, symbiotic bacteria, or parasites) to adequately develop regulatory T cells. Without that stimuli it becomes more susceptible to autoimmune diseases and allergic diseases, because of insufficiently repressed TH1 and TH2 responses, respectively. For example, all chronic inflammatory disorders show evidence of failed immunoregulation. Secondly, helminths, non-pathogenic ambient pseudocommensal bacteria or certain gut commensals and probiotics, drive immunoregulation. They block or treat models of all chronic inflammatory conditions. Thirdly, some such organisms (or molecules that they secrete), specifically expand populations of regulatory T cells (Treg), or cause dendritic cells to switch to regulatory forms that preferentially drive immunoregulation. Finally, when multiple sclerosis patients become infected with helminths, the disease stops progressing and circulating myelin-recognising regulatory T cells appear in the peripheral blood. This indicates that helminths act as adjuvants for regulatory T cells. This observation led to clinical trials.
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. This is true for asthma and other chronic inflammatory disorders.
Recently, Opisthorchis felineus chronic helminthic infection in the endemic region of Russia was found to be associated with lower total serum cholesterol levels and a significant attenuation of atherosclerosis in humans.
In developed countries where childhood diseases were eliminated, the asthma rate for youth is approximately 10%. In the 19th century, hay-fever, an easily recognisable allergy, was a very rare condition.
Longitudinal studies in Ghana demonstrate an increase in immunological disorders as it grew more affluent and presumably cleaner. These results have been replicated by Weinberg et al. who amassed data from a variety of African countries comparing urban and rural environments as well as high and low socioeconomic status (SES). In all four countries urban and high SES groups had a higher prevalence of exercise induced bronchospasm. The use of antibiotics in the first year of life has been linked to asthma and other allergic diseases. The use of antibacterial cleaning products has also been associated with higher incidence of asthma. Increased asthma rates are associated with birth by Caesarean section. The data supporting links to antibiotic use and caesarean section (but not to antibacterial use) are rapidly strengthening.
Antibiotic usage, which reduces the diversity of gut microbiota, is another cited factor. Although several studies have shown associations between antibiotic use and later development of asthma or allergy, other studies suggest that the effect is due to more frequent antibiotic use in asthmatic children. Trends in vaccine use may also be relevant, but epidemiological studies provide no consistent support for a detrimental effect of vaccination/immunization on atopy rates. In support of the old friends hypothesis, the intestinal microbiome was found to differ between allergic and non-allergic Estonian and Swedish children but this finding was not replicated in a larger cohort and the biodiversity of the intestinal flora in patients with Crohn’s disease was diminished.
In 2015, a study found that washing dishes by hand as opposed to using a dishwasher, along with eating food directly from a farm or fermented food, might lead to reduced risk of certain conditions, including asthma, eczema, and possibly hay fever, though the data found on hay fever was not regarded as statistically significant. It was stated, however, that more research was needed to determine if there was an actual causal effect between these practices and a reduced risk of allergies and asthma.
King et al. 2004 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 increases. 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 divide in such a state, causing multiplying auto reactive T cells with a greater risk of causing autoimmune diseases like Type 1 diabetes or multiple sclerosis.
Timing is crucial, and coxsackieviruses, rotaviruses and lymphocytic choriomeningitis virus that can be protective when given very early and can provoke autoimmunity when given late (for instance at weaning).[clarification needed]
Early life exposure to specific microbe-enriched environments decreases susceptibility to diseases such as inflammatory bowel disease and asthma, whereas its absence, as in antibiotic treatment during childhood, may have the opposite effect. Olszak and colleagues, compared germ-free mice and specific-pathogen-free mice, challenged with aerosol ovoalbumin to promote allergen-induced airway inflammation. They found that early exposure to conventional microbiota protected animals from developing asthma.
Public health trends
Since allergies and other chronic inflammatory diseases are largely diseases of the last 100 years or so, the "hygiene" revolution of the last 200 years came under scrutiny as a possible cause. During the 1800s radical improvements to sanitation and water quality occurred in Europe and North America. The introduction of toilets and sewer systems and the cleanup of city streets, and cleaner food were part of this program. This in turn led to a rapid decline in infectious diseases, particularly during the period 1900-1950, through reduced exposure to infectious agents.
