Bacterial Pathogenesis. Brenda A. Wilson
a second such loop (when made) and in the main intestine. Their results demonstrated that introduction of an immunogen at one site could confer mucosal immunity at a remote site. This characteristic of the MALT system is what makes oral vaccines feasible. Initially, oral vaccines stimulate the GALT, but sIgA against vaccine antigens is later detectable in other MALT sites. Thus, an oral vaccine can also be used to elicit immunity to respiratory and, presumably, urogenital pathogens.
Figure 4-13. Classic experiment by Husband and Gowans demonstrating mucosal immunity at remote sites. The experimental setup involved isolating Thiry-Vella loops of the small intestine of rats and connecting them to the skin, preserving the associated vascular and lymphatic systems attached to the loops. The IgA immune response to administering immunogen (cholera toxin) to the main intestine through the oral route or through the skin opening of the loop could then be observed. Results showed that local immunization through the isolated loops that contained Peyer’s patches generated Th cells and B cells that circulated through the lymph and blood to populate other mucosal sites. Based on Husband AJ, Gowans JL. 1978. J Exp Med 148:1146–1160.
Currently, efforts are being made to develop vaccines administered by inhalation, so that stimulation of the nasal MALT (NALT) would produce an sIgA response at other MALT sites. These vaccines would have the advantage of not having to pass through the stomach. Developing vaccines that target the GALT means developing vaccines capable of surviving the low-pH/protease-rich stomach environment, a barrier that has proven problematic in many cases. Administering vaccines by rectal or vaginal suppositories is theoretically possible, but this strategy has not been actively pursued to date. On the other hand, the SALT is gaining in attraction as a target for vaccine development (more on vaccines in chapter 17).
Activation of the GALT can also lead to production of cytotoxic T cells. These cells probably remain on the basal side of the mucosa, although it is possible that during an infection some of them migrate to the apical surface, especially in areas where damage to the mucosa has occurred. GALT cytotoxic T cells are important for protection against viral infections of the GI tract and some bacterial infections in which the bacteria multiply inside mucosal cells.
One of the many mysteries swirling around the intestinal immune system is the role of a particular type of mucosal cell called γδ T cells. The majority of γδ T cells are CD8+ T cells and would thus be grouped with CTLs. However, whereas CTLs have TCRs composed of αβ chains (Figure 4-8), the intestinal epithelial lymphocytes (IELs) have T-cell receptors composed of related but somewhat different γδ chains. These γδ T cells account for less than 4% of circulating CD8+ T cells, but they account for as much as 10 to 15% of the mucosal T cells found in the GI tract. In some regions, such as the colon, the levels may be as high as 40%.
Unlike αβ T cells, γδ T cells seem to recognize only a limited number of cell-surface antigens. Also, γδ T cells seem to bypass antigen presentation by MHCI and MHCII on the surfaces of macrophages and DCs and directly recognize nonpeptide antigens that have not been processed. Indeed, they are believed to play a predominant role in lipid-antigen recognition via CD1 complexes (Figure 4-6C). γδ T cells also respond to two human protein complexes related to MHC I, MICA and MICB. These proteins are displayed on the surface of cells that are stressed (e.g., by being infected) and are recognized by NKG2D receptors present on γδ T cells, as well as NK cells, which results in activation of cytotoxic responses that kill the stressed cells. γδ T cells also produce cytokines that stimulate αβ CD8+ cytotoxic T cells to migrate to the area and eliminate infected cells.
As with other immune responses, the GALT has a downside. Normally, bacteria and other viable antigens that pass through M cells are killed by the resident GALT macrophages. Some bacterial pathogens, however, have acquired the ability to avoid this fate and exploit the GALT as an entryway into the body. Because the M cell is an antigen-sampling cell, it usually does not take up substantial amounts of an antigen because only a few bacteria or other antigens are sufficient to stimulate a mucosal immune response. The bacteria that use the GALT as an entryway into the body, such as Salmonella enterica or Yersinia pseudotuberculosis, invade M cells or use them to move across the epithelial layer (see Figure 4-14).
Figure 4-14. Scanning electron micrographs of mouse Peyer’s patches (a) before and (b) after incubation with Yersinia pseudotuberculosis. Both images depict a central M cell surrounded by enterocytes (and part of a brush cell in the lower left of panel b). The M cell in panel a lacks adherent bacteria but, in contrast, the association of bacteria with the M cell in panel b is accompanied by disruption of the normal surface morphology of the M cell. Bars, 2 µm. Reprinted with permission from Clark MA, Hirst BH, Jepson MA. 1998. Infect Immun 66:1237–1243.
Development of the Adaptive Immune System from Infancy to Adulthood
Human infants do not develop fully effective immune defenses until they are one to two years of age. Infants have very low levels of NK cells and are deficient in mannose-binding proteins, one of the acute-phase proteins produced by the liver that helps opsonize some types of microbes. For the period up to one year of age, maternal antibodies that were transferred through the placenta during gestation or ingested in milk during infancy protect the infants at least partially. The infant’s antibody production begins to kick in at about two to three months of age, but the rate of production is still relatively slow with antibodies being short-lived and of low avidity. T-cell-independent responses do not start until about 18 months of age. The transition between the protection conferred by maternal antibodies and the development of the infant’s own immune system provides pathogenic microbes with a window of opportunity and is one of the reasons why children under the age of two are particularly vulnerable to infectious diseases.
Interestingly, circulating maternal antibodies can actually interfere with an immune response to some antigens, because high levels of antibody to a particular epitope discourage the development of an antibody response to that epitope. This is a consequence of immune regulation that normally protects the body from overreacting to a particular epitope. The dampening effect of circulating maternal IgG is the reason why some vaccines are not given to infants less than one year of age.
Adaptive Defense Systems in Nonmammals
Scientists have found primitive versions of the mammalian adaptive defense system in many different organisms, ranging from insects to sharks (Table 4-2). Insects such as Drosophila melanogaster (fruit fly) and slime molds such as Dictyostelium also have primitive defense systems that resemble mammalian defense responses, especially the innate immune response. Zebra fish not only have an innate immune response but also have a response that parallels the Th1/Th2 adaptive response. Sharks produce antibodies that can bind to human pathogens.
Table 4-2. Defense systems in higher organisms
Even plants have a primitive defense system in which proteins produced by the plant (R proteins) bind to invading bacteria, a reaction that produces apoptosis in the surrounding plant cells. This area of dead, dry tissue, which appears as black spots on leaves or fruit, traps the bacteria in the area. Bacteria need to move throughout the plant via the xylem and phloem in order to cause serious disease, and the plant’s defense response is designed to prevent this.
Assertions that systems in nonmammals are “immune systems” should be viewed with some skepticism. In the case of sharks, plants, and zebra fish, there is evidence that the systems are actually a response that protects the organism from infection. In the case of Drosophila, however, the Toll receptors that led to the discovery