nation for the rapid 20th century rise in allergic diseases such as asthma and hay fever.

[2]
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[3] and multiple sclerosis,[4] and also some types of
depression[4][5] and cancer.[6][specify]
In 2003 Graham Rook proposed the "old friends hypothesis" which seems to offer a more
rational explanation for the link between microbial exposure and inflammatory disorders.
[7] 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 we have become so dependent on these "old friends" that our
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".[2] 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 tocholera, typhoid and so on, they also deprived us of our exposure to
the "old friends" that occupy the same environmental habitats. [8][9]
The rise of autoimmune diseases and acute lymphoblastic leukemia in young people in the
developed world was linked to the hygiene hypothesis. [10][11]
Some evidence indicates that autism is correlated to factors (such as certain cytokines) that
are indicative of an immune disease.[12][13][14][15][16] One publication speculated that the
lack of early childhood exposure could be a cause of autism.[17]
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.[18][19][20]

History[edit]
Hygiene[edit]
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 (now the BMJ), in 1989.[21] 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.

Old friends[edit]
The "old friends hypothesis" proposed in 2003[7] may offer a better explanation for the link
between microbial exposure and inflammatory diseases.[5][7] This hypothesis argues that the
vital exposures are not common childhood and other recently evolved infections, over the last
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. 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.
The modified hypothesis later expanded to include exposure to symbiotic bacteria and
parasites.[22]

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 helminthes and
their association. These bacteria and parasites have commonly been found in vegetation,
mud, and water throughout evolution.[5][7]
Multiple possible mechanisms have been proposed for how the Old Friends microorganisms
prevent autoimmune diseases and asthma. They include: 1. 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. 2. Competition for cytokines, MHC receptors and growth
factors needed by the immune system to mount an immune response. 3. Immunoregulatory
interactions with host TLRs.[11]

Microbial diversity[edit]
The "microbial diversity" hypothesis, proposed by Paolo Matricardi[23] and developed by von
Hertzen,[24] 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
colonisation 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.
[8] 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[edit]

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, helminthes
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. Helminthes 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. [25][26][27][28]

Biological basis[edit]
Allergic conditions are caused by inappropriate immunological responses to
harmless antigens driven by a TH2-mediated immune response, TH2 cells produceinterleukin
4, interleukin 5, interleukin 6, interleukin 13 and predominantly immunoglobulin E.
[11] 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, IFN, and TNF. 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.[29] [30] [31]
The mechanism of action of the hygiene hypothesis was insufficient stimulation of the T H1
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.[32]

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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, includinginflammatory 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 developregulatory T cells.
Without that stimuli it becomes more susceptible to autoimmune diseases and allergic
diseases, because of insufficiently repressed TH1 and TH2 responses, respectively.[33] For
example, all chronic inflammatory disorders show evidence of failed immunoregulation.
[18] 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.[34][35]Thirdly, some such organisms (or molecules that they
secrete), specifically expand populations of regulatory T cells (Treg),[34][36] or cause dendritic
cells to switch to regulatory forms that preferentially drive immunoregulation. [37] 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.[38] This indicates that helminths act as adjuvants for regulatory T cells. This
observation led to clinical trials.[39]

Epidemiological evidence[edit]
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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.[11] This is true for asthma[40] and other chronic
inflammatory disorders.[5]
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.[41]

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.[42]
Longitudinal studies in Ghana demonstrate an increase in immunological disorders as it grew
more affluent and presumably cleaner.[43] 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. [44] The use
of antibiotics in the first year of life has been linked to asthma and other allergic diseases.
[45] 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.[46][47]