1) The document discusses how immune disorders like type 1 diabetes, asthma, and multiple sclerosis have increased in developed countries due to decreased exposure to microorganisms like helminth worms. 2) It explores the coevolutionary history between helminths and vertebrates, noting that helminths elicit a Th2 immune response that evolved to regulate the immune system but may now contribute to immune disorders. 3) Several studies are cited showing that exposure to helminths or their antigens can reduce symptoms of asthma, type 1 diabetes, multiple sclerosis, and intestinal inflammation by inducing regulatory cytokines and cells. This supports the possibility of using helminths or their molecules to treat immune disorders.

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LB 492
Evolutionary History:
Helminth Infections and
New Treatment Options
for Immune Related
Disorders
David Wenzel
4/26/2011

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Introduction
Over the last fifty years there has been a marked decrease in infectious diseases in
developed countries, with an almost equal increase in immune related disorders such as: type 1
diabetes, asthma, allergies, Crohn’s disease and multiple sclerosis (Gluckman et al, 2009). One
explanation for this phenomenon is the “hygiene hypothesis” which suggests the increase in
immune disorders is caused by a decrease in regulation of the immune system, as a result of
the decreased exposure to microorganisms that were prevalent in vertebrate’s evolution (Rook,
2008). This has led to an hyper reactive immune response in developed countries.This
hypothesis was coined in the 1980s by researchers Strachan and Matricardi who found that
children who had more siblings were less prone to having hay fever (Rook, 2008). Since the first
study, the “hygiene hypothesis” has been expanded to include helminth worms, cowshed,
lactobicilla and many other microorganisms associated with contaminated water and food. The
scope of research will focus on the helminth worms and their coevolutionary history with
vertebrates, their effects on the immune system and the possibility to be used to treat the
immune disorders: type-1 diabetes, asthma, intestinal inflammation and multiple sclerosis.
Helminths
Helminth parasites are a group of worms from three different phyla: nematodes
(roundworms), platyhelminths (tapeworms and flukes) and acanthocephalans (thorny-headed
worms) (Jackson et al, 2008). In summation, the helminth parasites are the most common
infectious agent in developing countries (Brindley et al, 2009). Some of the worms, such as
Brugia malayi, cause severe symptoms and are a major health concern for humans who are

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infected, but for the most part, helminth worm infections are asymptomatic and lead to no
negative outcomes to their hosts. The life cycles of helminths vary greatly amongst the different
phyla. For example the life cycle of Ascaris lumbricoides (an intestinal roundworm) starts as a
mature egg in soil and is ingested in contaminated food. The larvae then hatch from the egg
within the small intestine and migrate through hepatic circulation until it reaches the lungs and
reach the trachea and are swallowed again, the larvae then mature to adulthood in the large
intestine and produce more eggs which repeat this life cycle. Another example of the diverse
life cycles of helminths is seen in Dracunculus medinensis. This worm is ingested as larvae in
water fleas and migrates through the duodenal wall where they develop and mate. Then the
adult gravid females then migrate to the foot through subcutaneous tissue and poke through
blisters in the foot where they expel their eggs into the surrounding water. This large diversity
of worms and their life cycles allows people to be infected with up to 1000 worms at one time
and according to Jackson, there has been well over 100 different species of helminths
recovered from humans (Jackson et al, 2008).
Typical immune response
Helminth worms are all handled with the same general immune response, regardless of
whether they are asymptomatic or are extremely detrimental to human health. The helminth
worms have pathogen associated molecular patterns (PAMPS) that are recognized by antigen
presenting cells. When the antigen presenting cell binds to the PAMPS through a specific subset
of receptors on the antigen presenting cell, it shows bias toward one of two types of T-cell
responses: Th1 or Th2. Helminth infections almost exclusively elicit a Th2 immune response (Imai

