ESCAPE FROM THE IMMUNE RESPONSE
Many infectious agents have developed the capacity to avoid the immune response. Sev-eral mechanisms are involved:
1. Anticomplementary activity has been characterized for bacterial capsules and outer proteins of some bacteria. The anticomplementary activity of bacterial outer components has as a net result a decreased level of opsonization by C3b and other complement fragments.
2. Resistance to phagocytosis, either mediated by polysaccharide capsules, which repeal and inhibit the function of phagocytic cells, or by the ability to survive af-ter ingestion, is characteristic of the group of bacteria known as facultative in-tracellular (Mycobacteria, Brucella, Listeria, and Salmonella), as well as of some fungi and protozoa (Toxoplasma, Trypanosoma cruzi, and Leishmania). Infectious agents have developed many different strategies to survive intracellu-larly, including:
a. Secretion of molecules that prevent the formation of phagolysosomes allow-ing the infectious agent to survive inside phagosomes, relatively devoid of toxic compounds (e.g., Mycobacterium tuberculosis, Legionella pneu-mophila, and Toxoplasma gondii)
b. Synthesis of outer coats that protect the bacteria against proteolytic enzymes and free toxic radicals (such as the superoxide radical)
c. Depression of the response of the infected phagocytic cells to cytokines that usually activate their killing functions, such as interferon-γ
d. Exit from the phagosome into the cytoplasm, where the bacteria can live and multiply unharmed (e.g., T. cruzi)
Some organisms combine several of different mechanisms to survive intracellularly. For example, Mycobacterium leprae is coated with a phenolic glycolipid layer, which scav-enges free radicals and releases a compound that inhibits the effects of interferon-γ . In ad-dition, the release of IL-4 and IL-10 by infected macrophages is enhanced, contributing to the downregulation of TH1 lymphocytes.
Some infectious agents appear to have acquired evolutionary advantage by not inducing ef-fective immune responses. For example, well-developed polysaccharide capsules protect many bacteria and fungi. Polysaccharides are immunogenic but are not presented to helper CD4 T cells. In the absence of adequate T-cell help, the response to polysaccharides in-volves predominantly IgM and IgG2 antibodies, which are inefficient as opsonins (the FcγR of phagocytic cells recognize preferentially IgG1 and IgG3 antibodies). Another ex-ample is N. meningitidis, which often induces the synthesis of IgA antibodies. In vitro data suggests that IgA can act as a weak opsonin or induce ADCC (monocytes/macrophages and other leukocytes express Fc receptors on their membranes), but the physiological protec-tive role of IgA antibodies is questionable. Patient sera with high titers of IgA antibodies to N. meningitidis fail to show bactericidal activity until IgA-specific anti–N. meningitidis an-tibodies are removed. This observation suggests that IgA antibodies may act as “blocking factors,” preventing opsonizing IgG antibodies from binding to the same epitopes.
Release of soluble antigens from infected cells able to bind and block antibodies be-fore they can reach the cells has been demonstrated in the case of the hepatitis B virus. The circulating antigens act as a deflector shield, which protects the infected tissues from anti-body aggression.
Loss and masking of antigens with absorbed host proteins have been demonstrated with several worms, particularly schistosomula (the larval forms of Schistosoma). The abil-ity of parasitic worms to survive in the host is well known and is certainly derived from the ability to evade the immune system.
Antigenic variation has been characterized in bacteria (Borrelia recurrentis), proto-zoan parasites (trypanosomes, the agents of African sleeping sickness, Giardia lamblia), and viruses (human immunodeficiency virus, or HIV).
One of the best-studied examples is African trypanosomes. These protozoa have a surface coat constituted mainly of a single glycoprotein (variant-specific surface glycopro-tein, or VSG), for which there are about 103 genes in the chromosome. At any given time,only one of those genes is expressed, the others remaining silent. For every 106 or 107 try-panosome divisions, a mutation occurs, which replaces the active VSG gene on the ex-pression site by a previously silent VSG gene. The previously expressed gene is destroyed and a new VSG protein is coded, which is antigenically different. The emergence of a new antigenic coat allows the parasite to multiply unchecked. As antibodies to the newly ex-pressed VSG protein emerge, parasitemia will decline, only to increase as soon as a new mutation occurs and a different VSG protein is synthesized. Giardia lamblia has a similar mechanism of variation, but the rate of surface antigen replacement is even faster (once ev-ery 103 divisions).
Borrelia recurrentis, the agent of relapsing fever, carries genes for at least 26 differ-ent variable major proteins (VMP), which are sequentially activated by duplicative trans-position to an expression site. The successive waves of bacteremia and fever correspond to the emergence of new mutants, which, for a while, can proliferate unchecked until anti-bodies are formed.
HIV exhibits a high degree of antigenic variation that seems to be the result of errors introduced by the reverse transcriptase when synthesizing viral DNA from the RNA tem-plate. The mutation rate is relatively high (one in every 103 progeny particles), and the immune response selects the mutant strains, which present new configurations in the outer envelope proteins, allowing viable mutants to proliferate unchecked by preexisting neu-tralizing antibodies.
Cell-to-cell spread allows infectious agents to propagate without being exposed to specific antibodies or phagocytic cells. This strategy is commonplace for viruses, espe-cially for herpesviruses, retroviruses, and paramyxoviruses, which cause the fusion of in-fected cells with noninfected cells allowing viral particles to pass from cell to cell without exposure to the extracellular environment.
Some intracellular bacteria have also developed the ability to spread from cell to cell. The best known example is Listeria monocytogenes, which after becoming intracellular can travel along the cytoskeleton and promote the fusion of the membrane of an infected cell with the membrane of a neighboring noninfected cell, which is subsequently invaded.
Although immunosuppressive effects have been described in association with bacteria and parasitic infections, the best-documented examples of infection-associated immunosup-pression are those described in viral infections. The effects of HIV on the immune system will be described, but many other viruses have the ability to depress the immune system, such as the following:
Measles.Patients in the acute phase of measles are more susceptible to bacterial in-fections, such as pneumonia. Both delayed hypersensitivity responses and the in vitro lymphocyte proliferation in response to mitogens and antigens are sig-nificantly depressed during the acute phase of measles and the immediate con-valescence period, usually returning to normal after 4 weeks. Recent investi-gations suggest that infection of monocytes/macrophages with the measles virus is associated with a downregulation of interleukin-12 synthesis, which can explain the depression of cell-mediated immunity associated with measles.
Cytomegalovirus.Mothers and infants infected with cytomegalovirus show de-pressed responses to CMV virus but normal responses to T-cell mitogens, sug-gesting that in some cases the immunosuppression may be antigen-specific, while in measles it is obviously nonspecific.
Influenza virus.This virus has been found to depress cell-mediated immunity inmice, apparently due to an increase in the suppressor activity of T lymphocytes.
Epstein-Barr virus.This virus releases a specific protein that has extensive sequencehomology with interleukin-10. The biological properties of this viral protein are also analogous to those of interleukin-10; both are able to inhibit lym-phokine synthesis by T-cell clones.