These antigens are unable to induce antibody responses in animals or humans who lack T cells, and they are therefore known as thymus -dependent or TD antigens Fig. A second signal is required for B-cell activation by either thymus-dependent or thymus-independent antigens. The first signal required for B-cell activation is delivered through its antigen receptor top panel. For thymus-dependent antigens, the second more CD21 also known as complement receptor 2, CR2 is a receptor for the complement fragment C3d see Section When mice are immunized with hen egg lysozyme coupled to three linked molecules of the complement fragment C3dg , the modified lysozyme induces antibody without added adjuvant at doses up to 10, times smaller than unmodified hen egg lysozyme.
Whether binding of CD21 enhances B-cell responsiveness by increasing B-cell signaling, by inducing co-stimulatory molecules on the B cell , or by increasing the receptormediated uptake of antigen, is not yet known.
As we will see later in this chapter, antibodies already bound to antigens can activate the complement system, thus coating the antigen with C3d and producing a more potent antigen, which in turn leads to more efficient B-cell activation and antibody production. Although armed peptide-specific helper T cells are required for B-cell responses to protein antigens, many microbial constituents, such as bacterial polysaccharides, can induce antibody production in the absence of helper T cells.
These microbial antigens are known as thymus -independent or TI antigens because they induce antibody responses in individuals who have no T lymphocytes. The second signal required to activate antibody production to TI antigens is either provided directly by recognition of a common microbial constituent see Fig.
Thymus-independent antibody responses provide some protection against extracellular bacteria , and we will return to them later.
T-cell dependent antibody responses require the activation of B cells by helper T cells that respond to the same antigen ; this is called linked recognition. This means that before B cells can be induced to make antibody to an infecting pathogen, a CD4 T cell specific for peptides from this pathogen must first be activated to produce the appropriate armed helper T cells.
This presumably occurs by interaction with an antigen-presenting dendritic cell see Section Although the epitope recognized by the armed helper T cell must therefore be linked to that recognized by the B cell , the two cells need not recognize identical epitopes.
Indeed, we saw in Chapter 5 that T cells can recognize internal peptides that are quite distinct from the surface epitopes on the same protein recognized by B cells. For more complex natural antigens, such as viruses, the T cell and the B cell might not even recognize the same protein.
It is, however, crucial that the peptide recognized by the T cell be a physical part of the antigen recognized by the B cell, which can thus produce the appropriate peptide after internalization of the antigen bound to its B-cell receptors.
For example, by recognizing an epitope on a viral protein coat, a B cell can internalize a complete virus particle. After internalization, the virus particle is degraded and peptides from internal viral proteins as well as coat proteins can be displayed by MHC class II molecules on the B-cell surface. Helper T cells that have been primed earlier in an infection by macrophages or dendritic cells presenting these internal peptides can then activate the B cell to make antibodies that recognize the coat protein Fig.
B cells and helper T cells must recognize epitopes of the same molecular complex in order to interact. An epitope on a viral coat protein is recognized by the surface immunoglobulin on a B cell and the virus is internalized and degraded. Peptides derived more The specific activation of the B cell by a T cell sensitized to the same antigen or pathogen depends on the ability of the antigen-specific B cell to concentrate the appropriate peptide on its surface MHC class II molecules.
B cells that bind a particular antigen are up to 10, times more efficient at displaying peptide fragments of that antigen on their MHC class II molecules than are B cells that do not bind the antigen. Armed helper T cells will thus help only those B cells whose receptors bind an antigen containing the peptide they recognize.
The requirement for linked recognition has important consequences for the regulation and manipulation of the humoral immune response. One is that linked recognition helps ensure self tolerance , as will be described in Chapter An important application of linked recognition is in the design of vaccines, such as that used to immunize infants against Haemophilus influenzae type B.
This bacterial pathogen can infect the lining of the brain, called the meninges, causing meningitis and, in severe cases, neurological damage or death.
Protective immunity to this pathogen is mediated by antibodies against its capsular polysaccharide. Although adults make very effective thymus -independent responses to these polysaccharide antigens, such responses are weak in the immature immune system of the infant.
To make an effective vaccine for use in infants, therefore, the polysaccharide is linked chemically to tetanus toxoid, a foreign protein against which infants are routinely and successfully vaccinated see Chapter B cells that bind the polysaccharide component of the vaccine can be activated by helper T cells specific for peptides of the linked toxoid Fig.
