Download Ascariasis and Allergies,

Ascariasis and Allergies,
a rigorous exploration of relevant theories and studies
Part I
Jenssy Rojina
ID# 05268282
and
Part II
Jeffrey Tran
ID# 05458933
Human Biology 153: Parasites and Pestilence
Scott Smith, MD
February 26, 2010
Rojina & Tran 2
Part I: Relevant Immunology
In order to understand the differing theories concerning the relationship between Ascaris
infection and atopic diseases, a background in immunology is essential. Immunology is the
study of the body’s defense against infections from pathogens, and a pathogen is any organism
with the potential to cause disease (Janeway 1). The four categories of pathogens are bacteria,
viruses, fungi, and parasites (Parham 3). Immunology helps us understand the body’s defense
mechanisms against pathogens at the cellular and molecular level. There are four main tasks that
the immune system must fulfill in order to protect an individual from infection. First, the body
must be able to undergo immunological recognition, or detect the presence of an infection.
Second, the body must be able to contain the infection and if possible eliminate it completely.
Third, the body must have the ability to self regulate. An inability to self-regulate contributes to
conditions such as allergies and autoimmune diseases. Fourth, the body must be able to protect
an individual from experiencing a recurring disease from pathogens that invade the body. In
other words, the body must be able to establish immunological memory so that subsequent
exposures to an infectious agent result in a person making an immediate and stronger response
than previous exposures to pathogen infections (Janeway 3).
Blood and lymph tissue play vital roles in the immune system. Blood is composed of
plasma, red blood cells, white blood cells, and platelets. Red blood cells are confined to the
heart, arteries, capillaries and veins, while white blood cells and platelets can be found in the
lymph. White blood cells fall into one of two groups, granular cells or lymphocytes. Granular
cells include phagocytes, which engulf and digest foreign cells, dendritic cells, and macrophages
(Sadava 402). Dendritic cells have properties in common with macrophages, but the also have
the unique function of acting as cellular messengers that call up an adaptive immune response
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when needed (Parham 15). Macrophages, like phagocytes, have the ability to engulf and digest
foreign cells, but they also have the ability to present partly digested nonself materials to T cells.
On the other hand, lymphocytes include the B cells and the T cells. B cells are produced in the
bone marrow and differentiate to form antibody-producing cells and memory cells. T cells are
produced in the bone marrow and mature in the thymus, and in general they kill virus-infected
cells and regulate the activity of other white blood cells. Blood is important in the immune
system, but lymph also plays a significant role in protecting the human body from pathogen
infections. Lymph is defined as a fluid derived from blood and other tissues and it usually
accumulates in intercellular spaces throughout the body. As lymph passes through lymph nodes,
the lymph nodes inspect the body for nonself materials (Sadava 402).
The first lines of defense against infectious agents are physical and chemical barriers that
prevent microbes from entering the body, like the skin. These barriers are not generally
considered part of the immune system proper. Only when a pathogen overcomes these barriers
does the immune system come into play (Janeway 3). The immune system can be divided into
two main components, the innate system and the adaptive system. When a pathogen is
introduced in the body, the innate immune response is the first to respond. The word innate
stems from the fact that the immune responses are determined by the genes an individual inherits
from his or her parents. In the innate immune response, the first thing that occurs is that the
body recognizes that a pathogen is present in the body. In order for this recognition to take
place, soluble proteins and cell surface receptors bind to the pathogen. Once the body has
recognized that a pathogen is present, the body recruits destructive effector mechanisms that kill
and eliminate the pathogen. The effector mechanisms are carried out by effector cells.
Examples of effector cells are cells that engulf bacteria, cells that kill virus-infected cells, or cells
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that attack parasites. A collection of proteins known as complement proteins help the effector
cells by marking pathogens with molecular flags (Parham 9). Complement proteins work by first
attaching to pathogens, which allow phagocytes to recognize the pathogens and the destroy them.
Phagocytes are specialized cells that engulf and kill microorganisms. The second event that
occurs after complement proteins attach to pathogens is that they activate the inflammation
response and attract phagocytes to the site of infection. More specifically, the inflammation
response is initiated when there is a part of the body that is damaged. The damaged tissue
attracts mast cells to the damaged site. Mast cells release a chemical known as histamine, which
diffuses into capillaries. Next, the histamine cause the capillaries to dilate and become leaky.
