The Coevolution Of Human Immunity And Helminthic Parasite Biology Essay

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The human immune system evolved in the presence of infestation by extracellular parasitic worms known as helminths. Through coevolutionary check-and-balance mechanisms, the immune system has adapted to modulate worm load in chronically infested individuals. This relationship has been advantageous to both host and pathogen. Such symbiosis is maintained by the activation of an immune response mediated by IgE antibodies. These IgE antibodies are created through a pathway beginning with TH2 helper cells that target extracellular infections and allergens. In parts of the world where helminthiasis is still prevalent, there is a selective advantage for genes that increase IgE activity. However, the adaptation to the stress of chronic worms infestation accounts for the maladaptive response to innocuous substance - allergy - upon removal of the stress. In the absence of parasites and their antigens, IgE causes an overreaction to common proteins and manifests as an allergic response. In addition to the removal of the early evolutionary stress of helminths, many technological and infrastructure changes in developed countries have increased human exposure to allergens, thus increasing hypersensitivity to seemingly innocuous substances. 

Through the expansion of their ecological niche, early hominids encountered new foods and became intermediate hosts to a variety of helminth species. As they evolved, hominids would haved carried the parasites that plagued their ancestors. These parasites would have in turn evolved with the hominids. Adapting to the hominids would have been easy for the helminths as they have few environmental or host restrictions. Today, humans act as hosts for more than 25 species of helminths (Warren et al 1990). The shift from the hunter-gatherer lifestyle to agriculture increased sedentism and parasitic disease. Disease was spread through contact with animals, other humans, and their wastes. Agricultural practices such as irrigation and the use of feces as fertilizer would have exposed early humans to helminths such as schistosomes or intestinal flukes, respectively (Cockburn 1971).

For contemporary humans, acute infectious diseases are controlled in some areas of the world, while chronic, noninfectious, degenerative diseases are on the rise. Although new technology has allowed some human populations to benefit from the control of infectious disease, many individuals throughout the world are still affected by infection and parasites. It is estimated that, worldwide, approximately 200 million people are infected with schistosomes (WHO 1999) and 3800 million people are infected with soil-transmitted helminths (WHO 2001). These numbers indicate there is likely still selection for protective mechanisms against helminthiasis in a large proportion of the contemporary human population.

Given the prolonged mammalian history with parasites, the inflammatory system has evolved protective mechanisms to safeguard the heath of a host in the event of a parasitic infection. These mechanisms are regulated by the immune system, which is modulated by human helper T cells. These T cells can be divided into TH1 and TH2 subsets that fulfill separate functions in regulating response to infection. TH1 cells produce the response to intracellular infections while TH2 cells produce responses to extracellular infections and allergens. During helminth infections, the number of TH2 cells is greater than the number of TH1 cells. The TH2 cells secrete a particular cytokine, or signaling molecule, known interleukin-4 (IL-4) (Barnes et al 1999). IL-4 promotes parasite-specific IgE antibody, T cell, and mast cell production.

When a helminth enters a host, soluble antigens from the parasite diffuse across the host's intestinal mucosa. Through the movement of lymphatic fluid, the parasitic antigens are transported to the lymph nodes. IgE antibody is systematically released, where it attaches to cells bearing specific receptors, such as mast cells, located in virtually every tissue in the body, including the intestinal mucosa. Contact between the mast cells and the parasitic antigen results in mast cell degranulation and the release of pharmacological mediators such as histamine and cytokines, which attract eosinophiles and other cells to the site. The cascade of reactions functions to damage and expel the parasite (Barnes et al. 1999).

In addition to humoral, IgE-mediated immunity in the fight against helminths, a second line of defense has evolved in the immune system which is also antibody-mediated and is the primary mechanism for killing parasite larvae. Antibody-dependent cell-mediated cytotoxicity (ADCC) occurs when antibodies binds to antigen and leads to killer cells activating the engulfment or killing of the organism by cell mediators. Together the IgE antibody-mediated ADCC responses defend the host against extracellular parasites.

