IMMUNOLOGY - Roit A. - Mir 2000

Chapter 18. Immunity to Parasitic Infections

EFFECTOR MECHANISMS

To successfully establish itself in a new host before the host's immune system can mount a specific Immune Response, a parasite must overcome the host's pre-existing defense mechanisms. Complement plays a specific role among these mechanisms, as certain parasites—including adult worms and infective larvae of T. spiralis and Schistosoma mansoni—possess specific molecular structures on their surface coat that trigger the alternative complement activation pathway.

The first line of defense is formed by macrophages, neutrophils, eosinophils, and platelets.

Antibodies and cytokines specifically produced during the Immune Response to parasitic Antigens stimulate the anti-parasitic activity of all the aforementioned effector Cells. However, tissue macrophages, monocytes, and granulocytes also possess a certain baseline pre-existing activity.

The type of defense reaction evidently depends on the route by which the parasite enters the body.

✵ S. mansoni cercariae penetrate through the Skin—experimental depletion of macrophages, neutrophils, and eosinophils from mouse skin increases susceptibility to infection.

✵ Trypanosomes and malaria parasites entering the bloodstream are cleared from Circulation by phagocytic cells in the Spleen and Liver.

✵ A comparison of mouse strains with various immunological defects has shown that resistance to Trypanosoma rhodesiense infection is mediated by macrophages. At later stages of infection, they capture trypanosomes—opsonized by antibodies and the C3b complement fragment—even more rapidly in the liver.

Before macrophages begin functioning as antigen-presenting cells that initiate the immune response, they act as effector cells to suppress parasite Replication or even destroy the parasites. In addition, macrophages secrete substances that regulate the inflammatory response. Some of these—such as IL-1, IL-2, TNFα, and colony-stimulating factors (CSFs)—enhance Immunity by activating other cells or stimulating their proliferation. Other cytokines, such as IL-10, Prostaglandins, and TGFβ, can exhibit anti-inflammatory and immunosuppressive properties.

Macrophages are capable of destroying extracellular parasites.

Phagocytosis performed by macrophages provides an essential line of defense against small-sized parasites; furthermore, macrophages secrete numerous cytotoxic factors that allow them to destroy parasites without engulfing them. Upon cytokine activation, macrophages are capable of destroying both relatively small extracellular parasites, such as malaria parasites during the erythrocytic stage of their life cycle, and large-sized parasites, such as schistosomes at the schistosomula stage of development.

Macrophages also function as killer cells in antibody-dependent Cell-mediated cytotoxicity (ADCC). For instance, specific IgG and IgE antibodies enhance the capacity of macrophages to destroy schistosomula (juvenile schistosomes). In addition, macrophages secrete cytokines such as TNFα and IL-1, which interact with other cell types; for example, they render hepatocytes resistant to malaria parasites.

Following the phagocytosis of organisms such as T. cruzi, T. gondii, Leishmania spp., and malaria parasites, highly active oxygen metabolites are generated within macrophages and granulocytes; filariae and schistosomes also stimulate a respiratory burst. Cytokine-activated macrophages release greater amounts of superoxide oxygen radicals and hydrogen peroxide than resident tissue macrophages. Their O₂-independent mechanisms for destroying foreign cells are also activated.

One of the effective O₂-independent toxins is nitric oxide (NO), a metabolic product of L-Arginine. Its production is induced by the cytokines IFNγ and TNFα, and is significantly enhanced by their synergistic action. Nitric oxide can also be produced by endothelial cells. The Effect of NO contributes to resistance against leishmaniasis, Schistosomiasis, and malaria, and is presumably important for controlling most parasitic infections (Fig. 18.7). For instance, innate resistance to T. gondii infection, which is lost in immunodeficiencies, appears to be mediated by the suppression of parasite replication through this O₂-independent mechanism.

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Fig. 18.7. Evidence that the killing of Leishmania major by activated macrophages correlates with their release of nitric oxide. Cultured macrophages were activated with various doses of recombinant TNFα; at the highest doses used, parasite survival decreased by approximately one-third compared to controls. This correlated with an increase in The amount of NO released by macrophages (measured by nitrite concentration in the culture supernatant). When NO production was inhibited, parasite survival did not decrease (After Liew et al. 1990. Immunol. 71: 556.)

Macrophage activation is characteristic of the Cytology/cytology/16.html">Early stages of infection.

Following infection, all EFFECTOR Functions OF macrophages are rapidly upregulated. Specific activation of these cells is induced by T cell-derived cytokines (e.g., IFNγ, GM-CSF, IL-3, and IL-4), but macrophages can also be activated independently of T cells; for example:

✵ natural killer (NK) cells secrete IFNγ when stimulated by IL-12 produced by macrophages;

✵ macrophages secrete TNFα in response to certain parasitic antigens (e.g., phospholipid-containing antigens of malaria parasites and specific antigens of T. brucei); this cytokine subsequently activates other macrophages.

Although certain other cell types can also secrete TNFα, activated macrophages serve as the most important source of this factor, which is essential for a protective response against certain protozoan (e.g., Leishmania spp.) and helminth infections. Thus, TNFα activates macrophages, eosinophils, and platelets to destroy S. mansoni schistosomula, and its effect is enhanced in the presence of IFNγ.