Complement proteins leave the capillaries and attract phagocytes. Phagocytes move into the
infected tissue from the capillaries and engulf pathogens and dead cells. When the histamine and
complement signaling stops, phagocytes are no longer attracted to the site of infection and other
signaling molecules stimulate endothelial cell division, allowing a wound to heal (Sadava 406).
On the other hand, the adaptive immune system, also known as the specific immune
system, begins to function when a pathogen eludes the body’s innate immune responses. The
adaptive immune system can be subdivided into two categories, the humoral immune response
and the cellular immune response. Generally, the adaptive immune system has four key traits.
The adaptive immune system is specific, has the ability to respond to a large diversity of foreign
pathogens, has the ability to distinguish self from nonself, and the adaptive immune system also
develops immunological memory (Sadava 407).
In the humoral immune response, antibodies (proteins that bind specifically to nonself
substances and denature the nonself substances), secreted by B cells, react with epitomes, also
known as antigenic determinants, located on pathogens (Sadava 403). Antigenic determinants
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are sites on antigens that are recognized by an antibody or an antigen receptor (Janeway 815).
Antigens are simply defined as any molecule that can bind specifically to an antibody (807). The
first time a specific antigen invades the body, it may be detected by a B cell whose membrane
antibody recognizes one of its antigenic determinant. When an antigen binds to a B cell, the B
cell is activated and it makes and secretes multiple copies of the antibody with the same
specificity as its membrane antibody (Sadava 408). This process is called clonal selection.
Antibodies belong to a class of proteins called immunoglobulins. There are many types
of immunoglobulins, but they all share common characteristics. Primarily, immunoglobulins
consist of tetramers arising from four polypeptide chains. In each immunoglobulin molecule,
two of these polypeptides are identical light chains, and the other two polypeptides are identical
heavy chains. Disulfide bonds hold the heavy and light chains together. Furthermore, each
polypeptide chain has a constant and variable region (411).
The amino acid sequence of the constant regions determine the destination and function
of the antibody. Therefore, the constant region determines which class an immunoglobulin
belongs to. The amino acid sequences of the variable regions are different for each specific
immunoglobulin. Differences in the secondary structure result in contrasting three-dimensional
antigen-binding sites for each immunoglobulin, and these sites are responsible for antibody
specificity (Sadava 411).
There are five classes of immunoglobulins. The five classes of immunoglobulins are
IgG, IgM, IgD, IgA, and IgE. IgG antibodies are found in blood plasma and these types of
antibodies are able to cross the placenta. IgM antibodies are found on the surface of B cells and
also in the blood plasma. They serve as antigen receptors on B cell membranes and they are the
first class of antibodies released by B cells during a primary response. Next, IgD antibodies are
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found on the surface of B cells, they serve as the cell surface receptors of B cells, and they are
important for B cell activation. IgA antibodies are found in saliva, tears, milk, and other body
secretions. These antibodies protect mucosal surfaces and prevent attachment of pathogens to
epithelial cells. Finally, IgE antibodies are secreted by plasma cells in skin and tissues lining the
gastrointestinal and respiratory tract. When bound to antigens, IgE antibodies bind to mast cells
and basophils to trigger release of histamine, which contributes to inflammation and some
allergic responses (412).
Moving on to the cellular immune response, this component of the adaptive immune
system comes into play when an antigen has become established within a cell of the host animal.
T cells are heavily involved in the cellular immune response. They recognize and bind to
antigenic determinants, initiating a response that results in the destruction of the nonself or
altered self cell (Sadava 408).
Like B cells, T cells have specific membrane receptors. They do not have
immunoglobulins, but have glycoproteins that are made up of two polypeptide chains serving as
receptors. These two polypeptide chains are almost always different in their amino acid
sequence. A similarity between immunoglobulins and T cell receptors is that like the
immunoglobulins, T cell receptors have variable and constant regions. However, T cell receptors
bind to a piece of an antigen displayed on the surface of an antigen-presenting cell whereas
antibodies bind to intact antigens (414).
When a T cell is activated by an antigenic determinant, the T cell proliferates and forms a
clone. The descendants of the clonal selection can differentiate into two types of T cells called
cytotoxic T cells (Tc) and helper T cells (TH). TC cells recognize virus-infected or mutated cells
and induce lysis. The role of TH cells is to assist both the cellular and humoral immune
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responses. An example of how TH cells assist the humoral response is that they bind to antigenic
determinants presented on a B cell before that B cell can become activated (414).