There are benefits to the evolution of the IgE antibody immune response. High levels of IgE minimize the number of parasites that infest a host during chronic exposure (Dunne et al. 1992). Serum IgE antibodies and the degree of infestation are inversely correlated. This finding is supported by the work of Capron et al (1987) where the selective removal of IgE reduced protection against schistosomes in animal models.

Because contacts between the vector and the host may be infrequent, it is important for the parasite to maintain chronic infections. Most human parasitic infections last for years and must therefore not overwhelm the host if the parasite is to be maintained. Parasites produce self-limiting infections that allow the host to defend against lethal infection while maintaining a viable population. One strategy is through concomitant immunity, a response by which adult schistosomes induce an immune response that limits, but does not eliminate, subsequent infections of the host by infective larvae, but that does not cause rejection of the adult worms (Sher and Ottensen 1988). Although responses may become immunosuppressive during chronic infection, usually the initial encounter between parasites and host results in immune responsiveness. This suggests that it may be in the parasite's interest to be immunogenic, either to initiate an immunoregulatory chain of events that will eventually result in suppression or, alternatively to protect the host against the potentially lethal effects of overinfection or reinfection.

In summary, the immune system by which the human host battles parasitic disease is highly developed and specialize and depends on the humoral response, which calls for the generation of specific IgE. The worm-specific IgE signals there generation of killer cell activity and phagocytosis via effector cells such as eosinophils, macrophages, and platelets. IgE, the key player is synthesized and controlled by an elaborate network, the TH1/TH2 system, which is up-regulated by the cytokine IL-4. There are a variety of responses to helminths and a continuum of helminthic disease expression. For example, the more successful human host will produce higher levels of specific IgE with which to kill the worm, but the immune system of the host who succumbs to greater worm loads may be less proficient at producing sufficiently high levels of worm specific IgE.

Allergy is hypersensitivity to a typically innocuous substance. Allergy begins after sensitization of a specific allergen, a substance that elicits an allergic response. During sensitization, antibodies are generated that are specific to the allergens to which an individual has been exposed. Antibodies are molecules produced by B lymphocytes, a type of white blood cell that are part of the adaptive immune system. There are five major classes of antibodies referred to as immunoglobins, and they are, in order of concentration, IgG, IgA, IgM, IgD, and IgE (Barnes et al. 1999). Each type of immunoglobin has a specific function in the immune system and IgE is most relevant in allergic disease.

During an allergic response, plasma cells release IgE antibodies that bind to receptors on mast mast cells in epithelial tissues, such as those of the respirator or urinary tracts and the skin. This allergic response is similar to the immune systems response to helminthiasis (Zanders et al. 1992). After IgE antibodies encounter an antigen, the antibodies cross link, and mast cells degranulate to release mediators such as histamine and proinflammatory cytokines. Unlike in helminthiasis, in which IgE antibodies are directed at the worm and its by-produces, the allergic response is directed at seemingly innocuous substances.

A typical allergic response includes bronchial constriction, vascular dilation, and an increase in mucous secretions, which lead to the associated symptoms of wheezing, coughing, itching, sneezing, and vomiting. During anaphylaxis, a severe form of allergic reaction, there is an intense generation and release of mediators. Such a response has effects on various organs may be fatal. Examples of anaphylaxic allergens include antibiotics, foods, and foreign proteins, such as venom.

In developed countries, the prevalence of allergies and conditions such as asthma is increasing. According the American Asthma Foundation, 23 million Americans suffer from asthma (2001). These countries have a better-developed infrastructure that has resulted in the elmination of helminths and an increase in chronic disease. One of the most significant consequences of modernization is the creation of a microenvironment that increases our exposure to domestic arthropods, such as dust mites, and other pests. Research has shown that there is a positive correlation between level of infestation of household pests and the degree of urbanization (Barnes et al. 1999).

