The human immune system has evolved in concert with microbes and is very sophisticated, especially with regard to host defenses against microbes, but the system is not perfect. Interactions of the immune system with microbes are an ongoing affair. Microbes have a high mutation rate compared to human beings. Microbes have evolved a diversity of mechanisms that can enable microorganisms to subvert immediate immunologically mediated elimination. Persistence within the host is necessary for the propagation of some parasites.
There are multiple mechanisms by which microbes can persist in the body and evade the immune system. Tolerance is defined as specific reduction in the response of the immune system to a given antigen.101,102 In the case of transplacental infection, the fetus develops a certain degree of tolerance to antigens to which it is exposed. The immune system of fetuses is rather incompletely developed in utero, and microorganisms survive easily. Cytomegalovirus infects the fetus transpla-centally and produces extensive damage to multiple tissues. After delivery, infants continue shedding virions for weeks to months because they are unable to destroy the virus. Other mechanisms include the production of superantigens that stimulate a large population of T cells, which then become deleted if the encounter occurs during early development. Exposure to massive amounts of antigen in the circulation can also lead to tolerance.2,98 Immunosuppression is a well-demonstrated phenomenon that occurs during certain infections caused by viruses, bacteria, protozoa, and helminths. These infections usually involve the lymphoid tissues and macrophages and hamper the immune response.
Intracellular pathogens that are able to spread from cell to cell without exposure to the extracellular compartment can avoid exposure to some elements of the immune system. In other cases, pathogens reside in sites relatively inaccessible to the immune system, such as glandular luminal spaces or kidney tubules. In many infections, antibodies are produced but do not effect microbial killing. Sometimes, antibody avidity is low, the epitopes against which the antibody is directed are not critical to the microorganism's survival, or the mechanism of immune elimination is not antibody dependent.2
Other microorganisms have developed means of counteracting specific elements of immune responses, such as production of an IgA-degrading enzyme, IgAase, by certain strains of N. gonorrhoeae 103 Some strains of amebae also produce proteases that destroy complement.2 Reactivation of infections in old age due to waning immunity has been well demonstrated in cases of tuberculosis and varicella-zoster virus, allowing transmission to new hosts.
One well-studied mechanism of immune evasion is the capability of changing the antigenic structure by genetic mutation or by programmed sequential expression of genes encoding different surface antigens. 104Antigenic drift and recombination between influenzaviruses affecting humans and animals are well documented. Borrelia recurrentis and Trypanosoma gambiense are also capable of changing their surface antigens after antibodies control the initial bloodstream infection.105,106 The new antigens are not recognized by the antibodies, allowing relapse of the infection. Parasites in which sexual reproduction is possible benefit enormously.107 Genetic variability introduced by crossing over during meiotic divisions is much greater than the variability introduced by asexual reproduction. As many as four crossovers on a single pair of chromosomes have been demonstrated in E falciparum.108
Microparasites also have multiple mechanisms by which they can evade the initial line of defense provided by phagocytes. These strategies include killing of the phagocyte (e.g., Streptococcus pyogenes and Entamoeba histolytica), inhibition of chemotaxis (e.g., Clostridiumperfringens), decreased internalization of microbes by phagocytic cells (e.g., T. gondii), inhibition of opsonins (e.g., Treponema pallidum), inhibition of phagolyso-some fusion (e.g., M. leprae and Mycobacterium tuberculosis), and escape from the phagosome into the cytoplasm (e.g., Rickettsia spp., Trypanosoma cruzi, and Listeria).2,40,70,87 With cell-to-cell spread, microorganisms may be minimally exposed to complement, antibodies, or phagocytes in the extracellular or intravascular spaces.77,78 Rickettsial infections spread from cell to cell throughout the infected foci in the endothelial layer of the microvasculature.77,78,89
Macroparasites, the helminths, have evolved diverse mechanisms that enable them to survive in vivo.80 Characteristically, helminths live for months to years in infected hosts within the lumen of the bowel, within tissues, or in the blood or lymphatic vessels. Many helminths are in intimate and recurring contact with all elements of the immune system. As a consequence of their size, helminthic worms do not use intracellular mechanisms to evade immune responses but have evolved a number of capabilities that permit their survival. For instance, interference with antigen processing has been well documented in animal models and patients infected with the filarial nema-todes Brugia malayi and Onchocerca volvulus. These helminths produce a family of proteins called the cystatins that are capable of inhibiting proteases responsible for antigen degradation and subsequent presentation through MHC class II pathways in antigen-presenting cells. These proteins are also capable of modulating T cell proliferation and elicit upregulation of IL-10 expression. Other modulators include helminthic derivatives of arachidonic acid such as lipoxin A4, which is capable of blocking production of IL-12 in dendritic cells. Helminthic prostaglandins can also inhibit IL-12 production by dendritic cells. Since helminths have very complex genomes (~2l,000 protein encoding genes in some of them), they are capable of producing a large variety of proteins. Some of them are cytokines and related proteins also capable of modulating the host immune response to their advantage. For example, B. malayi has been shown to express transforming growth factor (TGF)-P-like proteins capable of binding TGF-0 human receptors. Other cytokines include macrophage-migration inhibition factors produced by several nematodes including B. malayi. Blockade of effector mechanisms has also been demonstrated in some helminth infections, including proteases that target effector molecules such as eotaxin. Neutrophil proteases can also be inhibited by serpins.
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