The Coevolution of Human Immunity and Helminthic Parasites
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Most multicellular organisms, both vertebrate and invertebrate, have an evolutionary history of infestation by extracellular parasitic worms known as helminths. The immune systems of these species have adapted to the stress of helminth infection, or helmnithiasis, through the development of mechanisms to modulate worm load in chronically infested individuals. Most marsupials and mammals, including humans, use a particular immune response mediated by IgE antibodies - molecules that identify and neutralize foreign objects - to defend against helminths (Poulsen & Hummelshoj 2007). In parts of the world where helminthiasis is still prevalent, there is a selective advantage for genes that increase production of IgE antibodies. However, the adaptation to the stress of chronic worm infestation accounts for the maladaptive response to innocuous substance - allergy - upon removal of the stress. The presence of parasites triggers the production of molecules known as interleukin-10 (IL-10) cytokines that damped the inflammation response. However, in the absence of parasites, IgE antibodies target harmless proteins and the lack of IL-10 production results in a potentially dangerous inflammatory response. In addition to the removal of the early evolutionary stress of helminths, many technology and infrastructure changes in developed countries have increased human exposure to allergens, thus increasing hypersensitivity to seemingly innocuous substances.
Many species, including humans, evolved under the stress of helminth infestation. As early hominids expanded their ecological niche and encountered new foods, they became hosts for an increased number of helminth species, which would have, in turn, evolved with the hominids. 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 disease, including parasitic infection. Such disease was spread through contact with animals, other humans, and their wastes. The development of agricultural methods such as irrigation and the use fertilizer would have increased the exposure of early humans to soil-transmitted helminths (Cockburn 1971).
For contemporary humans, parasitic and 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. Globally, more than two billion people are chronically infected with soil-transmitted helminths such as schistosomes and hookworms (Florh et al. 2008). These numbers indicate there is still selection for protective mechanisms against helminthiasis in a large proportion of the contemporary human population.
Given the prolonged mammalian history with parasites, the immune system has evolved protective mechanisms to safeguard the heath of a host in the event of a parasitic infection. When a helminth enters a host, antigens from the parasite diffuse across the host's internal membranes. Two types of white blood cells, B cells and T cells, recognize antigens in the blood stream. B cells are released into the blood and carried to capillary beds serving the tissues and organs of the lymphatic system - a system of vessels and organs that helps balance the fluid content of blood and the surrounding tissues while participating in the body's defense against invading disease organisms (Russel et al. 2008). T cells are released into the blood and carried to the thymus, an organ of the lymphatic system.
The adaptive immune responses are regulated by two mechanisms: antibody-mediated immunity and cell-mediated immunity. During antibody-mediated immunity, derivatives of B cells known as plasma cells secrete antibodies that circulate throughout the blood and lymphatic fluid, recognizing, binding, and removing antigens. Each plasma cell is specific for at least one particular antigen, but some are capable of recognizing any antigen, even if it has never before been encountered. Plasma cells are capable of secreting are five major classes of antibodies. These antibodies are, in order of decreasing concentration, IgG, IgA, IgM, IgD, and IgE (Barnes et al. 1999). Each type of antibody has a specific function in the immune system and IgE is most relevant in combating infection by parasitic worms and mediating many allergic responses such as hay fever, asthma, and hives (Russell et al 2008). Cell-mediated immunity serves as the primary mechanism for killing parasite larvae. During cell-mediated immunity, a subset of T cells becomes activated and, with other cells of the immune system, attacks and kills foreign cells directly. These two mechanisms interact to defend the host against extracellular parasites.
Parasitic antigens are first detected by plasma cells in the membranes of the gastrointestinal and respiratory tracts, triggering the production of two types of IgE antibodies: those that are specific for a particular parasite and those that are nonspecific (Grant et al 2008). These antibodies bind to mast cells. Mast cells are a particular type of cell found within many body tissues that contain granules of molecules such as histamine. The mast cells are activated to degranulate when the antigen binds to the attached IgE antibody, causing the internal histamine to be released. The release of histamine causes various physiological changes associated with inflammation (Flohr et al. 2008). The cascade of reactions functions to damage and expel the parasite (Barnes et al. 1999).
Inflammation is complex biological process that occurs in vascular tissues as a response to pathogens (such as helminths), damaged cells, or irritants. In an inflammatory response, an individual may experience 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 inflammation, there is an intense generation of mast cells and release of their mediators. Such a response has effects on various organs and may be fatal. Examples of anaphylaxis-inducing antigens include antibiotics, foods, and foreign proteins, such as venom. Thus the inflammatory response to the presence of a particular antigen may in an of itself harmful to the organism (Florh et al. 2008)
Once an immune reaction has run its course and the invading parasites have been eliminated, long-lived T helper cells, derived from the encounter with the antigen remain in an inactive state in the lymphatic system and provide an immunological memory of the foreign antigen (Poulsen & Hummelshoj 2007). When a foreign antigen enters the body for a subsequent time, a secondary immune response is triggered. The helper T cells recognize the antigen and secrete small proteins known as cytokines that regulate or assist in an immune response.
Helper 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. When TH2 cells detect previously recognized parasitic antigens, they secrete a particular cytokine, or known interleukin-4 (IL-4) (Barnes et al 1999). IL-4 promotes parasite-specific IgE antibody, helper T cell, and mast cell production.