An essential part of the cellular immune response concerns the products of a cluster of
genes called the major histocompatiblity complex (MHC). The primary role of MHC proteins is
to present antigens to a T cell receptor so that the body can distinguish between self and nonself
antigens. There are two kinds of MHC proteins, MHC I and MHC II. MHC I proteins are
present on the surface of every cell in the human body. When a cellular protein is degraded into
peptide fragments by a proteasome, an MHC I protein binds to a fragment and travels to the
plasma membrane where the MHC I protein presents the cellular peptide to TC. TC cells
recognize MHC I because TC cells have a surface protein known as CD8 that recognizes and
binds to MHC I (Sadava 415). In a virus-infected cell, foreign proteins combine with MCH I
molecules and the resulting complex is displayed on the cell surface and presented to TC cells.
When a TC cell recognizes and binds to the antigen-MHC I complex, it is activated and begins to
proliferate. At this point, the TC cell produces a substance called perforin and perforin lysis the
target cell (417).
The next kind of MHC protein, MHC II, is mostly found on the surfaces of B cells,
macrophages, and other antigen-presenting cells. MHC II proteins bind to fragments that result
when an antigen is broken down by a phagosome. The MHC II molecule carries the fragment to
the cell surface and presents it to a TH cell. TH cells recognize MHC II because TH cells have
CD4 proteins that help in the recognition (415). When a TH cell binds to an antigen presenting
macrophage, the TH cell releases cytokines, and the cytokines activate the TH cells to produce a
clone of the TH cells with the same specificity. After clonal selection, the TH cells activate B
cells with identical specificity in order to produce antibodies (417).
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MHC proteins play a significant role in establishing self-tolerance. Self-tolerance does
not mount an immune response to self antigens. Throughout an individual’s life, T cells are
tested in the thymus. Only if the T cells are able to recognize the body’s MHC proteins and if
the cells bind to both self MCH proteins and to one of the body’s own antigens, does the cell
survive (417).
With this basic immunology background in mind, understanding the mechanisms in
which the body might react to allergies is possible. When the adaptive immune system elicits an
immune response by antigens not associated with infectious agents, an allergic reaction occurs.
An allergy is the body’s hypersensitive response to an innocuous antigen, an allergen. The body
responds to allergens by producing IgE antibodies against them and by triggering a TH2 response
(Janeway 555). If a person has become sensitized to an allergen, this means that the individual
produces IgE antibodies against it. An exaggerated tendency to mount IgE responses to
allergens is called atopy. Atopy has strong familial basis and is influenced by many genetic loci.
Individuals who are atopic have higher total levels of IgE in their circulation and higher levels of
eosinophils than individuals who are not atopic. As a consequence, these individuals are more
susceptible to allergic diseases (560).
Certain antigens favor the production of IgE and there are special kinds of cells that drive
the production of IgE. The cells that favor production of IgE are known as CD4 TH2 cells (357).
It is necessary to understand the different types of cells that CD4 T cells differentiate into. The
main subsets of the CD4 effector T cells are TH1, TH2, TH17, and regulatory T cells. TH1, TH2,
TH17 are defined on the basis of the different cytokines they release (350). Cytokines are small
proteins usually made by lymphocytes that affect the behavior of other cells. TH1 and TH2
secrete the cytokines interferon-gamma, Interleukin-4 (IL-4), IL-5, and IL-10, among other
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cytokines (606). TH1 cells have a dual function. First, they control bacteria that can set up
intravesicular infections in macrophages. These bacteria are taken up by macrophages in the
usual way but can evade the killing mechanisms. The killing mechanisms are evaded when the
TH1 cell recognizes bacterial antigens displayed on the surface of an infected macrophage. Thus,
it interacts with the infected cell and stimulates the macrophage’s microbicidal activity to enable
it to kill the intracellular bacteria. The second function of TH1 cells is to stimulate the production
of antibodies against extracellular pathogens by producing co-stimulatory signals for antigenactivated B lymphocytes. Next, TH2 cells can also activate B cells and induce class switching.
TH2 cells are required for the switching of B cells to produce the IgE class of antibody whose
primary role is to fight parasite infections. Finally, regulatory T cells suppress T-cell responses
rather than activate them. They are involved in limiting the immune response and preventing
autoimmune responses. Two main groups of regulatory T cells are known, the natural regulatory
T cells and the adaptive regulatory T cells (Janeway 350).
Atopic individuals have a tendency to secrete TH2 cytokines after nonspecific stimulation
whereas those who are not atopic do not. This suggests that regulatory mechanisms have an
important role in preventing IgE responses to allergens. Natural regulatory T cells in atopic
individuals are defective in suppressing TH2 cytokine production (565). There are numerous
approaches to treating and preventing allergies. One treatment is desensitization.
