Immunity to Parasites

Innate Immunity

The first line of defence against parasitic infection are the effector mechanisms of the innate immune system. The macrophages are important players in the defence against extracellular parasites. This is because macrophages are able to secrete cytokines as well as perform phagocytosis. In this they can act as 'killer cells' through antibody-dependent cell-mediated cytotoxicity, for example specific IgG/IgE enhances the ability of macrophages to kill schistosomules through the interaction of Fc receptors on the surface of the macrophage. Of the secreted cytokines, the secretion of TNFα is of particular importance. This is because TNFα activates other macrophages and can have toxic effects in high amounts. TNFα also renders hepatocytes resistant to malarial infection when in conjunction with IL-1. Cytokine secretion (in particular IFNγ) can also enhance killing by mechanisms using free radicals and O₂-independent toxins (e.g. nitric oxide).

As well as the macrophages, the granulocytes form the main effector response to parasitic infection. Eosinophils are very important in the destruction of larger parasites even though they are less phagocytic than neutrophils. Most activity from eosinophils is controlled by antigen-specific mechanisms, for example binding to worms coated with IgG/IgE increases degranulation. Degranulation, through the process known as exocytosis, releases enzymes that degrade the parasite into smaller chunks so it can be cleared by phagocytosis. The eosinophils also form the end point of the adaptive immune response to larger parasites with the killing of some larvae being enhanced by the activity of mast cells, for example antigens released by S. mansoni cause IgE-dependent degranulation of mast cells, the products of which selectively attract eosinophils.

The other granulocytes present in parasite-infected inflammatory lesions and involved in the anti-parasitic response are the neutrophils. In the parasitic response they have similar properties to macrophages with activation caused by cytokines such as TNFα, IFNγ and GM-CSF. Their mechanism for killing is by an intense respiratory burst, with extracellular killing being mediated by hydrogen peroxide (H₂O₂). In addition, they also express Fc and complement receptors so can participate in antibody-dependent cell-mediated cytotoxicity and phagocytosis.

• Platelets- cytotoxic activity is increased by cytokines such as TNF-alpha and IFN-γ
  • Potential targets include the larval stage of flukes, e.g. T. gondii and T. cruzi
  • Like other effector cells, platelets express Fc receptors, making them able to perform antibody-dependent cytotoxicity

Adaptive Immunity

Although the innate immune system provides an effective first line of defence, T cells are fundamental in the development of immunity, demonstrated using T-cell deprived mice that fail to resolve otherwise non-lethal infections of, for example, T. cruzi.

• Both CD4+ and CD8+ cells are required for protection, e.g CD4+ cells protect against the blood stage of a Plasmodium infection (erythrocytes do not express MHC class I), while CD8+ cells are required to mediate immunity against the liver stage (hepatocytes do not express MHC class II).
• Th1 cells are required to fight intracellular protozoa- the release of IFN-γ activates macrophages to kill the protozoa residing within them
• Helminth infections require both Th1 and Th2 responses, e.g. during S. mansoni the secretion of IFN-γ by Th1 cells activates mechanisms that destroy larvae in the lungs, although the Th2 subset, secreting IL-5, predominate
• Th2 cells are required for the destruction of intestinal worms, where they induce mucosal mast cells and interact with eosinophils

While cell-mediated immunity is important in tissue infections, such as Leishmania, specific antibodies are important in controlling parasites that live in the bloodstream, e.g. malaria. Mechanisms of antibody-mediated immunity include:

• Directly damaging protozoa
• Activating complement
• Blocking attachment to host cells
• Enhancing macrophage phagocytosis
• Involvement in antibody-dependent cell-mediated cytotoxicity

Immunopathology

• The increase in macrophages and lymphocytes in the liver and spleen can lead to swelling of these organs, e.g. visceral leishmaniasis
• T-cell dependent granulomas forming in organs, e.g. schistosomiasis in the liver
• The pathology of elephantiasis is thought to be due to changes in the adult filariae in the lymphatic system
• Formation of immune complexes, e.g. deposition in the kidney during malarial infection
• Anaphylactic shock caused by IgE production, e.g. after the rupture of hydatid cysts
• Cross-reaction of antibodies with host tissue, e.g. O. volvulus, the cause of river blindness, expresses an antigen similar to a protein in the retina
• Excessive production of cytokines, such as TNF-alpha, may contribute to pathology of diseases such as malaria

Evading immune defences

Parasites can evade an immune response from the host by changing the antigens presented to the host, produce antigens that mimic the host's antigens and can produce down-regulating factors which suppress or modify the host's immune responses. Having a rapid turnover of their surface coat when host cells bind and by being able to live in sites which are protected from the host's immune response allow parasites to establish themselves in a particular species.

• Selection of innapropriate defences- by exploiting the 'adjuvant' mechanism, some parasites are able to activate the inappropriate helper T cell subset, e.g Leishmania
• Antigenic variation avoids recognition by antibody and complement, e.g. T. brucei
• Inhibiting fusion of lysosomes
• Escaping into the cytoplasm, e.g. T. cruzi
• Inhibiting respiratory burst, e.g. Leishmania
• Forming cysts in muscle tissue, e.g. T. spiralis- also develops decay accelerating factor (DAF)
• Production of antioxidants, e.g. W. bancrofti

Also see Adaptive Immunity to Parasites