Public health activities have also played a part in affecting diet and lifestyle, such as physical activity levels and locations.
It has been suggested that public awareness of the initial form of the "hygiene hypothesis" has led to an "increased disregard" for hygiene in the home.
While no hygiene-related treatments are part of the standard of care, various approaches are under investigation. Helminth therapy is one alternative. Probiotics (drinks or foods) have never been shown to reintroduce microbes to the gut. As yet, therapeutically relevant microbes have not been specifically identified.
Lifestyle changes could increase microbial exposure, but whether this on balance improves the balance of risks remains the subject of research. Proposals include natural childbirth, sustained breast feeding and physical interaction between siblings, and encouraging children to spend more time in "uncleaned" outdoor environments.
Should these therapies become accepted, public policy implications include providing green spaces in urban areas or even providing access to agricultural environments for children.
Helminthic therapy is the treatment of autoimmune diseases and immune disorders by means of deliberate infestation with a helminth larva or ova. Helminthic therapy is currently being studied as a promising treatment for several (non-viral) autoimmune diseases including Crohn's disease, multiple sclerosis, asthma, and ulcerative colitis. Autoimmune liver disease can be modulated by active helminth infections.
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. Their increased incidence cannot be solely attributed to environmental factors. Recent research explored the eradication of helminths as contributing to this discrepancy.
Related therapies include use other types of infectious organisms, such as protozoa.
No evidence supports the idea that reducing modern practices of cleanliness and hygiene would have any impact on rates of chronic inflammatory and allergic disorders, but a significant amount of evidence that it would increase the risks of infectious diseases.
If home and personal cleanliness contributes to reduced exposure to vital microbes, its role is likely to be small. The idea that homes can be made “sterile” through excessive cleanliness is implausible. The evidence shows that, as fast as they are removed by cleaning, microbes are replaced, via dust and air from outdoors, by shedding from the body and other living things as well as from food. The key point may be that the microbial content of urban housing has altered, not because of home and personal hygiene habits, but because they are part of urban environments. Diet and lifestyle changes also affects the gut, skin and respiratory microbiota.
At the same time that concerns about allergies and other chronic inflammatory diseases have been increasing, so also have concerns about infectious disease. Infectious diseases continue to exert a heavy health toll. Preventing pandemics and reducing antibiotic resistance are global priorities. Hygiene is a cornerstone of containing these threats.
Infection risk management
The International Scientific Forum on Home Hygiene has developed a risk management approach to reducing home infection risks. This approach uses microbiological and epidemiological evidence to identify the key routes of infection transmission in the home. These data indicate that the critical routes involve the hands, hand and food contact surfaces and cleaning utensils. Clothing and household linens involve somewhat lower risks. Surfaces that contact the body, such as baths and hand basins, can act as infection vehicles, as can surfaces associated with toilets. Airborne transmission can be important for some pathogens. A key aspect of this approach is that it maximises protection against pathogens and infection, but is more relaxed about visible cleanliness in order to sustain normal exposure to other human, animal and environmental microbes.
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There are other hypotheses that try to explain the increase in allergies in developed nations. Major areas of focus include infant feeding, over-exposure and exposure to certain pollutants.
Infant feeding topics includes breastfeeding, when babies begin to eat solid foods and the type of these foods, cow's milk vs other milks and variations in milk processing.
- Antibacterial soap
- Diseases of affluence
- Hookworm in therapy
- Helminthic therapy (includes more discussion of hygiene hypothesis)
- Vaginal seeding
- Microbiomes of the built environment
- William Parker (2010-10-13). "Reconstituting the depleted biome to prevent immune disorders". The Evolution & Medicine Review. Retrieved 2014-03-31.
- Strachan, D. (2000). "Family size, infection and atopy: The first decade of the 'hygiene hypothesis'". Thorax. 55 (90001): 2S. doi:10.1136/thorax.55.suppl_1.S2.
- Stene LC, Nafstad P. Relation between occurrence of type 1 diabetes and asthma" Lancet 2001;357:607
- Raison CL, Lowry CA, Rook GAW. Inflammation, sanitation and consternation: loss of contact with co-evolved, tolerogenic micro-organisms and the pathophysiology and treatment of major depression" Arch Gen Psychiatry 2010;67(12) 1211-24
- Rook, G. A. W.; Lowry, C. A.; Raison, C. L. (2013). "Microbial 'Old Friends', immunoregulation and stress resilience". Evolution, Medicine, and Public Health. 2013: 46–64. doi:10.1093/emph/eot004.