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et al, 2004). The differentiated antigen presenting cell then releases specific immune related
type-2 cytokines. This release of cytokines is so potent that any naive T-cells in the vicinity
quickly differentiate into Th2 cells (Maizels et al, 2003). One of the most important cytokines
that is released in the cascade is interleukin-10 (IL-10). This cytokine has a multitude of effects,
one of the most important is blocking the production of tumor necrosis factor α (TNF-α), which
is the most important pro-inflammatory cytokine produced in a Th1 response (Maizels et al,
2003). IL-10 also induces class switching of immunoglobulins (Ig) from IgG to IgE. The IgE
molecules then lead to cross linking onto eosinophils, mast cells and other granulocytes and
causes degranulation of the granulocytes (Harris, 2011). This leads to increased epithelial cell
permeability, mucous production by goblet cells and smooth muscle contraction, which helps
to expel the parasite from the GI tract. The Th2 type response is one theory as to why the
helminth worm evolved to evoke this part of the immune system (Maizels et al, 2003).
Another cytokine that is released during a helminth infection is transforming growth
factor-β (TGF-β) which causes naïve T-cells to differentiate to T-regulatory cells (Treg) (Maizels et
al, 2003). The increase in the number of Treg cells leads to more self-antigen binding by
regulatory immune cells rather than activator T-cells and an overall decrease of any
autoimmune reactions that could occur. TGF-β also functions in activating a special subset of
macrophages, the alternately activated macrophages. These macrophages are much different
than classical ones because they are anti-inflammatory and used normally called to action in
damage repair caused by both the hosts immune system and outside forces such as worms,
bacteria and viruses (Jackson et al, 2008). The overall immune response to helminths is a severe

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decrease in inflammation and the Th1 response and an overall increase in regulation of the
immune system.
Evolutionary history
Helminths and vertebrates have been in contact with each other for over 500 million
years, going back to the first platyhelminth infections (Jackson et al, 2008). It is believed that
early hominids become exposed to helminths from their ape-like ancestors (Rook, 2008).
Shortly after exposure to helminths the immune system developed T-cells, B-cells and the
immunoglobulin class E (Jackson et al, 2008). For this reason it is believed that these subsets of
adaptive immunity evolved along side of and developed with helminth infections, this has led to
an arms race between the evolution of the Th2 immune response and helminth worms. From
the host’s point of view, the Th2 response and overall tolerance, increases its fitness because it
does not generate an energetically wasteful, damaging response against a relatively low threat.
This can also be viewed as a trade off for the host because it is risking its ability to combat the
few detrimental worm species in order to not waste precious energy on fighting low threat
worms. In terms of helminths, the activation of the Th2 immune response increases its fitness in
a few ways. It activates the Th2 response in the gut which leads to an expulsion of some of the
eggs leading to further spread to other hosts. The Th2 response is also believed to thwart off
future invaders leading to increased fitness of the already infectious worm (Jackson et al, 2008).
As explained in the earlier section, helminth worms also elicit Th2 immune pathways that
normally are used for wound and damage repair regardless of origin or manifestation. It is

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believed that this role may have evolved along side of helminths due to the fact that most
worm infections cause a large amount of tissue damage to their host.
So the question begs: How can our knowledge of the evolutionary histories of helminths
and vertebrates immune system explain the increase in immune disorders and possible
treatments for them? I believe and recent research has shown that the answer is evident when
looking at the last ten thousand years of our species’ development. Hominids have quickly
changed from a hunter-gatherer society to one that lives in clean homes and modern cities
(Rook, 2008). For the most part we have handled this quick change of environment not through
genetic evolution but with technology, but our immune system is not as readily helped with
technology. As eluded to in the previous paragraph our modern immune system evolved to
anticipate chronic exposure to Th2/Treg inducing pathogens and therefore would have to up-
regulate its responses to counteract the chronic regulatory input. When we moved to a cleaner
more hygienic habitat our immune system lost the control it was used to. An analogy to this
would be driving a car for 500 million years with the e-brake on then all of asudden losing the
e-brake, leading to out-of-control driving with no regulation. In the next few sections I will go
into detail on multiple immune disorders and how their increase in prevalence can be traced
back to a 500 million year old friend.
Asthma
Asthma is the prototypical immune disorder that most people think of when talking
about the immune system. Asthma is a chronic inflammatory disease of the airways that leads
to bronchospams, airway obstruction and shortness of breath. Studies have found that people

