Unlike protozoans, which are unicellular and often grow within human cells, helminths are large, multicellular organisms that reside in humans but do not ordinarily multiply there and are not intracellular pathogens. Although helminths are more accessible to the immune system than protozoans, most infected individuals carry few of these parasites; for this reason, the immune system is not strongly engaged and the level of immunity generated to helminths is often very poor.
Parasitic worms are responsible for a wide variety of diseases in both humans and animals. More than a billion people are infected with Ascaris, a parasitic roundworm that infects the small intestine, and more than 300 million people are infected with Schistosoma, a trematode worm that causes a chronic debilitating infection. Several helminths are important pathogens of domestic animals and invade humans who ingest contaminated food. These helminths include Taenia, a tapeworm of cattle and pigs, and Trichinella, the roundworm of pigs that causes trichinosis.
Several Schistosoma species are responsible for the chronic, debilitating, and sometimes fatal disease schistosomiasis (formerly known as bilharzia). Three species, S. man-soni, S. japonicum, and S. haematobium, are the major pathogens in humans, infecting individuals in Africa, the Middle East, South America, the Caribbean, China, Southeast Asia, and the Philippines. A rise in the incidence of schis-tosomiasis in recent years has paralleled the increasing worldwide use of irrigation, which has expanded the habitat of the freshwater snail that serves as the intermediate host for schistosomes.
Infection occurs through contact with free-swimming infectious larvae, called cercariae, which are released from an infected snail at the rate of 300-3000 per day. When cercariae contact human skin, they secrete digestive enzymes that help them to bore into the skin, where they shed their tails and are transformed into schistosomules. The schistosomules enter the capillaries and migrate to the lungs, then to the liver, and finally to the primary site of infection, which varies with the species. S. mansoni and S. japonicum infect the intestinal mesenteric veins; S. haematobium infects the veins of the urinary bladder. Once established in their final tissue site, schis-tosomules mature into male and female adult worms. The worms mate and the females produce at least 300 spiny eggs a day. Unlike protozoan parasites, schistosomes and other helminths do not multiply within their hosts. The eggs produced by the female worm do not mature into adult worms in humans; instead, some of them pass into the feces or urine and are excreted to infect more snails. The number of worms in an infected individual increases only through repeated exposure to the free-swimming cercariae, and so most infected individuals carry rather low numbers of worms.
Most of the symptoms of schistosomiasis are initiated by the eggs. As many as half of the eggs produced remain in the host, where they invade the intestinal wall, liver, or bladder and cause hemorrhage. A chronic state can then develop in which the adult worms persist and the unexcreted eggs induce cell-mediated delayed-type hypersensitive reactions, resulting in large granulomas that are gradually walled off by fibrous tissue. Although the eggs are contained by the formation of the granuloma, often the granuloma itself obstructs the venous blood flow to the liver or bladder.
Although an immune response does develop to the schis-tosomes, in most individuals it is not sufficient to eliminate the adult worms, even though the intravascular sites of schis-tosome infestation should make the worm an easy target for immune attack. Instead, the worms survive for up to 20 years. The schistosomules would appear to be the forms most susceptible to attack, but because they are motile, they can evade the localized cellular buildup of immune and inflammatory cells. Adult schistosome worms also have several unique mechanisms that protect them from immune defenses. The adult worm has been shown to decrease the expression of antigens on its outer membrane and also to enclose itself in a glycolipid and glycoprotein coat derived from the host, masking the presence of its own antigens. Among the antigens observed on the adult worm are the host's own ABO blood-group antigens and histocompatibility antigens! The immune response is, of course, diminished by this covering made of the host's self-antigens, which must contribute to the lifelong persistence of these organisms.
The relative importance of the humoral and cellmediated responses in protective immunity to schistosomia-sis is controversial. The humoral response to infection with S. mansoni is characterized by high titers of antischistosome IgE antibodies, localized increases in mast cells and their sub sequent degranulation, and increased numbers of eosino-phils (Figure 17-13, top). These manifestations suggest that cytokines produced by a TH2-like subset are important for the immune response: IL-4, which induces B cells to class-switch to IgE production; IL-5, which induces bone-marrow precursors to differentiate into eosinophils; and IL-3, which (along with IL-4) stimulates growth of mast cells. Degranulation of mast cells releases mediators that increase the infiltration of such inflammatory cells as macrophages and eosino-phils. The eosinophils express Fc receptors for IgE and IgG and bind to the antibody-coated parasite. Once bound to the parasite, an eosinophil can participate in antibody-dependent cell-mediated cytotoxicity (ADCC), releasing mediators from its granules that damage the parasite (see Figure 14-12). One eosinophil mediator, called basic protein, is particularly toxic to helminths.
Immunization studies with mice, however, suggest that this humoral IgE response may not provide protective immunity. When mice are immunized with S. mansoni vaccine, the protective immune response that develops is not an IgE response, but rather a TH1 response characterized by IFN-7 production and macrophage accumulation (Figure 17-13, bottom). Furthermore, inbred strains of mice with deficiencies in mast cells or IgE develop protective immunity from vaccination, whereas inbred strains with deficiencies in cellmediated CD4+ T-cell responses fail to develop protective immunity in response to the vaccine. These studies suggest that the CD4+ T-cell response may be the most important in immunity to schistosomiasis. It has been suggested that the ability to induce an ineffective TH2-like response may have evolved in schistosomes as a clever defense mechanism to ensure that TH2 cells produced sufficient levels of IL-10 to inhibit protective immunity mediated by the TH1-like subset in the CD4+ T response.
Antigens present on the membrane of cercariae and young schistosomules are promising vaccine components because these stages appear to be most susceptible to immune attack. Injecting mice and rats with monoclonal antibodies to cercariae and young schistosomules passively transferred resistance to infection with live cercariae. When these protective antibodies were used in affinity columns to purify schistosome membrane antigens from crude membrane extracts, it was found that mice immunized and boosted with these purified antigens exhibited increased resistance to a later challenge with live cercariae. Schisto-some cDNA libraries were then established and screened with the protective monoclonal antibodies to identify those cDNAs encoding surface antigens. Experiments using cloned cercariae or schistosomule antigens are presently under way to assess their ability to induce protective immunity in animal models. However, in developing an effective vaccine for schistosomiasis, a fine line separates a beneficial immune response, which at best limits the parasite load, from a detrimental response, which in itself may become pathologic.
Overview of the immune response generated ing CD4+ T cells (bottom). C = complement; ECF = eosinophil against Schistosoma mansoni. The response includes an IgE hu- chemotactic factor; NCF = neutrophil chemotactic factor; PAF = moral component (top) and a cell-mediated component involv- platelet-activating factor.
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