- Rook GA, Dalgleish A (2011). "Infection, immunoregulation and cancer". Immunological Reviews. 240 (1): 141–59. doi:10.1111/j.1600-065x.2010.00987.x. PMID 21349092.
- Rook GA, Martinelli R, Brunet LR. Innate immune responses to mycobacteria and the downregulation of atopic responses" Curr Opin Allergy Clin Immunol 2003 Oct;3(5) 337-42.
- Stanwell-Smith R, Bloomfield SF, Rook GA. (2012). "The hygiene hypothesis and its implications for home hygiene, lifestyle and public health". International Scientific Forum on Home Hygiene.
- Bloomfield SF, Stanwell-Smith R, Rook GA. (2012) The hygiene hypothesis and its implications for home hygiene, lifestyle and public health: summary. International Scientific Forum on Home Hygiene. http://www.ifh-homehygiene.org/best-practice-review/hygiene-hypothesis-and-its-implications-home-hygiene-lifestyle-and-public
- Smith, M. A.; Simon, R.; Strickler, H. D.; McQuillan, G.; Gloeckler Ries, L. A.; Linet, M. S. (1998). "Evidence that Childhood Acute Lymphoblastic Leukemia is Associated with an Infectious Agent Linked to Hygiene Conditions". Cancer Causes & Control. 9 (3): 285–298. doi:10.1023/A:1008873103921.
- Okada, H.; Kuhn, C.; Feillet, H.; Bach, J. -F. (2010). "The 'hygiene hypothesis' for autoimmune and allergic diseases: An update". Clinical & Experimental Immunology. 160: 1–9. doi:10.1111/j.1365-2249.2010.04139.x.
- Croonenberghs, J.; Wauters, A.; Devreese, K.; Verkerk, R.; Scharpe, S.; Bosmans, E.; Egyed, B.; Deboutte, D.; Maes, M. (2002). "Increased serum albumin, γ globulin, immunoglobulin IgG, and IgG2 and IgG4 in autism". Psychological Medicine. 32 (8). doi:10.1017/S0033291702006037.
- Gupta, S.; Aggarwal, S.; Rashanravan, B.; Lee, T. (1998). "Th1- and Th2-like cytokines in CD4+ and CD8+ T cells in autism". Journal of Neuroimmunology. 85 (1): 106–109. doi:10.1016/S0165-5728(98)00021-6. PMID 9627004.
- Ashwood, P.; Wakefield, A. J. (2006). "Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms". Journal of Neuroimmunology. 173 (1–2): 126–134. doi:10.1016/j.jneuroim.2005.12.007. PMID 16494951.
- Zimmerman, A. W.; Jyonouchi, H.; Comi, A. M.; Connors, S. L.; Milstien, S.; Varsou, A.; Heyes, M. P. (2005). "Cerebrospinal Fluid and Serum Markers of Inflammation in Autism". Pediatric Neurology. 33 (3): 195–201. doi:10.1016/j.pediatrneurol.2005.03.014. PMID 16139734.
- Molloy, C.; Morrow, A.; Meinzen-Derr, J.; Schleifer, K.; Dienger, K.; Manning-Courtney, P.; Altaye, M.; Wills-Karp, M. (2006). "Elevated cytokine levels in children with autism spectrum disorder". Journal of Neuroimmunology. 172 (1–2): 198–205. doi:10.1016/j.jneuroim.2005.11.007. PMID 16360218.
- Becker, K. G. (2007). "Autism, asthma, inflammation, and the hygiene hypothesis". Medical Hypotheses. 69 (4): 731–740. doi:10.1016/j.mehy.2007.02.019. PMC . PMID 17412520.
- Rook GAW. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: darwinian medicine and the 'hygiene' or 'old friends' hypothesis. Clin Exp Immunol. 2010 Apr;160(1) 70-9.
- Filippi CM, von Herrath MG (2008). "Viral trigger for type 1 diabetes: pros and cons". Diabetes. 57 (11): 2863–2871. doi:10.2337/db07-1023. PMC . PMID 18971433.