Desensitization involves reducing the tendency to mount an IgE response. In order for this
therapy to work, regulatory T cells secreting Interleukin-10 (IL-10) must be induced (581).
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Part II: Ascariasis and Allergies
Ascaris infection and atopic diseases have a complex and controversial relationship.
Older arguments state that Ascaris infection is preventative against atopic diseases while much
of the newer research suggests that the relationship is quite the opposite; namely that ascariasis is
a risk factor for atopic diseases. This paper will attempt to explain the theory behind both sides
of this debate and present exhaustive evidence for both sides. It will work towards establishing
the idea that the relationship between ascariasis and atopy is far more complex than any
bipartisan argument could hope to fully address, and that ascariasis may have both a modulating
and exacerbating effect on atopic diseases, dependant on the burden of infection.
The relationship between ascaris and allergies has long been observed; it was quickly
noticed that as countries developed, the prevalence of atopic diseases increased substantially
while simultaneously in the underdeveloped countries, the prevalence was maintained at much
lower levels. In the famous Hygiene Hypothesis by Dr. Stachan, it was suggested that increasing
development leads to increasing sanitation and hygiene, which in turn leads to a decline in
exposure to common infections and diseases. As a hypothetical result, the immune system is not
“primed” and becomes overly reactive to even the smallest amount of stimulation.i As a result,
increased incidences of atopic diseases are observed.
The idea that ascariasis and other helminth infections might be a protective factor against
atopic disease was put forth as early as 1976 by a Lancet article explaining the theoretical basis
of the IgE blocking hypothesis. The idea put forth was that helminth infection induces the mass
production of highly polyclonal, non-specific IgE antibodies. These antibodies occupy FcεRI
binding sites on mast cells, and since they are non-specific for any antigen, they simply saturate
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all the binding sites on the mast cells and prevent mast cell activation by other antibodies,
including allergens.ii Thus, helminth infection helps to mediate atopic disease. Subsequent
studies done with mice seem to support this hypothesis. In an experimental study conducted in
2004, mice were infected with Ascaris suum and subsequently tested for ragweed sensitization, a
common marker used to test for atopic disease in humans and animal models. The mice
demonstrated a protected response from further allergic reactions to ragweed while
simultaneously exhibiting an increased total of IgE as compared to control groups.iii Ordinarily,
an increase in total IgE corresponds to an increased atopic response, but the fact that it did not
lends to the idea that the IgE produced in response to Ascaris must be non-specific to common
allergens (or in this case, at least ragweed) and is therefore possibly able to block mast cell
activation by filling up all the activation binding sites. Multiple cross-sectional studies of human
subjects are similarly supportive of the theory. For example, a study done in 1987 by Lynch et.
al. correlated increased IgE levels to ascaris infection. Higher IgE levels were subsequently
associated to decreased prevalence of atopic diseases in this group of individuals.iv
Unfortunately, the mechanics for the ascaris-allergy relationship formulated by the IgE
blocking hypothesis were largely dismissed by two critical studies, identified by Maria
Yazdanbakhsh in her exploration of the Hygiene Hypothesis.v A study done by E. Jarrett and S.
Machenzie demonstrated that although saturation with non-specific, helminth-generated IgE
antibodies could block passive sensitization of mast cells, it was unable to “inhibit
hypersensitivity reactions mediated by an actively produced IgE antibody.”vi In other words,
activation of the immune system by new allergens could still stimulate an atopic response despite
saturation of FcεRI binding sites on mast cells by non-specific ascaris-generated antibodies. The
results of another study by D.W. MacGlashan et. al. concluded that FcεRI binding is mediated by
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levels of plasma-free IgE levels. The paper found that the number of FcεRI receptors displayed
at the surface of mast cells was based on the concentration of free IgE antibodies.vii In context of
the ascaris-allergy relationship, this meant that no matter how many non-specific IgE were
produced, saturation of mast cells was impossible because mast cells would create more FcεRI
receptors in response to antibody production. In essence, these two studies rendered the IgE
blocking hypothesis obsolete.