Protein antigens attached to polysaccharide antigens allow T cells to help polysaccharide-specific B cells. Haemophilus influenzae type B vaccine is a conjugate of bacterial polysaccharide and the tetanus toxoid protein. The B cell recognizes and binds more Linked recognition was originally discovered through studies of the production of antibodies to haptens see Appendix I, Section A Haptens are small chemical groups that cannot elicit antibody responses on their own because they cannot cross-link B-cell receptors and they cannot recruit T-cell help.
When coupled at high density to a carrier protein, however, they become immunogenic, because the protein will carry multiple hapten groups that can now cross-link B-cell receptors. In addition, T-cell dependent responses are possible because T cells can be primed to peptides derived from the protein. Coupling of a hapten to a protein is responsible for the allergic responses shown by many people to the antibiotic penicillin, which reacts with host proteins to form a coupled hapten that can stimulate an antibody response, as we will learn in Chapter As with armed T H 1 cells acting on macrophages, recognition of peptide:MHC class II complexes on B cells triggers armed helper T cells to synthesize both cellbound and secreted effector molecules that synergize in activating the B cell.
Binding of CD40 by CD40L helps to drive the resting B cell into the cell cycle and is essential for B-cell responses to thymus-dependent antigens. Armed helper T cells stimulate the proliferation and then the differentiation of antigen-binding B cells. The specific interaction of an antigen-binding B cell with an armed helper T cell leads to the expression of the B-cell stimulatory molecule CD40 more B cells are stimulated to proliferate in vitro when they are exposed to a mixture of artificially synthesized CD40L and the cytokine interleukin-4 IL IL-4 is also made by armed T H 2 cells when they recognize their specific ligand on the B-cell surface, and IL-4 and CD40L are thought to synergize in driving the clonal expansion that precedes antibody production in vivo.
IL-4 is secreted in a polar fashion by the T H 2 cell and is directed at the site of contact with the B cell Fig. The combination of B-cell receptor and CD40 ligation, along with IL-4 and other signals derived from direct T-cell contact, leads to B-cell proliferation. Some of these contact signals have recently been elucidated. After several rounds of proliferation, B cells can further differentiate into antibody-secreting plasma cells. Two additional cytokines, IL-5 and IL-6, both secreted by helper T cells , contribute to these later stages of B-cell activation.
When an armed helper T cell encounters an antigen-binding B cell, it becomes polarized and secretes IL-4 and other cytokines at the point of cell-cell contact. On binding antigen on the B cell through its T-cell receptor, the helper T cell is induced more Antibodies are remarkable not only for the diversity of their antigen -binding sites but also for their versatility as effector molecules. The specificity of an antibody response is determined by the antigen-binding site , which consists of the two variable V domains, V H and V L ; however, the effector action of the antibody is determined by the isotype of its heavy-chain C region see Section A given heavy-chain V domain can become associated with the C region of any isotype through the process of isotype switching see Section We will see later in this chapter how antibodies of each isotype contribute to the elimination of pathogens.
The DNA rearrangements that underlie isotype switching and confer this functional diversity on the humoral immune response are directed by cytokines, especially those released by armed effector CD4 T cells.
Much of the antibody in plasma has therefore been produced by B cells that have undergone isotype switching. Little IgD antibody is produced at any time, so the early stages of the antibody response are dominated by IgM antibodies.
Later, IgG and IgA are the predominant isotypes , with IgE contributing a small but biologically important part of the response. The overall predominance of IgG results, in part, from its longer lifetime in the plasma see Fig. Isotype switching does not occur in individuals who lack functional CD40L, which is necessary for productive interactions between B cells and helper T cells ; such individuals make only small amounts of IgM antibodies in response to thymus-dependent antigens and have abnormally high levels of IgM Hyper IgM Immunodeficiency, in Case Studies in Immunology , see Preface for details in their plasma.
These IgM antibodies may be induced by thymus-independent antigens expressed by the pathogens that chronically infect these patients, who suffer from severe humoral immunodeficiency, as we will see in Chapter Most of what is known about the regulation of isotype switching by helper T cells has come from experiments in which mouse B cells are stimulated with bacterial lipopolysaccharide LPS and purified cytokines in vitro.
These experiments show that different cytokines preferentially induce switching to different isotypes. Some of these cytokines are the same as those that drive B-cell proliferation in the initiation of a B-cell response. T H 2 cells make both of these cytokines as well as IL-5, which induces IgA secretion by cells that have already undergone switching. The role of cytokines in directing B cells to make the different antibody isotypes is summarized in Fig.