- Rook GA (2012). "Hygiene hypothesis and autoimmune diseases". Clin Rev Allergy Immunol. 42 (1): 5–15. doi:10.1007/s12016-011-8285-8. PMID 22090147.
- Strachan, D. P. (1989). "Hay fever, hygiene, and household size". BMJ. 299 (6710): 1259–60. doi:10.1136/bmj.299.6710.1259. PMC . PMID 2513902.
- Grammatikos Alexandros P (2008). "The genetic and environmental basis of atopic diseases". Annals of Medicine. 40 (7): 482–95. doi:10.1080/07853890802082096. PMID 18608118.
- Matricardi PM (2010). "99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: controversial aspects of the 'hygiene hypothesis'". Clin Exp Immunol. 160 (1): 98–105. doi:10.1111/j.1365-2249.2010.04130.x. PMC . PMID 20415858.
- von Hertzen L, Hanski I, Haahtela T (2011). "Natural immunity. Biodiversity loss and inflammatory diseases are two global megatrends that might be related". EMBO Rep. 12 (11): 1089–1093.
- Sironi, Manuela, and Mario Clerici. "The Hygiene Hypothesis: An Evolutionary Perspective." Microbes and Infection: 421-27
- Wolfe N.D.; Dunavan C.P.; Diamond J. (2007). "Origins of major human infectious diseases". Nature. 447 (7142): 279–283. doi:10.1038/nature05775.
- Kosiol C.; Vinar T.; Hubisz M.J.; Bustamante C.D.; Nielsen R.; Siepel A. (2008). "Patterns of positive selection in six mammalian genomes". PLoS Genet. 4 (8): e1000144. doi:10.1371/journal.pgen.1000144. PMC . PMID 18670650.
- Fumagalli M.; Pozzoli U.; Cagliani R.; Comi G.P.; Riva S.; Clerici M.; Bresolin N.; Sironi M. (2009). "Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions". J. Exp. Med.: 206.
- Kramer; et al. (2013). "Maintaining Health by Balancing Microbial Exposure and Prevention of Infection: the Hygiene Hypothesis versus the Hypothesis of Early Immune Challenge". Journal of Hospital Infection. 83: 51.
- Lee et. al. "Inflammatory Bowel Disease." 2014. Evolution, Medicine, and Public Health. P.95.
- Weinberg (2000). "Urbanization and Childhood Asthma: An African Perspective". Journal of Allergy and Clinical Immunology. 105 (2): 224–231. doi:10.1016/s0091-6749(00)90069-1.
- Folkerts, Gert; Walzl, Gerhard; Openshaw, Peter J.M. (2000). "Do common childhood infections 'teach' the immune system not to be allergic?". Immunology Today. 21 (3): 118–20. doi:10.1016/S0167-5699(00)01582-6. PMID 10777250.
- Bufford, Jeremy D.; Gern, James E. (2005). "The Hygiene Hypothesis Revisited". Immunology and Allergy Clinics of North America. 25 (2): 247–62, v–vi. doi:10.1016/j.iac.2005.03.005. PMID 15878454.
- Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK (May 2011). "The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota". Science. 332 (6032): 974–7. doi:10.1126/science.1206095. PMC . PMID 21512004.
- Osada Y, Kanazawa T (2010). "Parasitic helminths: new weapons against immunological disorders". J Biomed Biotechnol. 2010: 743–58.
- Grainger JR, Smith KA, Hewitson JP, McSorley HJ, Harcus Y, Filbey KJ, Finney CA, Greenwood EJ, Knox DP, Wilson MS, Belkaid Y, Rudensky AY, Maizels RM (2010). "Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway". J Exp Med. 207 (11): 2331–41. doi:10.1084/jem.20101074. PMC . PMID 20876311.
- Smits HH, Engering A, van der Kleij D, de Jong EC, Schipper K, van Capel TM, Zaat BA, Yazdanbakhsh M, Wierenga EA, van Kooyk Y, Kapsenberg ML (Jun 2005). "Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin". J Allergy Clin Immunol. 115 (6): 1260–7. doi:10.1016/j.jaci.2005.03.036. PMID 15940144.
- Correale J, Farez M (Feb 2007). "Association between parasite infection and immune responses in multiple sclerosis". Ann Neurol. 61 (2): 97–108. doi:10.1002/ana.21067. PMID 17230481.