The prevalence of allergy is lower in less developed countries. Populations in regions of the world where helminthiasis prevalence is high frequently demonstrate a lower prevalence of asthma and other allergic responses than do populations than with low helminthiasis prevalence. It is hypothesized that the IgE antibodies are typically dedicated to target parastic allergens are only usually unavailable to respond to innocuous agents. In the absence of helminths, these antibodies are not saturated and the immune system can react to the harmless allergens (Bazaral et al. 1975). It has been found that an individual is more likely to development asthma during the absence of helminthiasis, or during mild helminthiasis during which time less antibody is directed at the parasite than in during a chronic infection (Lynch 1992). Therefore, helminthiasis and allergy are not likely mutually exclusive, but allergy is much less likely to occur in severe helminthic disease than in mild helminthic disease (Barnes et al. 1999).

Marsh et al. (1980) has found that non-European descendents living in developed countries have a higher propensity for allergic response. This is associated with those individuals' greater propensity to produce IgE as well, in addition to the increase in exposure to inhalant allergens. There is a selective advantage for a predisposition to produce high levels of IgE, as this antibodies serves as a key regulator in the maintenance of helminthic infection in populations that are chronically exposed to parasites. Additionally, it has been found that high levels of allergens affect people with family histories of allergy, but do not trigger an allergic response in most other people (Sporik et al. 1990). These finding imply that allergy and asthma reactions occur only in genetically susceptible individuals after adequate or persistent exposure to specific allergens.

There is also a genetic propensity for susceptibility or resistance to parasitic infection (Tingley et al. 1988). This predisposition may depend on factors such as nutrition, behavior, or environment. For example, antibodies to Onchorcera volvulus, the nematode that causes River Blindness, in Ecuadorian Indians was found to be higher when compared to individuals of African origin in the same area (Kron et al. 1993).

Through modernization, populations acquire objects that promote allergens such as upholstered furniture, carpeting and domestic pets. The introduction of such objects has been correlated to a rapidly increase the prevalence of asthma in populations with either high or low helminthiasis prevalence. An example in a study by Dowse et al. (1985) showed that asthma incidence increased over ten years within vEastern Highland villages of Papua New Guinea that was attributed to the introduction of wool blankets to the villagers and the sudden and profound exposure to house dust mites within the blankets. Barnes et al. (1997) found that house dust mite allergen concentrations in Barbados were higher in better-built homes, likely because the plumping contributed to a higher humidity levels that were more conducive to dust might proliferation than the drier wood homes. During the process of modernization, in addition to the acquisition of homes and objects that increase allergen exposure, the reduction or elimination of helminthiasis, increases the risk of allergic disease more dramatically.

Adaptation often results in trade-offs that may compromise an individual's adjustment to his or her environment. The coevolution of helminths and humans shaped the immune response to be highly sensitive to parasitic antigens. This response, which is beneficial to host and parasites, is modulated by many mechanisms. TH2 activation stimulates the production of IL-4 cytokines that trigger production of IgE antibodies. IgE mediate an immune response targeted the antigens released by parasites as well as allergens. When the stress of helminthiasis is removed, IgE antibodies are free to react to harmless antigens. Although levels of IgE are highest during a parasitic infection or an allergic response, levels are also affected by genetic predisposition. Selective pressures maintain high levels of IgE expression in regions of the world with high helminthiasis prevalence.

Through modernization, the stress of helminthiasis has been removed while the stress of allergen exposure has increased. Activation of IgE by innocuous allergens triggers the maladaptive response of an allergic reaction. Individuals who are not infested by helminths who have the genetic propensity for high IgE antibody expression are most susceptible to allergic hypersensitivity. In developed countries, decreased helminthiasis prevalence in junction with increased allergen exposure are responsible for the increase in allergic disease prevalence.

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