More recently, other mechanisms have been put forth to explain the ascaris-allergy
relationship. In the Old Friends Hypothesis, Rook and Brunet suggest that infection by a group
of organisms, later termed the “old friends” (certain helminthes, particularly Ascaris, lactobacilli,
and saprophytic environmental mycobacteria) is essential in mediating the balance between
immuno-regulatory cells and immuno-functional cells. In theory, these organisms induce the
secretion IL-10 and transforming growth factor-ß, which mediate the activation of Treg and
regulator dendritic cells.viii Studies in 2006 and 2007, by groups led by Boesen and Trivedi,
respectively, support Rook and Brunet’s Old Friends hypothesis. Both studies tested the effect
of Ascaris-secreted pseudocoelomic fluid (PCF) on the mouse model. Boesen et. al. found that
ascaris antigens of A. suum in PCF were able to down-regulate the expression of costimulatory
molecules on regulator dendritic cells and subsequently decrease the inflammatory response to
the ragweed allergen. It was proposed that the suppression of innate immunity was the possible
cause of decreased allergic inflammation in the PCF treated mice.ix Trivdei’s experiment in
2007 essentially repeated the experiment done by Boesen’s group in 2006 and produced similar
findings: A. suum infection leads to decreased release of costimulatory molecules by dendritic
cells, leading to decreased inflammatory response to ragweed allergens.x
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Unfortunately, later studies were not able to link the immunosuppressive effect of PCF to
enhanced IL-10 secretion. Particularly, a study published in 2008 on Ecuadorian school children
exposed to two common allergens showed that “there was no evidence of association between
the level of A. lumricoides induced IL-10 or IL-10+ T cells and skin test-measured reactivity to
allergens.”xi The authors concluded that ascaris-induced production of IL-10 did not mediate the
observed declines in atopy in the group studied. A new mechanism to explain the allergymediating effects of ascaris infection is still waiting to be proposed.
In any case, regardless of the inability to produce an experimentally-supported
mechanisms for the ascaris-allergy relationship, the suppressive effect of ascariasis on atopic
disease in cross-sectional studies cannot be ignored. In 2004, a randomized, controlled
experiment was performed treating high-burden individuals with anthelminth treatments over a
long duration. As the intervention proceeded, data was taken regarding skin-test sensitivity to
mites (another common marker used to test for atopic disease in humans), helminth infection
status, and levels of total IgE. Treatment resulted in significant declines in both helminth
infection status and total IgE levels and significant increases in skin sensitivity to dust mites,
indicating increased propensity towards atopic disease. This led the authors to conclude that
“helminth infection plays a direct role in suppressing allergy reactions.”xii In 2006, a large crosssectional study was conducted of 1500+ Vietnamese children. In this study, infection with
ascaris, measured by egg burden per gram feces, was observed to substantially reduce the risk of
positive skin sensitization to dust mites, odds ratio: 0.28.xiii Then in 2008, a study between
various helminthes, including ascaris, and a variety of allergy/asthma marker tests in 1320
children from Cuban municipalities demonstrated that “A. lumbricoides infection is negatively
associated with atopic dermatitis, odds ration: 0.22; p = 0.007.”xiv Most recently a study
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published in 2010 found that Ascaris infection in South Africa is associated with increased serum
levels of IgE, and subsequently that ascariasis is correlated with a decline in positive skin test
responses, odds ratio: 0.63.xv It is clear from this wealth of studies that Ascaris infection is
somehow tied to a decline in atopic disease prevalence, but the mechanism through which the
two might be related is still unknown.
Many more recent studies are beginning to suggest that ascaris infection plays a direct
role in increasing risk for developing atopic disease. The basis of the theory, primarily put forth
by Finkelman and Urban in 2001, is backed by the idea that infection with nematodes such as
Ascaris results in an increased differentiation of T0H into T2H. T2H are associated with the
production of cytokines, IL-3 and IL-4, which are protective against worm invasion, but also
result in enhanced inflammatory effects associated with atopy and asthma. Thus, patients with
limited parasite infection have an increased propensity towards allergic reactions due to
increased T2H production levels and their thus associated cytokines. xvi
However, this theory
goes on to state that severe chronic infection of Ascaris may also result in active production and
perpetual saturation of mast cells with parasite-specific IgE. This presents an interesting
mechanism through which Ascaris infection might mediate atopic symptoms. The IgE blocking
hypothesis was earlier refuted by studies stating that the saturation of mast cells with nonspecific IgE was impossible because the number of FcεRI on the mast cells was mediated by the
levels of free-plasma IgE. This study could refute the IgE blocking hypothesis on the theory that
ascaris-induced IgE are not actively produced. However, if it were the case that Ascaris-specific
IgE were actively produced, they could then act as a sort of competitive inhibitor to mast cells
binding sites, taking up new ones as soon as they are displayed on the mast cell. While this
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second part of the theory is heavily theoretical, it nevertheless suggests an interesting mechanism
to explain the observed trends in the allergy-ascaris relationship.