- Fleming J, Isaak A, Lee J, Luzzio C, Carrithers M, Cook T, Field A, Boland J, Fabry Z (Mar 2011). "Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study". Mult Scler. 17 (6): 743–54. doi:10.1177/1352458511398054. PMC . PMID 21372112.
- Gibson, Peter G.; Henry, Richard L.; Shah, Smita; Powell, Heather; Wang, He (2003). "Migration to a western country increases asthma symptoms but not eosinophilic airway inflammation". Pediatric Pulmonology. 36 (3): 209–15. doi:10.1002/ppul.10323. PMID 12910582.
- Magen Eli; Bychkov Vitaly; Ginovker Alexander; Kashuba Eduard (2013). "Chronic Opisthorchis felineus infection attenuates atherosclerosis – an autopsy study". International Journal for Parasitology. 43 (10): 819–24. doi:10.1016/j.ijpara.2013.04.008. PMID 23792298.
- Blackley CH (1873) Experimental Researches on the Causes and Nature of Catarrhus Aestivus (Hay-fever and Hay-asthma) (Baillière Tindall and Cox, London).
- Addo-Yobo, Emmanuel O. D.; Woodcock, Ashley; Allotey, Adorkor; Baffoe-Bonnie, Benjamin; Strachan, David; Custovic, Adnan (2007). "Exercise-Induced Bronchospasm and Atopy in Ghana: Two Surveys Ten Years Apart". PLoS Medicine. 4 (2): e70. doi:10.1371/journal.pmed.0040070. PMC . PMID 17326711.
- Weinberg (2000). "Urbanization and Childhood Asthma: An African Perspective." 2000". Journal of Allergy and Clinical Immunology. 105 (2): 224–231. doi:10.1016/s0091-6749(00)90069-1.
- Marra, F.; Lynd, L; Coombes, M; Richardson, K; Legal, M; Fitzgerald, JM; Marra, CA (2006). "Does Antibiotic Exposure During Infancy Lead to Development of Asthma?: A Systematic Review and Metaanalysis". Chest. 129 (3): 610–8. doi:10.1378/chest.129.3.610. PMID 16537858.
- Thavagnanam, S.; Fleming, J.; Bromley, A.; Shields, M. D.; Cardwell, C. R. (2008). "A meta-analysis of the association between Caesarean section and childhood asthma". Clinical & Experimental Allergy. 38 (4): 629–33. doi:10.1111/j.1365-2222.2007.02780.x. PMID 18352976.
- Zock, Jan-Paul; Plana, Estel; Jarvis, Deborah; Antó, Josep M.; Kromhout, Hans; Kennedy, Susan M.; Künzli, Nino; Villani, Simona; Olivieri, Mario; Torén, Kjell; Radon, Katja; Sunyer, Jordi; Dahlman-Hoglund, Anna; Norbäck, Dan; Kogevinas, Manolis (2007). "The Use of Household Cleaning Sprays and Adult Asthma". American Journal of Respiratory and Critical Care Medicine. 176 (8): 735–41. doi:10.1164/rccm.200612-1793OC. PMC . PMID 17585104.
- Magnus MC, Haberg SE, Stigum H, Nafstad P, London SJ, Vangen S, Nystad W (Dec 2011). "Delivery by Cesarean section and early childhood respiratory symptoms and disorders: the Norwegian mother and child cohort study". Am J Epidemiol. 174 (11): 1275–85. doi:10.1093/aje/kwr242. PMC . PMID 22038100.
- Metsala J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM (2013). "Mother's and offspring's use of antibiotics and infant allergy to cow's milk". Epidemiology. 24 (2): 303–309. doi:10.1097/ede.0b013e31827f520f.
- Netburn, Deborah (February 23, 2015). "How hand-washing dishes may prevent kids from getting allergies". Los Angeles Times. Retrieved February 26, 2015.
- King, Cecile; Ilic, Alex; Koelsch, Kersten; Sarvetnick, Nora (2004). "Homeostatic Expansion of T Cells during Immune Insufficiency Generates Autoimmunity". Cell. 117 (2): 265–77. doi:10.1016/S0092-8674(04)00335-6. PMID 15084263.
