Adaptive Immunity to Parasites

Different protozoa and helminths vary greatly in their structural and biochemical properties, life cycles, and pathogenic mechanisms. It is therefore not surprising that different parasites elicit distinct adaptive immune responses (Table 15-4). Some pathogenic protozoa have evolved to survive within host cells, so protective immunity against these organisms is mediated by mechanisms similar to those that eliminate intracellular bacteria and viruses. In contrast, metazoa such as helminths survive in extracellular tissues, and their elimination is often dependent on special types of antibody responses.

The principal defense mechanism against protozoa that survive within macrophages is cell-mediated immunity, particularly macrophage activation by TH1 cell-derived cytokines. Infection of mice with Leishmania major, a protozoan that survives within the endosomes of macrophages, is the best documented example of how dominance of TH1 or TH2 responses determines disease resistance or susceptibility (see Fig. 15-5). Resistance to the infection is associated with activation of Leishmania-specific Th1 CD4+ T cells, which produce IFN-y and thereby activate macrophages to destroy intracellular parasites. Conversely, activation of TH2 cells by the protozoa results in increased parasite survival and exacerbation of lesions because of the macrophage-suppressive actions of TH2 cytokines, notably IL-4. A good example of this difference is seen in Leishmania infections in different inbred mouse strains. Most inbred strains of mice

TABLE 15-4 Immune Responses to Disease-Causing Parasites



Principal Mechanisms of Protective Immunity


Plasmodium species


Antibodies and CD8+ CTLs

Leishmania donovani


(mucocutaneous disseminated)

CD4+ Th1 cells activate macrophages to kill phagocytosed parasites

Trypanosoma brucei

African trypanosomiasis


Entamoeba histolytica


Antibodies, phagocytosis


Schistosoma species


Killing by eosinophils, macrophages

Filaria, e.g., Wuchereria bancrofti


Cell-mediated immunity; role of antibodies?

Selected examples of parasites and immune responses to them are listed.

are resistant to infection with L. major, but inbred BALB/c and some related strains of mice are highly susceptible and die if they are infected with large numbers of parasites. After infection, the resistant strains produce large amounts of IFN-y in response to leishmanial antigens, whereas the strains that are susceptible to fatal leish-maniasis produce more IL-4 in response to the parasite. Promoting the TH1 response or inhibiting the TH2 response in susceptible strains increases their resistance to the infection. Multiple genes appear to control the balance of protective and harmful immune responses to intracel-lular parasites in inbred mice and presumably in humans as well. Attempts to identify these genes are ongoing in many laboratories.

Protozoa that replicate inside various host cells and lyse these cells stimulate specific antibody and CTL responses, similar to cytopathic viruses. An example of such an organism is the malaria parasite, which resides mainly in red blood cells and in hepatocytes during its life cycle. It was thought for many years that antibodies were the major protective mechanism against malaria, and early attempts at vaccinating against this infection focused on generating antibodies. It is now apparent that the CTL response against parasites residing in hepato-cytes is an important defense against the spread of this intracellular protozoan. The cytokine IFN-y has been shown to be protective in many protozoal infections, including malaria, toxoplasmosis, and cryptosporidiosis.

Defense against many helminthic infections is mediated by the activation of TH2 cells, which results in production of IgE antibodies and activation of eosinophils. Helminths stimulate differentiation of naive CD4+ helper T cells to the TH2 subset of effector cells, which secrete

IL-4 and IL-5. IL-4 stimulates the production of IgE, which binds to the Fce receptor of eosinophils and mast cells, and IL-5, which stimulates the development of eosinophils and activates eosinophils. IgE, mast cell and eosinophil-mediated effector mechanisms are described in Chapter 19. The combined actions of mast cells and eosinophils also contribute to expulsion of the parasites from the intestine, so-called barrier immunity (see Chapter 10, Fig. 10-9). The expulsion of some intestinal nematodes may be due to IL-4-dependent mechanisms that do not require IgE, such as increased peristalsis.

Adaptive immune responses to parasites can also contribute to tissue injury. Some parasites and their products induce granulomatous responses with concomitant fibrosis. Schistosoma mansoni eggs deposited in the liver stimulate CD4+ T cells, which in turn activate macrophages and induce DTH reactions. DTH reactions result in the formation of granulomas around the eggs; an unusual feature of these granulomas, especially in mice, is their association with TH2 responses. (Granulomas are generally induced by TH1 responses against persistent antigens; see Chapter 18.) Such TH2-induced granulomas may result from the process of "alternative macrophage activation" that is induced by IL-4 and IL-13 (see Chapter 10). The granulomas serve to contain the schistosome eggs, but severe fibrosis associated with this chronic cellmediated immune response leads to cirrhosis, disruption of venous blood flow in the liver, and portal hypertension. In lymphatic filariasis, lodging of the parasites in lymphatic vessels leads to chronic cell-mediated immune reactions and ultimately to fibrosis. Fibrosis results in lymphatic obstruction and severe lymphedema. Chronic and persistent parasitic infestations are often associated with the formation of complexes of parasite antigens and specific antibodies. The complexes can be deposited in blood vessels and kidney glomeruli and produce vasculi-tis and nephritis, respectively (see Chapter 18). Immune complex disease is a complication of schistosomiasis and malaria.

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