Bacterial Pathogenesis. Brenda A. Wilson
href="#ulink_294ff177-f723-54fd-846f-868e8905bcf7">Figure 4-11), without the involvement of T cells. Polysaccharides are a well-studied class of T-cell-independent antigens. Those B cells displaying mIg with affinity for the sugar repeat units will bind to the polysaccharide chain. Because these epitopes are repeated many times, numerous mIgs and BCRs are linked together, which causes them to cluster and activate cellular signaling pathways. This acts as one signal to stimulate the B cells to proliferate and differentiate into mature antibody-producing plasma cells. A second signal, such as binding of cytokines produced at the infection site, is also required to initiate the T-cell-independent response.
Figure 4-11. T-cell-independent production of antibodies. Macromolecules with highly repetitive structures, such as carbohydrates (polysaccharides, capsules) and nucleic acids, are able to directly stimulate naïve B cells to proliferate, mature, and produce antibodies through antigen-mediated clustering of IgG2 and IgM antibodies on the surface of the B cells.
The T-cell-independent response is particularly important for protection against bacterial pathogens that can avoid phagocytosis by covering themselves with an exopolysaccharide layer (capsule), which is not effectively opsonized through coating with C3b. Such bacterial pathogens are only ingested and killed by phagocytes if antibodies that bind to capsular antigens are elicited and act as opsonins.
Although the T-cell-independent response provides protection against capsule-producing bacteria, it has some important drawbacks. First, the antibody response elicited by T-cell-independent antigens is not as strong as the T-cell-dependent response. It is also not long-lasting, because no memory B cells are developed. Second, the main antibodies elicited by T-cell-independent antigens are IgM and IgG2. IgG2 does not opsonize and IgM does so less effectively than IgG1 and IgG3 (Table 4-1). Third, infants do not mount a T-cell-independent response. Polysaccharides and lipids can elicit an immune response in children and adults, but not in infants under the age of two years. Thus, the ability to respond to T-cell-independent antigens, such as capsule exopolysaccharide, is acquired after birth. This is an important consideration because it means that vaccines consisting of T-cell-independent antigens are not effective until an infant has become old enough to respond to these antigens. Unfortunately, infants are one of the highest risk groups for contracting serious infections due to capsule-producing bacteria (e.g., pneumonia and meningitis).
A strategy for improving the immune response to T-cell-independent antigens and extending this response to infants is to covalently link epitopes of the polysaccharide capsule to a protein. This type of vaccine is called a conjugate vaccine (more about this in chapter 17). APCs process conjugate vaccines as if they were proteins and elicit a Th2-cell-dependent response that culminates in production of antibodies that also recognize the polysaccharide antigens. This immune response is long-lived because it involves T cell activation and memory cell generation and produces opsonizing IgG1 antibodies, IgG3, and IgG4.
Mucosal Immunity: IgA/sIgA Antibodies
An important immune defense against infectious diseases, but one that is much less well understood than the humoral or cell-mediated responses, is the immune system that produces sIgA. The first step in many microbial infections is colonization and invasion of a mucosal surface. sIgA can prevent such infections by blocking colonization. Thus, while the cell-mediated or humoral antibody responses may cause collateral damage to tissues in the area where infection is occurring, the sIgA-mediated defense is usually innocuous to the host because it occurs in the mucus layer.
As we mentioned in chapter 2, skin and mucosal surfaces all have attendant mucosa-associated lymphoid tissues (MALT) located just below the epithelial layer in the lamina propria. The mucosal surface of the small intestine is underlain with the GALT, while the lungs have BALT, the upper respiratory tract has NALT, and the vaginal tract has vaginal-associated lymphoid tissue (VALT). Skin also has a similar system (called SALT).
The intestinal cells that comprise the GALT are visible as a collection of follicles, called Peyer’s patches, which are most highly concentrated in the ileum and rectum of the intestine. Similar mucosal lymphoid tissues are found in the respiratory and vaginal tracts, although they are not as pronounced. The cells that form the Peyer’s patches are illustrated in Figure 4-12. M (microfold) cells take up antigens from the lumen of the intestinal tract and pass them to closely associated GALT macrophages, which act as the APCs of the GALT. M cells have never been successfully cultivated in vitro, so little is known about the activities of M cells. The mechanism by which GALT macrophages process antigens and elicit production of cytotoxic T cells or antibodies is the same as that described in earlier sections, except that the macrophages, B cells, and T cells of the GALT reside specifically in the lamina propria of mucosal surfaces. Two additional types of T cells, Th17 and Tregs, appear to be important for IgA production in the intestine, both of which appear to help modulate the B cells.
Figure 4-12. Cells of the GALT that confer mucosal immunity. M cells and their associated macrophages and lymphoid cells (T and B cells) are sometimes called follicles. Collections of such follicles in the gut are called Peyer’s patches. M cells sample the contents of the gut lumen and transfer the antigens to closely associated resident macrophages, which in turn ingest the bacteria and present antigens to the underlying T cells that then stimulate nearby B cells to produce IgA. The IgA binds to receptors on the basal surface of the mucosal epithelial cell and is transcytosed across the cell and secreted into the lumen of the gut as sIgA.
When the GALT is stimulated, one outcome is production of IgA (see Figure 4-12). Dimeric IgA is produced by plasma cells in the lamina propria at mucosal sites. The secretory piece is acquired when IgA dimer is transported through the mucosal epithelial cell into mucosal secretions covering various mucosal surfaces. IgA dimer binds to the poly-Ig receptor on the basal surface of mucosal cells and is then taken up by endocytosis and transported in vesicles, through a process called transcytosis, to the apical surface, where it is released into the lumen of the gut. Release involves proteolytic cleavage of the poly-Ig receptor, where the secretory piece comes from the portion of the receptor that remains attached to the IgA, making it sIgA. sIgA can trap microbes in mucus because the Fc portion of sIgA binds to glycoprotein constituents of the mucin and the Fab portion binds to antigens on the microbes in the gut. By trapping the microbes in the mucus layer, the sIgA-antigen-mucin complex essentially forms a protective barrier that blocks the microbes and their toxic products from gaining access to the epithelial cell layer. Mucus laden with sIgA-coated microbes is then sloughed off and excreted from the body.
The mucosal and skin tissues that have contact with the external environment are also constantly patrolled by DCs (APCs), which engulf and kill the invading microbes and process the antigens for presentation to the adaptive immune system. Once activated, DCs migrate to the lymph nodes, where they present the antigens to Th cells and stimulate adaptive immunity. The Langerhans cells of the epidermis are the DCs of SALT.
As part of the mucosal immune system, some T cells and B cells stimulated by antigen processing at the GALT can migrate to other mucosal sites and vice versa. Thus, stimulation at one of the MALT sites can transfer to other sites, resulting in general mucosal immunity. The first evidence for this feature of the mucosal immune system came from elegant experiments performed by Husband and Gowans in the late 1970s. These researchers excised a segment of the small intestine from a rat, preserving its vascular and lymphatic supplies, and reconnected the ends of the intestinal segment to the skin surface of the animal, forming a so-called Thiry-Vella loop (Figure 4-13). They then introduced an antigen, in this case cholera toxin (CT), into the loop and found that sIgA was secreted in not