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living in Western European counties have a higher incidence of asthma as compared to
genetically similar people living in Eastern Europe countries (Liu et al, 2010). This is believed to
be due to the increase in hygiene and development in Western European countries compared
to Eastern European countries. The onset of asthma is caused by an allergen binding to immune
cells leading to a Th2-type immune response against it. This immune response is very similar to
the helminth worm immune response, so it was originally thought that helminth worms would
exacerbate asthma (Liu et al, 2010). Although, research on helminths found that it suppresses
allergen-induced asthma in a variety of hypothesized mechanisms. One mechanism is through
the increase in the release of non-specific polycolonal IgE molecules (Liu et al, 2010). The high
concentration of non-specific polyclonal IgE molecules released in a worm infection can out-
compete the antigen specific IgE molecules for the receptors on mast cells and basophils, thus
decreasing the allergic response to the allergen (Liu et al, 2010). Helminth infections also
increase the number of Treg cells through IL-10 signaling which have been shown to decrease
the host’s hyper immune response to allergens (Liu et al, 2010). This is a positive outcome
because if the host is not combating every innocuous antigen it comes into contact with it can
devote more time to fighting off dangerous pathogens.
Type-1 diabetes
Type-1 diabetes also known as insulin dependent diabetes is a disease that is increasing
in prevalence in developed countries. Type-1 diabetes is a multi-genic disorder that also can be
influenced by environmental factors such as exposure to viruses, chemicals and certain dietary
intakes (Liu et al, 2010). The disease is characterized by pancreatic β cells that are destroyed by

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IFN-γ producing Th1 cells of our own immune system. The destruction of the pancreatic β cells
leads to a marked decrease in insulin production and release which leads to high levels of blood
glucose that cannot be stored as glycogen and ultimately deprives the host of a fuel reserve.
Some of the typical signs and symptoms of the disease include: frequent urination, and fatigue.
The main problem with diabetes is that it dramatically increases your risk for heart disease,
poor peripheral circulation that can lead to the need for limb amputation, blindness and many
other debilitating and life-threatening conditions. For many years, people have looked for
answers for the increasing prevalence of type-1 diabetes without finding conclusive evidence
(Cooke, 2008). One hypothesis that has promise for both the answer and possible preventative
treatment is the “hygiene hypothesis”, more specifically helminth worms. Helminth worm
infection leads to a bias toward Th2 cell response and an increase in the secretion of the
important cytokine IL-4 (Liu et al, 2010). IL-4 has many effects that can help to prevent the
onset of type-1 diabetes, the most important of which is the direct suppression of IFN-γ and the
Th1 inflammatory response that is seen in non-obese diabetic mice (Liu et al, 2010). The
cytokine IL-4 also leads to the increase in alternately activated macrophages that in turn
regulate the immune system and are seen to be protective against the onset of type-1 diabetes
(Liu et al, 2010). Another important cytokine that is released during helminth infection is IL-10.
This cytokine leads to differentiation of naïve T-helper cells to T-regulatory cells, the increase of
Treg cells compared to Th1 cells leads to more sampling of self-antigens an overall decrease in
autoimmunity.

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Multiple Sclerosis
Multiple sclerosis is another example of an autoimmune disease affecting more and
more people in developed countries. The disease is characterized by inflammatory
demyelination of the nerve cells in the brain. This demyelination leads to a multitude of
symptoms and complications depending on its location and severity. The disease can affect
your muscles, bladder, eyesight, speech and brain function. The symptoms are what is called
relapsing and remitting because they come and go based on when and where your immune
system is attacking the myelin sheath around your nerves. Like all other immune related
disorders, multiple sclerosis is characterized by an out of control Th1 immunity and its
prevalence increases as you move further from the equator. One explanation for this increase
in prevalence as you move away from the equator is the fact that most helminth worms are
tropical and cannot survive in the colder climates in northern latitudes.
Two major types of studies have been done with respect to multiple sclerosis and
helminth infections. One of these studies uses a mouse model of multiple sclerosis called
encephalomyelitis (Sewell et al, 2003). In this study the researchers infected mice with
encephalomyelitis and then immunized the test group with Schistosoma mansoni (a type of
helminth) eggs and left the control group uninfected with helminths (Sewell et al, 2003). They
found that the mice pre-immunized with the S. mansoni eggs showed significantly reduced
disease course and symptoms when compared to the control group. They also found up-
regulation of IL-4 and IL-10 and a decrease in TNF-α as seen in the other cases of helminth
infections.