- Serreze DV, Ottendorfer EW, Ellis TM, Gauntt CJ, Atkinson MA (2000). "Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets". Diabetes. 49 (5): 708–711. doi:10.2337/diabetes.49.5.708.
- Harrison LC, et al. (2008). "Type 1 diabetes: lessons for other autoimmune diseases?". J Autoimmun. 31 (3): 306–310.
- "Dirt can be good for children, say scientists". BBC News. 23 November 2009. Retrieved 2012-04-25.
- Lai, Yuping; Di Nardo, Anna; Nakatsuji, Teruaki; Leichtle, Anke; Yang, Yan; Cogen, AnnaL; Wu, ZiRong; Hooper, Lora V; Schmidt, Richard R; Von Aulock, Sonja; Radek, Katherine A; Huang, Chun-Ming; Ryan, Allen F; Gallo, Richard L (2009). "Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury". Nature Medicine. 15 (12): 1377–82. doi:10.1038/nm.2062. PMC . PMID 19966777.
- Olszak, T.; An, D.; Zeissig, S.; Vera, M. P.; Richter, J.; Franke, A.; Glickman, J. N.; Siebert, R.; Baron, R. M.; Kasper, D. L.; Blumberg, R. S. (2012). "Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function". Science. 336 (6080): 489–93. Bibcode:2012Sci...336..489O. doi:10.1126/science.1219328. PMC . PMID 22442383.
- Taché, J.; Carpentier, B. (2014). "Hygiene in the home kitchen: Changes in behaviour and impact of key microbiological hazard control measures". Food Control. 35: 392–400. doi:10.1016/j.foodcont.2013.07.026.
- Sanders ME, Guarner F, Guerrant R, Holt PR, Quigley EM, Sartor RB, Sherman PM, Mayer EA. An update on the use and investigation of probiotics in health and disease" Gut 2013 May;62(5) 787-96
- Rook GA (2013) Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health. PNAS 2013 Oct 23. doi:10.1073/pnas.1313731110
- Hunter, M. M.; McKay, D. M. (2004). "Helminths as therapeutic agents for inflammatory bowel disease". Alimentary Pharmacology and Therapeutics. 19 (2): 167–77. doi:10.1111/j.0269-2813.2004.01803.x. PMID 14723608.
- Croese, J; O'Neil, J; Masson, J; Cooke, S; Melrose, W; Pritchard, D; Speare, R (2006). "A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors". Gut. 55 (1): 136–7. doi:10.1136/gut.2005.079129. PMC . PMID 16344586.
- Summers, R W; Elliott, DE; Urban Jr, JF; Thompson, R; Weinstock, JV (2005). "Trichuris suis therapy in Crohn's disease". Gut. 54 (1): 87–90. doi:10.1136/gut.2004.041749. PMC . PMID 15591509.
- Summers, Robert W.; Elliott, David E.; Qadir, Khurram; Urban Jr, Joseph F.; Thompson, Robin; Weinstock, Joel V. (2003). "Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease". The American Journal of Gastroenterology. 98 (9): 2034–41. doi:10.1111/j.1572-0241.2003.07660.x. PMID 14499784.
- Correale, Jorge; Farez, Mauricio (2007). "Association between parasite infection and immune responses in multiple sclerosis". Annals of Neurology. 61 (2): 97–108. doi:10.1002/ana.21067. PMID 17230481.
- Falcone, Franco H.; Pritchard, David I. (2005). "Parasite role reversal: Worms on trial". Trends in Parasitology. 21 (4): 157–60. doi:10.1016/j.pt.2005.02.002. PMID 15780835.
- Leonardi-Bee, Jo; Pritchard, David; Britton, John (2006). "Asthma and Current Intestinal Parasite Infection". American Journal of Respiratory and Critical Care Medicine. 174 (5): 514–23. doi:10.1164/rccm.200603-331OC. PMID 16778161.
- Summers, Robert W.; Elliott, David E.; Urban Jr, Joseph F.; Thompson, Robin A.; Weinstock, Joel V. (2005). "Trichuris suis therapy for active ulcerative colitis: A randomized controlled trial". Gastroenterology. 128 (4): 825–32. doi:10.1053/j.gastro.2005.01.005. PMID 15825065.