While the mechanism behind the protective effects of ascaris infection against atopy
remain controversial, substantial evidence supports the mechanisms through which ascaris can
contribute to atopy. As early as 1996 it was noted that secretions by nematodes resulted in the
activation of T cells to produce IL-4 and related cytokines.xvii IL-4 cytokines enhance
inflammatory reactions to allergens, producing symptoms associated with atopy and asthma. In
2006, an elegant study was published studying individuals infected with both Ascaris and
mycobacterium tuberculosis (MTB). Ascaris infection is associated with an increased T2H
response, and this imbalance of T2H to T1H is said to contribute to the atopic symptoms seen in
infected individuals. MTB stimulates differentiation into T1H, which should restore the balance
and therefore alleviate atopic symptoms. In the 2006 study, individuals co-infected with both
MTB and ascaris were tested for atopic asthma, atopic rhinitis, skin prick test sensitivity to
aeroallergens, and increased atopy related bronchial hyper-responsiveness. Individuals positive
for ascariasis but negative for MTB demonstrated a significantly increased risk of atopic
symptoms (adjusted odds ratio 6.5; 95% confidence interval), but for individuals positive for
both infections, the association disappeared (adjusted odds ration 0.96; 95% confidence interval).
According to the authors, “This suggests that immune response to Ascaris may be a risk factor
for atopic disease in populations exposed to mild Ascaris infection and that MTB infection
mediates this risk, possibly through the stimulation of anti-inflammatory networks.”xviii This
study strongly supports the notion that increased production of T2H cells due to ascaris secretions
cause atopic diseases to become more prevalent.
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The case of enhanced atopy prevalence through ascariaisis is observed in a plethora of
cross-sectional case studies. It is interesting to explore how certain aspects of the studies make
them fit into the model proposed above.
In a study of over 2000 children ages 8-18 years old in the Anqing province of China, A.
lumbricoides infection (or history of) was associated with increased risk of asthma (p < 0.001)
and an increased number of positive skin tests to aeroallergens (p < 0.001).xix One should
quickly note two things in this study. The first is that the prevalence of ascaris infection was
only 24.5%, suggesting that most individual burdens were probably not extremely high relative
to other endemic countries in less developed areas. Only acute levels of burden would be able to
inspire protective effects from atopic symptoms. Mild burdens would only increase the strength
of the correlation between ascariasis and atopy, similar to the trend observed here. The second
thing to notice is that history of Ascaris infection was not differentiated from ongoing Ascaris
infection. According to our theory, this makes a huge difference in the inhibiting effects of
active secretion of ascaris-specific or ascaris-specific polyclonal non-specific IgE antibodies. If
Ascaris secretions are not maintaining a high free-plasma IgE concentration, then the IgE
blocking hypothesis is voided. Hence, in terms of Finkelman and Urban’s theory, low ascaris
burden and use of history of ascaris infection as a marker for ascaris infection should lead to
trends that positively correlate ascaris to atopy.
On the other side of the coin, mild infection burdens of A. suum in 4-year-old children in
the Netherlands demonstrated increased frequency of asthma diagnosis as well as increased food
and aero-allergen sensitization. The authors concluded that “that low level or transient infection
with helminthes enhances allergic reactivity.”xx Again, this fits into Finkelman and Urban’s
theory as low burdens of Ascaris only serve to enhance inflammatory immune reactions. Not
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enough IgE would be actively produced by low levels of infection to create an IgE blocking
effect. Hence an increased observation of atopic symptoms should be expected.
Finally, a study published in 2010 in Brazil measured atopic dermatitis in response to
burden of ascaris infection. It was found that more severe cases of atopic dermatitis (AD) were
correlated to lower infection burdens of A. lumbricoides. Mild infection of A. lumbricoides
increased the frequency of mild AD (Risk ratio: 1.7; p = 0.009) while higher burdens of infection
decreased the frequency of AD (Risk ratio = 0.86; p = 0.46).xxi These findings strongly fit into
the mechanistic proposal laid down be Finkelman and Urban’s theory.