Different cytokines induce switching to different isotypes. The individual cytokines induce violet or inhibit red production of certain isotypes. Much of the inhibitory effect is probably the result of directed switching to a different isotype. These more Recent data suggest that the production of a spliced switch transcript has a role in directing switching, but the mechanism is not yet clear. Each of the cytokines that induces switching seems to induce transcription from the switch regions of two different heavy-chain C genes, promoting specific recombination to one or other of these genes only.
Such a directed mechanism is supported by the observation that individual B cells frequently undergo switching to the same C gene on both chromosomes, even though the antibody heavy chain is only being expressed from one of the chromosomes.
Thus, helper T cells regulate both the production of antibody by B cells and the isotype that determines the effector function of the antibody. Isotype switching is preceded by transcriptional activation of heavy-chain C-region genes. Bacterial lipopolysaccharide LPS , which more One of the most puzzling features of the antibody response is how an antigenspecific B cell manages to encounter a helper T cell with an appropriate antigen specificity.
This question arises because the frequency of naive lymphocytes specific for any given antigen is estimated to be between 1 in 10, and 1 in 1,, Thus, the chance of an encounter between a T lymphocyte and a B lymphocyte that recognize the same antigen should be between 1 in 10 8 and 1 in 10 Achieving such an encounter is a far more difficult challenge than getting effector T cells activated, because, in the latter case, only one of the two cells involved has specific receptors.
Moreover, T cells and B cells mostly occupy quite distinct zones in peripheral lymphoid tissue see Fig. As in naive T-cell activation see Chapter 8 , the answer seems to lie in the antigen-specific trapping of migrating lymphocytes. When an antigen is introduced into an animal, it is captured and processed by professional antigen-presenting cells, especially the dendritic cells that migrate from the tissues into the T-cell zones of local lymph nodes.
Recirculating naive T cells pass by such cells continuously and those rare T cells whose receptors bind peptides derived from the antigen are trapped very efficiently. This trapping clearly involves the specific antigen receptor on the T cell, although it is stabilized by the activation of adhesion molecules and chemokines as we learned in Sections and Ingenious experiments using mice transgenic for rearranged immunoglobulin genes show that, in the presence of the appropriate antigen, B cells with antigen-specific receptors are also trapped in the T-cell zones of lymphoid tissue by a similar mechanism.
Trapping of B cells in the T-cell zones provides an elegant solution to the problem posed at the beginning of this section. T cells are themselves trapped and activated to helper status in the T-cell zones, and when B cells migrate into lymphoid tissue through high endothelial venules they first enter these same T-cell zones. Most of the B cells move quickly through the T-cell zone into the B-cell zone the primary follicle , but those B cells that have bound antigen are trapped. Thus, antigen-binding B cells are selectively trapped in precisely the correct location to maximize the chance of encountering a helper T cell that can activate them.
Interaction with armed helper T cells activates the B cell to establish a primary focus of clonal expansion Fig. Here, at the border between T-cell and B-cell zones, both types of lymphocyte will proliferate for several days to constitute the first phase of the primary humoral immune response.
Antigen-binding cells are trapped in the T-cell zone. Upon entry into lymphoid tissues through a high endothelial venule HEV , T cells and B cells home to different regions, as described in Chapter 7. Antigen-specific T cells remain in the T-cell zone more After several days, the primary focus of proliferation begins to involute. Many of the lymphocytes comprising the focus undergo apoptosis. Humoral response to protein and most other antigens requires the interaction of B cells with helper T cells.
These are thymus-dependent or simply T-dependent TD responses. Conjugate vaccines: A way of developing IgG response against polysaccharide antigen. Capsular polysaccharides e. Salmonella typhi , E. But these polysaccharide antigens are mostly poor immunogen; the antibody response to these antigens is mostly restricted to IgM lack of isotype switching because of their T-lymphocyte independent TI nature. IgM antibodies though excellent in activating complement penetrate poorly into tissues and are not themselves opsonizing.
Anti-polysaccharide immune response is also characterized by a lack of T-lymphocyte memory. Immunity against these surface components confers protection against the disease caused by these pathogens but the most vulnerable age group children below 2 years of age and elderly responds poorly to carbohydrate antigen.
If the B cells are switched to produce IgG , the vaccine would be more effective. To overcome the problem that arises due to TI nature of carbohydrate antigen and to produce IgG response against such antigen conjugate vaccine is being used. Together they form a unique fingerprint. View full fingerprint. Noelle, R. AU - Snow, E. AU - Uhr, J. AU - Vitetta, E.
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