It should be noted that TNFα can exert either beneficial or detrimental effects during infection, depending on its quantity and whether it is freely circulating or localized. For instance, serum levels of this cytokine in malaria caused by Plasmodium falciparum correlate with disease severity. Administration of TNFα to susceptible mice infected with the rodent malaria parasite P. chabaudi exerts a therapeutic effect, whereas it proves fatal in genetically resistant animals. It is possible that mice of this resistant strain already produce sufficient amounts of TNFα to prevent parasite replication, and administering additional amounts of this factor leads to toxic effects.

Neutrophils are capable of destroying large and small parasites.

The effector properties exhibited by macrophages are also characteristic of neutrophils. They possess phagocytic activity and are capable of destroying parasites using both O₂-dependent and O₂-independent mechanisms, including those mediated by NO. Furthermore, neutrophils display a more intense respiratory burst compared to macrophages, and their secretory granules contain highly cytotoxic Proteins (see Ch. 2). Neutrophil activation can be triggered by cytokines such as IFNγ, TNFα, and GM-CSF. Extracellular parasite killing by neutrophils is mediated by the release of H₂O₂, whereas intracellular destruction of ingested parasites occurs through the action of granule components. Neutrophils are present at sites of inflammation caused by parasite invasion and likely contribute to the destruction of parasites released from cells destroyed by them. Like macrophages, neutrophils bear Fc receptors and complement receptors and can participate in antibody-dependent cell-mediated cytotoxicity reactions, such as the destruction of S. mansoni schistosomula. Owing to this activity, they are more efficient at destroying certain nematode species, including T. spiralis, than eosinophils, although the relative efficacy of these two cell types may depend on antibody isotype and Specificity.

Eosinophil activity is typically associated with helminth infections

Eosinophils are thought to have evolved specifically to defend against tissue-dwelling stages of parasites that are too large to be eliminated by phagocytosis. According to this hypothesis, the localization of eosinophils near parasites and the enhancement of their anti-parasitic functions are mediated by IgE-dependent mast cell reactions, which are primarily designed for this very purpose.

The important role of eosinophils in vivo has been demonstrated in experiments using specific anti-eosinophil sera. In mice infected with T. spiralis and treated with such antiserum, a greater number of cysts formed in the Muscles compared to control animals: under conditions of eosinophil depletion, the host Organism was unable to destroy the parasites and instead contained them as best as possible through encapsulation.

However, recent studies have shown that although eosinophils are capable of participating in the host's defense against helminths—specifically by restricting parasite migration in Tissues—they do not always do so. For example, depletion of eosinophils does not impair immunity in mice infected with S. mansoni, nor does it reduce parasite burden in tapeworm infections.

Eosinophils are capable of destroying helminths using O₂-dependent and O₂-independent mechanisms

Eosinophils exhibit lower phagocytic activity compared to neutrophils. Eosinophil degranulation occurs in response to alterations in their surface membrane, and their activity is enhanced by cytokines such as TNFα and GM-CSF. However, the majority of eosinophil functions rely on antigen-specific mechanisms. Thus, upon binding of eosinophils in vitro to helminth larvae (e.g., S. mansoni and T. spiralis), The rate of degranulation onto the parasite surface increases if the larvae are coated with IgE or IgG. Damage to schistosomula can be mediated by major basic protein (MBP) derived from the crystalloid cores of eosinophils. MBP is not directed against any specific target, yet it does not cause significant damage to nearby host cells because it is localized within the narrow space between the eosinophil and the schistosome.

Eosinophils and mast cells act in concert

The destruction of S. mansoni schistosomula by eosinophils is enhanced by mast cell products, and in vitro experiments show that eosinophils from patients with schistosomiasis exhibit greater activity than those from healthy individuals. Parasite-derived antigens trigger local IgE-dependent mast cell degranulation with the release of mediators that selectively recruit eosinophils to a specific site and boost their activity. Other eosinophil-derived products subsequently downregulate mast cell responses. The operation of these effector mechanisms in vivo has been established in experiments on monkeys, in which schistosome elimination correlates with the accumulation of eosinophils (Fig. 18.8).

Fig. 18.8. Destruction of a schistosomulum by eosinophils. Eosinophils are able to attach to schistosomula and destroy them via degranulation, releasing granule contents onto the parasite surface. This series of electron micrographs illustrates the attachment of eosinophils, degranulation, and release of granule contents onto the parasite surface (1), as well as the stages of tegument destruction and eosinophil migration through the damaged areas (2 and 3). (Photographs kindly provided by Dr. D. McLaren.)

Platelets are capable of destroying various parasites

Potential targets for platelets include juvenile trematodes, as well as T. gondii and T. cruzi. Like other effector cells, their cytotoxic activity is enhanced by cytokine Treatment (e.g., IFNγ and TNFα). In rats infected with S. mansoni, platelets acquire the capacity to destroy parasites concurrently with the appearance of acute-phase proteins in the serum, but prior to the detection of antibodies. Incubation of normal platelets in such serum can promote their activation. Platelets, similarly to macrophages and other effector cells, bear surface Fcε receptors, through which they mediate IgE-associated antibody-dependent cellular cytotoxicity.