Regardless of the evidence provided by these three cross-sectional studies, definitive
evidence for Finkelman and Urban’s theory still needs to be presented. It is still a highly
theoretical concept that active production of Ascaris-induced IgE can act as a competitive
inhibitor for mast cell FcεRI binding sites. This demands an area for further research. It should
also be noted, however, that there have been case studies where no significant relationship
between ascaris and atopic symptoms was identified.xxii,xxiii Furthermore, an alternative
hypothesis to Finkelman and Urban’s theory was proposed by Calvert and Burney in 2010,
stating that perhaps “Ascaris might induce an inflammatory response in the lungs independent of
its effect on IgE production.”xxiv This could explain some of the contradictory findings seen in
studies in which high burdens of ascaris were seen to increase instances of atopic
asthma.xxv,xxvi,xxvii This paper did not go into Calvert and Burney’s proposal largely because no
mechanism was discussed through which this observation could explained. All in all, it is clear
that even Finkelman and Urban’s theory is not sufficient at completely explaining the trends seen
in the Ascaris-allergy relationship. Further observation and experimental approaches are
definitely mandated for clarification of this complex association.
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This paper has explored the progression of theories concerning the ascaris and allergy
relationship. It first explored the old “IgE blocking effect” but found that passive saturation of
FcεRI binding sites was not sufficient to alleviate atopic symptoms in the presence of more
active allergen exposure. We next moved on to the Old Friends Hypothesis, and explored the
possibility that Ascaris-induced secretion of IL-10 might mediate the inflammatory response
responsible for producing atopic symptoms. However, we found that increased IL-10 secretion
was not observed in conjunction with Ascaris infection. Then we moved onto Finkelman and
Urban’s theory, which, by using a synthesis between a modified version of the IgE blocking
effect and the T1H/T2H balance theory, was capable of explaining both the decline in atopy
associated with high ascaris burden and the increase in atopic symptoms found in individuals
with low ascaris burden. Although numerous case studies fit into the mechanistic framework
laid out by this theory, large parts of the theory need to be backed by experimental studies. Thus
further study is needed in this sector. It was also noted that Calvert and Burney identified an
interesting contrast in atopic asthma, which deviates from the trend observed by other atopic
symptoms. Further research is required in this department as well. Finally, it should be noted
that there were a few studies in which no relationship was observed between ascaris and
allergies, either suppressing or exacerbating. This suggests that none of the theories that we have
put forth is sufficiently complex to explain the ascaris-allergy relationship. We must continue to
observe and study the relationship between ascaris and immunology if we want to discover the
truth behind this complex and important connection.
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Works Cited
Boesen, et. al. 2006 Feb. “The Role of Innate Immunity in Suppression of Allergic Inflammation
by Ascaris suum Antigens”. Journal of Allergy and Clinical Immunology: S134.
Calvert, James and Peter Burney. 2010. “Ascaris, atopy, and aexercie-induced
bronchoconstriction in rural and urban South African children”. Journal of Allergy and
Clinical Immunology 125: 100-105. Web.
Caraballo, et. al. 2007 Jan. “The Prevalence of IgE Antibodies to Ascaris in Asthmatic Patients
Living in a Tropical Environment”. Journal of Allergy and Clinical Immunology 121:
S210. Web.
Cooper, et. al. 2008 May 1. “Ascaris lumbricoides-induced interleukin-10 is not associated with
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60. Web.
ii
Editorial, 1976. Lancet 1, 894. Web.
iii
J. Wetzel, et. al. 2004 Feb. “Duration of Ascaris Infection Modulates Allergic Disese in a
Mouse Model of Allergic Conjunctivitis”. Journal of Allergy and Clinical Immunology 113 (2):
S178. Web.
4
NR Lynch, et. al. 1987 Jan-Feb. “Measurement of Anti-Ascaris IgE Antibody Levels in
Tropical Allergic Patients, Using modified EILSA”. Allergol Immunopathol 15(1): 19-24. Web.
v
Yazdanbakhsh, et. al. 2002 April 19. “Allergy, Parasites, and the Hygiene Hypothesis”. Science
296: 409-494. Web.
vi
E. Jarrett, et. al. 1980. “Parasite-induced 'nonspecific' IgE does not protect against allergic
reactions”. Nature 283: 302. Web.
vii
DW MacGlashan, et. al. 1997. “Down-regulation of Fc(epsilon)RI expression on human
basophils during in vivo treatment of atopic patients with anti-IgE antibody”. Journal of
Immunology 148: 1438-1445. Web.
viii
Rook, G.A.W. and Rosa Bruent. 2005. “Old friends for breakfast”. Clinical & Experimental
Allergy 35: 841-842. Web.
ix
Boesen, et. al. 2006 Feb. “The Role of Innate Immunity in Suppression of Allergic
Inflammation by Ascaris suum Antigens”. Journal of Allergy and Clinical Immunology: S134.
x
Trivedi, et. al. 2007. “Ascaris Antigens Suppress Experimental Allergic Inflammation”.
