Immune responses to parasites

Because of the long-lasting nature of parasitic infections it was widely believed until comparatively recently that there were very few effective immune responses against most parasites. However, it is now clear that immunity is the rule. The evidence for this comes from a number of sources. First, there is the epidemiological evidence: in endemic areas rhe majority of people develop clinical immunity to parasitic infections, the prevalence of infection falls with age while immunological parameters increase and some immunity to reinfection occurs. Second, there is the experimental evidence: in every animal model investigated some degree of immunity can be demonstrated and it can be argued that there is no reason why humans should be any different. However, immunity is seldom complete and tends to be unstable and individuals suffering from concurrent infections or undergoing immunosuppressive therapy often suffer recrudescences of their dormant infections.

The immune response to any parasite, as with other infectious agents, begins when the host becomes infected and the parasite is recognized as foreign. In order for this to occur, the parasite must come into contact with the ceils of the immune system and if it does not, then no immune response will be initiated. Intestinal parasites, such as the nematode worm Enterobius vermicularis and the nonpathogenic strains of the amoeba, Entamoeba histolytica, that do not breach the integrity of the gut wall cannot and do not initiate any immune response.

Most parasitic infections, however, do come in contact with the cells of the immune system and are recognized as foreign. The actual events involved in recognition are complex and much of what we know about them is concerned with protein antigens and, in the context of parasitic infections, little is known about what happens to carbohydrate antigens. In parasitic infections macrophages seem to be the cells usually involved as antigen-presenting cells and the effector cells of the immune system, as in all other infections, are cytotoxic T lymphocytes (CTI.s), natural killer (NK) cells, activated macrophages and B lymphocytes. Each of these has its own specific role and can act concurrently or sequentially to bring about the immobilization or destruction of the invading parasite.

Parasites, particularly helminths, represent large targets and are antigenically very complex but the immune response is normally only able to recognize a limited number of surface antigens, not all of which are involved in protection and some are even able to deflect the immune response away from more vulnerable targets. A great deal of research has been devoted to the identification and characterization of protective antigens in order to try to understand the mechanism of immunity to parasites and to target vaccines to relevant molecules. Much research has also been directed towards the identification of antigens that are irrelevant to protection, or are even counterprotective, those involved in the evasion of the immune response and those which may possibly contribute to pathology. The antigens that drive the cytokine response towards protection or pathology have only recently begun to receive any attention (see below).

What is known is that the totality of the immune responses to any particular parasite is complex but individual components are relatively simple and there is nothing unique or special about them. CTLs are frequently involved in viral infections but are seldom implicated in parasitic infections, the most important exception being Theileria parva in cattle in which CTLs predominate in protective immune responses, particularly in vaccinated animals. However, there is increasing experimental evidence for the involvement of CTLs against a number of intracellu lar protozoa, including malaria parasites. NK cells are also being increasingly implicated in protection against parasites. Activated macrophages are among the most important cells involved in protection against parasites and can kill parasites either intra-cellularly or extracellularly. If small, the target cell can be phagocytosed and destroyed in the phagolysosome via a number of pathways such as proteolytic enzymes and directly or indirectly by other toxic molecules, including reactive oxygen intermediates (ROI) and nitric oxide (NO), either on their own or together with other molecules. One of the key features of macrophage-mediated killing is that the toxic molecules produced are released not only into the phagolysosome but also extracellularly and are thus able to destroy cells in the close vicinity of the activated macrophage, including helminths, especially if the macrophage is closely bound to the target cell via an antibody bridge. These toxic molecules, however, can also damage host cells and their release in an inappropriate place or in excess is a major cause of immunopathology in parasitic infections.

Antibodies are effective against parasites in a number of ways including neutralization, agglutination, complement activation, opsonization and antibody-dependent cellular cytotoxicity (ADCC). The main function of immunoglobulin A (IgA) is the inhibition of invasion of the mucosa, either by agglutinating the parasites or blocking attachment to host cells, and this class of antibody is mainly concerned with defense against intestinal protozoa. IgG and IgM initiate complement-mediated lysis of parasites while both IgG and IgE bind to effector cells, activated macrophages or eosinophils respectively, and thus facilitate the destruction of the target cell via ADCC. Antibodies are also involved in ADCC by NK cells.

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