- Aoyama, H; Hirata, T; Sakugawa, H; Watanabe, T; Miyagi, S; Maeshiro, T; Chinen, T; Kawane, M; Zaha, O; Nakayoshi, T; Kinjo, F; Fujita, J (2007). "An inverse relationship between autoimmune liver diseases and Strongyloides stercoralis infection". The American Journal of Tropical Medicine and Hygiene. 76 (5): 972–6. PMID 17488925.
- Magen, Eli; Borkow, Gadi; Bentwich, Zvi; Mishal, Joseph; Scharf, Shimon (2005). "Can worms defend our hearts? Chronic helminthic infections may attenuate the development of cardiovascular diseases". Medical Hypotheses. 64 (5): 904–9. doi:10.1016/j.mehy.2004.09.028. PMID 15780483.
- Pugliatti, Maura; Sotgiu, Stefano; Rosati, Giulio (2002). "The worldwide prevalence of multiple sclerosis". Clinical Neurology and Neurosurgery. 104 (3): 182–91. doi:10.1016/S0303-8467(02)00036-7. PMID 12127652.
- Zaccone, P.; Fehervari, Z.; Phillips, J. M.; Dunne, D. W.; Cooke, A. (2006). "Parasitic worms and inflammatory diseases". Parasite Immunology. 28 (10): 515–23. doi:10.1111/j.1365-3024.2006.00879.x. PMC . PMID 16965287.
- Weinstock, J V; Summers, R; Elliott, DE (2004). "Helminths and harmony". Gut. 53 (1): 7–9. doi:10.1136/gut.53.1.7. PMC . PMID 14684567.
- Juckett, David A.; Aylsworth, Charles F.; Quensen, Janet Murphy (2008). "Intestinal protozoa are hypothesized to stimulate immunosurveillance against colon cancer". Medical Hypotheses. 71 (1): 104–10. doi:10.1016/j.mehy.2008.01.024. PMID 18343044.
- Bloomfield SF. Exner M, Signorelli C, Nath KJ, Scott EA. 2012. The chain of infection transmission in the home and everyday life settings, and the role of hygiene in reducing the risk of infection.http://www.ifh-homehygiene.org/best-practice-review/chain-infection-transmission-home-and-everyday-life-settings-and-role-hygiene
- Hygiene procedures in the home and their effectiveness: a review of the scientific evidence base (2008). International Scientific Forum on Home Hygiene. http://www.ifh-homehygiene.org/best-practice-review/hygiene-procedures-home-and-their-effectiveness-review-scientific-evidence-base
- Bloomfield SF, Exner M, Fara GM, Nath KJ, Scott, EA; Van der Voorden C. The global burden of hygiene-related diseases in relation to the home and community. (2009) International Scientific Forum on Home Hygiene. http://www.ifh-homehygiene.org/review/global-burden-hygiene-related-diseases-relation-home-and-community
- Bloomfield SF, Scott EA A risk assessment approach to use of antimicrobials in the home to prevent spread of infection American Journal of Infection Control 2013; 41: (5, Suppl) A1-A10, In Disinfection, Sterilization and Antisepsis: Current Issues, New Research and New Technologies. Edited by William A. Rutala and David J. Weber
- Bernard, A; Carbonnelle, S; Michel, O; et al. (2003). "Lung hyperpermeability and asthma prevalence in schoolchildren: Unexpected associations with the attendance at indoor chlorinated swimming pools". Occupational and Environmental Medicine. 60 (6): 385–94. doi:10.1136/oem.60.6.385. PMC . PMID 12771389.
- Hadley, C. (2004). "Should auld acquaintance be forgot". EMBO Reports. 5 (12): 1122–1124. doi:10.1038/sj.embor.7400308. PMC . PMID 15577925.
- Rook, G. A. W.; Brunet, L. R. (2005). "Microbes, immunoregulation, and the gut". Gut. 54 (3): 317–320. doi:10.1136/gut.2004.053785. PMC . PMID 15710972.
- Rook, G. A. W.; Adams, V.; Hunt, R.; Palmer, L. R.; Martinelli, J.; Brunet, R. (2004). "Mycobacteria and other environmental organisms as immunomodulators for immunoregulatory disorders". Springer Seminars in Immunopathology. 25 (3–4): 237–255. doi:10.1007/s00281-003-0148-9. PMID 15007629.