Ascariasis and Allergies,
a rigorous exploration of relevant theories and studies
Human Biology 153: Parasites and Pestilence
Scott Smith, MD
February 26, 2010
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 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 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 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 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 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).
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 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 antigen-activated 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).
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 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 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]
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 allergy-mediating 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 cross-sectional 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 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 non-specific 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 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.
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 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.
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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