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Another study on multiple sclerosis was done on a small group of twelve people who
presented with eosinophilia (a sign chronic helminth worm infection) (Correale et al, 2007). The
test group was compared to uninfected multiple sclerosis patients of similar age and social
background. The helminth infected patients were found to have a significant decrease in
relapses and had very small changes in disabilities (Correale et al, 2007). The uninfected control
group had 56 clinical relapses during the 4.6 years as compared to only 3 relapses in the
infected group (Correale et al, 2007). There was also an increase in IL-4, IL-10 and TGF-β which
lead to a decrease in inflammation and a Th1 response. This study was very important because
it helped to show that all of the findings from animal model testing and helminth infections
were very similar to the human model.
Intestinal inflammation
Another immune related disorder that is increasing in prevalence in developed countries
is intestinal inflammatory diseases. Some of the main intestinal disorders are ulcerative colitis,
Crohn’s disease and irritable bowel syndrome IBS. Some of the complications of inflammatory
bowel disease include diarrhea, weight loss, cramps and can also lead to a perforated ulcer
which can be life threatening if it is not resolved quickly. This is an emergency situation because
a perforated ulcer is a hole in your gastrointestinal tract that allows the contents of the
gastrointestinal tract to spill into other cavities in your body. All of these disorders are
autoimmune diseases that affect different parts of the gastrointestinal tract. Like type-1
diabetes, inflammatory bowel disorders have both genetic factors and strong environmental
factors. One of the main culprits in the development of inflammatory bowel disorders is the Th1

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arm of the immune system (Wang et al, 2008). Like many of the other immune related
disorders helminth worms help to control them by increasing the synthesis and release of non-
inflammatory cytokines and differentiating naïve T-cells to regulatory T-cells that help to
control the immune system. Helminth worms activate alternatively activated macrophages that
are seen to help in the amelioration and prevention of inflammatory bowel disease. Helminth
worms are again being looked at as one of the causative agents in the increase in these
disorders. As brought up before, helminths lead to an enormous increase in the Th2 arm of the
immune system and help to dampen the Th1 effects.
Numerous studies have been done showing the protective effects of helminth worms
on the development of inflammatory bowel disorders. Infection of mice with Hymenolepis
diminuta a type of tapeworm prevented the onset of sodium-sulphate induced colitis (Wang et
al, 2008). Another type of worm infection Schistosoma mansoni was protective against the
onset of trinitrobenzene sulphonic acid-induced colitis (Wang et al, 2008). These findings help
to show that helminth infections can help to prevent and relieve chemically induced
inflammatory bowel disorders in mice models. This is a positive outcome because it shows that
helminth infections can not only help to control already developed inflammatory bowel
disorders but can be used to prevent the onset of them altogether.
How evolutionary history can lead to better treatment
For the last 50 to 60 years, scientific researchers and physicians have been trying to
explain the increase in immune disorders in developed countries in order to design a plan of
attack to combat the multitude of diseases. Without an evolutionary perspective, researchers

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may have never postulated a simple worm as being the culprit of this increase in prevalence of
immune disorders in humans. When looking at our immune system’s evolution, it becomes
obvious that its development occurred in the presence of helminth worms. This is seen in the
quick development of T-cells, B-cells and immunoglobulins short after the first exposure to
platyhelminths (Jackson et al, 2008). This has lead to an immune system that works optimally
in the presence of helminths and when they are removed the immune system acts
inappropriately, as seen in the increase in immune related disorders in hygienic developed
countries. The polarizing Th2/Treg inducing effect of helminth infections could lead to global
health changes in both helminth-free parts of the world and helminth exposed areas (Jackson
et al, 2008). With the knowledge of our evolutionary history with helminths, researchers can
begin to develop new and inexpensive ways to treat immune disorders. Schistosoma mansoni
eggs have already been shown to decrease the occurrence of relapses in encephalomyelitis in
mice models. This treatment option could also be used prophylactically or as a vaccine to
prevent the onset of immune disorders such as type-1 diabetes, asthma, intestinal
inflammation and multiple sclerosis. Helminth treatment could also be used for disorders that
lead to highly excessive immune responses such as influenza or malaria (Jackson et al, 2008).
Anti-helminth treatment could also be used as adjuncts to help treat people who are severely
immunocompromised such as human immunodeficiency virus (HIV) and tuberculosis patients. If
they were to be “de-wormed” their Th1 immune response would be unregulated and this could
help fight off or even prevent the onset of many dangerous infectious diseases.