Journal of Allergy and Clinical Immunology 119 (1): S133. Web.
xi
Cooper, et. al. 2008 May 1. “Ascaris lumbricoides-induced interleukin-10 is not associated
with atopy in school children in a rural area of the tropics”. Journal of Infectious Disease 197(9):
1333-1340. Web.
xii
van den Biggelaar, et. al. 2004 Mar 1. “Long-term treatment of intestinal helminthes increases
mite skin-test reactivity in Gabonese schoolchildren”. Journal of Infectious Disease 189(5): 892900. Web.
xiii
Flohr, et. al. 2006 December. “Poor sanitation and helminth infection protect against skin
sensitization in Vietnamese children: A cross-sectional study.” Journal of Allergy and Clinical
Immunology 118: 1305-1311. Web.
xiv
M. Wördemann, et. al. 2008 Feb. “Assocation of atopy, asthma, allergic rhinoconjunctivitis,
atopic dermatitis and intestinal helminth infections in Cuban children”. Tropical Medicine and
International Health 18(2): 180-186. Web.
xv
Calvert, James and Peter Burney. 2010. “Ascaris, atopy, and aexercie-induced
bronchoconstriction in rural and urban South African children”. Journal of Allergy and Clinical
Immunology 125: 100-105. Web.
i
Rojina & Tran 24
Finkelman, Fred D. and Joseph F. Urban. 2001. “The other side of the coin: The protective
role of the TH2 cytokines”. Journal of Allergy and Clinical Immunology 107: 772-780. Web.
xvii
Lee, Timothy D.G. and Chang Yue Xie. 1995. “IgE regulation by nematodes: the body fluid
of Ascaris contains a B-cell mitogen”. Journal of Allergy and Clinical Immunology 95: 1246-54.
Web.
xviii
Obihara, et. al. 2006 May. “Respiratory atopic disease, Ascaris-immunoglobulin E and
tuberculin testing in urban South African children.” Clinical & Experimental Allergy 36(5): 640648. Web.
xix
LJ Palmer, et. al. 2002 June 1. “Ascaris lumbricoides infection is associated with increased
risk of childhood asthma and atopy in rural China”. American Journal of Respiratory Critical
Care Medicine 165(11): 1489-93. Web.
xx
Pinelli, et. al. 2009 Nov. “Prevalence of antibodies against Ascaris suum and its association
with allergic manifestations in 4-year-old children in The Netherlands: the PIAMA birth cohort
study”. European Journal of Clinical Microbiology & Infectious Diseases 28(11): 1327-34.
Web.
xxi
Silva, et. al. 2010 Jan-Feb. “Atopic dermatitis and ascariasis in children aged 2 to 10 years”.
Jornal de Pediatria 86(1): 53-58. Web.
xxii
Nascimento, et. al. 2003 May-June. “Asthma and ascariasis in children aged two to ten living
in a low income suburb”. Jornal de Pediatria 79(3): 227-232. Web.
xxiii
Karadag, et. al. 2006 Aug. “The Role of Parasitic infections in atopic diseases in rural
schoolchildren”. Allergy 61(8): 996-1001. Web.
xxiv
Calvert, James and Peter Burney. 2010. “Ascaris, atopy, and aexercie-induced
bronchoconstriction in rural and urban South African children”. Journal of Allergy and Clinical
Immunology 125: 100-105. Web.
xxv
Sales, et. al. 2002. “Infection with Ascaris lumbricoides in Pre-School Children: Role in
Wheezing and IgE Responses to Inhalant Allergens”. Journal of Allergy and Clinical
Immunology 109(1): S27. Web.
xxvi
Hunninghake, et. al. 2007. “Sensitization to Ascaris lumbricoides and
severity of childhood asthma in Costa Rica”. Journal of Allergy and Clinical Immunology 119:
654-661. Web.
xxvii
Caraballo, et. al. 2007 Jan. “The Prevalence of IgE Antibodies to Ascaris in Asthmatic
Patients Living in a Tropical Environment”. Journal of Allergy and Clinical Immunology 121:
S210. Web.
xvi