The adaptation of the IgE antibody immune response is beneficial during helminth infection. High levels of IgE minimize the number of parasites that infest a host during chronic exposure (Dunne et al. 1992). Individuals infected with helminths may have IgE antibody levels that are up to 100 times greater than the normal level, which typically decrease after anti-helminth treatment (Poulsen & Hummelshoj 2007). Additionally, the type of IgE antibody produced may change throughout a human's life to better target a particular parasite. Studies have shown that humans acquire a natural immunity to schistosome infection in adolescence (Grant et al 2008). This natural immunity corresponds to increased levels of IgE from schistosome-specific antigens and decreased production of non-specific IgE. For young children, the greater nonspecific component in IgE production occurs at the expense of schistosome-specific IgE, resulting in a less protective antibody-mediated immune response when compared to adolescents and adults.
To establish long-term immunity and because contacts between vector - an agent that transmits an infectious disease - and host may be infrequent, it is important for the both the host and parasite to maintain chronic infections. Most human parasitic infections last for years and must therefore not overwhelm the host. 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 seen in adult schistosomes, where an immune response is induced to limit, but not eliminate, subsequent infections of the host by infective larvae, without causing the rejection of the adult worms (Sher & Ottensen 1988). Schistosomes and hookworms also trigger the production of the anti-inflammatory cytokine interleukin-10 (IL-10) in parasite-induced T cells. IL-10 protects the host from extreme mast cell degranulation and the initiation of intense inflammation (Florh et al. 2008). The level of IL-10 decreases after anti-helminth treatments once the parasite is no longer present to induce production.
In summary, the immune system of most mammalian and marsupial hosts is highly adapted to battle parasitic disease. The generation of parasite-specific IgE antibodies by plasma cells initiates an inflammatory response and killer cell activity. During subsequent encounters with an antigen, the synthesis of IgE is controlled by TH2 cells and up-regulated by the cytokine IL-4. The inflammatory response is, however modulated by the release of anti-inflammatory IL-10 cytokines, in order to protect the host from the dangerous effects of intense mast cell degranulation. Through these mechanisms, the more successful human host will produce higher levels of parasite-specific IgE antibodies with which to prevent overwhelming worm infestation. Hosts less proficient at producing sufficiently high levels of parasite-specific IgE antibodies are more likely to succumb to greater worm loads.
Allergy is hypersensitivity to a typically innocuous substance. Allergy begins after sensitization of a specific allergen, an antigen that elicits an allergic response. Similar to a helminthic infestation, plasma cells generate IgE antibodies during sensitization that are specific to the allergens to which an individual has been exposed. These IgE antibodies bind to receptors on mast cells. The binding of the allergen to an IgE antibody triggers a cascade of events resembling the immune response to helmthiasis (Zanders et al. 1992). The mast cells degranulate to release mediators, including histamine. 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. Also, the allergens are not capable of initiating the parasite-induced production of IL-10 that protects the host from the potentially harmful effects of the inflammatory response (Flohr et al. 2008). Thus, humans have adapted to respond to the outside world in the presence of helminths and in their absence we are unable to modulate the maladaptive inflammatory response that may result in annoying or dangerous symptoms.
In industrialized countries, the prevalence of allergies and conditions such as asthma have increased over the last three or four decades (Poulsen & Hummelshoj 2007). These countries have better-developed infrastructures that have resulted in the elimination of helminths and an increase in noninfectious disease. Similarly, allergic disease prevalence is increasing in industrializing countries such as India and China (Flohr et al. 2008). Besides the removal of helminths, a significant consequence 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).
Evidence suggests that allergic reactions are less pronounced in individuals infected with helminths. Thus, areas where helminthic infection is endemic typically have lower levels of allergic disease when compared with areas free of helminths (Grant et al. 2008). Studies have consistently found that most helminths investigated imbue their hosts with protective effects during skin prick tests (SPT) - tests used to diagnose allergies by eliciting a small, controlled allergic response. However, while all helminths increase the level of IgE antibody produced by a host, infection by schistosomes and hookworms - parasites found to trigger the production of IL-10 - have the strongest association with protection against allergy and asthma (Flohr et al. 2008). Individuals are more likely to develop asthma during the absence of helminthiasis, or during mild helminthiasis - a time during which less parasite-specific IgE antibody is produced than during a chronic infection, and less IL-10 is produced to reduce inflammation (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).
The removal of helminths from infected populations in Venezuela, Vietnam, and Gabon has shown a resultant increase in allergic skin sensitization during SPT (Florh et al. 2008). Marsh et al. (1980) found that non-European descendents living in developed countries have a higher propensity for allergic response. These results are expected because those individuals likely had a greater genetic propensity to produce IgE, resulting in an increased inflammation response, a decrease in IL-10 production to modulate inflammation, and an increased 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 certain 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. While the total level of serum IgE does not appear to directly reflect natural immunity against asthma in helminth infection-endemic populations, linkage studies have implicated a particular chromosome locus, or region, in controlling asthma and intensity of schistosomiasis in Brazilian and Senegalese populations. Because this same locus is identified with both helminthic infection and for allergy susceptibility in a number of independent studies, there may be a common genetic basis for host protection against helminthic infection and susceptibility allergic disease (Grant et al. 2008).
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 Eastern 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 plumbing contributed to a higher humidity levels that were more conducive to dust mite 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. Parasites presence triggers anti-inflammatory IL-10 cytokines production by specialized T cells that reduce the inflammatory effects of mast cell degranulation. Removal of the stress helminthiasis also removes the modulation of the inflammatory response through IL-10. Under these conditions, the maladapted response of IgE antibodies reacting to harmless allergens is allergy in the form of disproportioned, potentially dangerous inflammation event. 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 with a 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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