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Conclusion
“Nothing in biology makes sense except in the light of evolution” a famous statement by
Theodosius Dobzhansky is very relevant in terms of helminth worms and immune disorders.
Without the theory of evolution and its driving forces researchers would still be looking for
possible explanations for the rapid increase in immune related disorders seen over the past 60
years in developed countries all over the world. Now that researchers have isolated a possible
explanation for this phenomenon we can begin to test helminths as therapeutic drugs to help
treat and prevent the onset of the large diversity of immune related disorders. With more
research on helminths and their effects on our immune system we could also learn a lot about
how our immune system works since worm infections have helped to shape vertebrates
adaptive and innate immunity over the past 500 million years

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Annotated Bibliography
Brindley P et al. 2009. Helminth genomics: the implications for human health. PLoS Negl Trop
Dis. 3:1-9
Cook A. 2008. Review Series on Helminths, immune modulation and the hygiene hypothesis:
How might infection modulate the onset of type 1 diabetes? Immunology. 126: 12-17
The article focused on how type-1 diabetes can be altered and treated with helminth
worms. This article gave very good evolutionary history helminths and also the mechanisms of
action of our immune system. This article will be one of the sole sources I use to talk about
type-1 diabetes and how helminths can be used to treat the disorder.
Correale J et al. 2007. Association between parasite infection and immune response in multiple
sclerosis. American Neurology. 61: 97-108
This article will be used because it is the first study related helminth infections to a
human model. This article will help me bridge the gap between animal models and human
applications.
Gluckman et al. 2009. Principles of evolutionary medicine. Oxford University press. New York,
NY
This source had a very good figure that I will use in order to show the prevalence of
immune disorders and how the increase is inversely related to infectious diseases. I will also use
this book to help explain the overall definition of the hygiene hypothesis and how it relates to
helminth worms.
Harris N, Gause W. 2010. To B or not to B: B cells and the Th2-type immune response to
helminths. Cell. 32:80-88
Imai S et al. 2001. A factor of inducing IgE from a filarial parasite prevents insulin-dependent
diabetes mellitus in nonobese diabetic mice. Environmental Parasitology. 286: 1051-1058
Imau S et al. 2004. Molecules of parasites as immunomodulatory drugs. Current Topics in
Medicinal Chemistry. 4: 539-552
Jackson J et al. 2008. Review series on helminths, immune modulations and the hygiene
hypothesis: immunity against helminths and immunological phenomena in modern human
populations: co evolutionary legacies. Immunology. 126: 18-27
This article makes the point to argue for the “co-evolutionary legacies” of mammals and
helminths. I will use this article to better explain the how the evolutionary history of worms and
mammals led to an immune system that acts differently in the presence and absence of worm
infection. This article will help lead into the separate immune disorders I will be looking at (MS,
type 1 diabetes, IBS ect).

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Maizels R et al. 2003. Immune regulation by helminth parasites: Cellular and molecular
mechanisms. Nature. 3: 733-744
Nausch N et al. 2011. Regulatory and activated T cells in human schistosoma haematobium
infections. PLoS ONE. 6:e16860
Rook G. 2008. Review series on helminths, immune modulation and the hygiene hypothesis: the
broader implications of the hygiene hypothesis. Immunology 126:3-11
This article brings to light the hygiene/ old friend’s hypothesis in terms of Darwinian
medicine. I will use this papers idea to help explain the evolutionary history of mammals and
helminths in terms of rapid environmental change and its effects on our immune system and
health more broadly.
Sewell D et al. 2003 Immunomodulation of experimental autoimmune encephalomyelitis by
helminth ova immunization. International Immunology. 15: 59-69
This article gave very strong evidence of the immune modulating effects of helminth
worms on encephalomyelitis (animal model for MS). I will use this article to show the promising
research in new treatment for MS and also to strengthen my argument that helminth worms
can be used to combat a large diversity of immune related disorders.
Wang Li et al. 2008. Helminth infections and intestinal inflammation. World Journal of
Gastroenterol. 33: 5125-5132
This article gives very good background on the increase in prevalence of intestinal
inflammation and argues that one if it’s main factors in increase in helminth worms. This article
will be used to show the mechanisms and effect of helminth infections on intestinal
inflammation and how it can be used to prevent and treat ongoing helminth infections.
Zhugong L. 2009 Regulations of type 1 diabetes, tuberculosis, and asthma by parasites. J of Mol
Med. 88: 27-38
This article will give me very good background information on the immune
disease I will be looking at. It will allow me to look at each disorder mechanistically and be able
to explain helminths effects on them.
Corrections
The peer review was very helpful in correcting my paper. I took a lot of the suggestions
and tried to incorporate them into my final paper. I went through and fixed a lot of the run on
sentences that my reviewer pointed out. I also added a few things to my thesis statement that

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were suggested to me. One of the things I added were the names of the immune disorders that
I will be looking at since they were a major part of my paper.