Destruction of Antigens or Cell Lysis Can Be Caused by All of the Following Except

Having considered how an appropriate chief immune response is mounted to pathogens in both the peripheral lymphoid organization and the mucosa-associated lymphoid tissues, we now plough to immunological memory, which is a characteristic of both compartments. Perhaps the most important effect of an adaptive allowed response is the institution of a state of immunological memory. Immunological memory is the ability of the immune system to respond more rapidly and effectively to pathogens that have been encountered previously, and reflects the preexistence of a clonally expanded population of antigen-specific lymphocytes. Retentivity responses, which are chosen secondary, 3rd, then on, depending on the number of exposures to antigen, too differ qualitatively from master responses. This is particularly clear in the case of the antibody response, where the characteristics of antibodies produced in secondary and subsequent responses are singled-out from those produced in the primary response to the same antigen. Memory T-cell responses have been harder to study, only can too be distinguished from the responses of naive or effector T cells. The principal focus of this section will exist the altered graphic symbol of memory responses, although nosotros will besides discuss emerging explanations of how immunological memory persists after exposure to antigen. A long-standing debate nigh whether specific memory is maintained by distinct populations of long-lived memory cells that can persist without residual antigen, or by lymphocytes that are nether perpetual stimulation by residual antigen, appears to take been settled in favor of the sometime hypothesis.

10-21. Immunological memory is long-lived afterward infection or vaccination

Most children in the U.s.a. are now vaccinated confronting measles virus; before vaccination was widespread, most were naturally exposed to this virus and suffered from an acute, unpleasant, and potentially dangerous viral affliction. Whether through vaccination or infection, children exposed to the virus acquire long-term protection from measles. The aforementioned is true of many other acute infectious diseases: this land of protection is a consequence of immunological memory.

The basis of immunological memory has been hard to explore experimentally. Although the miracle was beginning recorded by the ancient Greeks and has been exploited routinely in vaccination programs for over 200 years, it is merely at present becoming articulate that memory reflects a persistent population of specialized retentiveness cells that is contained of the continued persistence of the original antigen that induced them. This mechanism of maintaining retentivity is consistent with the finding that only individuals who were themselves previously exposed to a given infectious amanuensis are immune, and that memory is not dependent on repeated exposure to infection equally a result of contacts with other infected individuals. This was established by observations fabricated on remote isle populations, where a virus such as measles can cause an epidemic, infecting all people living on the island at that fourth dimension, after which the virus disappears for many years. On reintroduction from outside the island, the virus does not affect the original population just causes disease in those people born since the first epidemic. This means that immunological memory demand not exist maintained by repeated exposure to infectious virus.

Instead, information technology is most likely that retention is sustained past long-lived antigen-specific lymphocytes that were induced by the original exposure and that persist until a second see with the pathogen. It was thought that retained antigen, bound in immune complexes on follicular dendritic cells, might be crucial in maintaining these cells, just recent experiments advise otherwise. While most of the memory cells are in a resting state, careful studies have shown that a pocket-sized percentage are dividing at whatever one fourth dimension. What stimulates this exceptional cell partitioning is unclear. Nevertheless, cytokines such as those produced either constitutively or during the course of antigen-specific immune responses directed at noncross-reactive antigens could exist responsible. Ane such cytokine, IL-15, has been implicated in maintaining CD8 retention T cells. Regardless of cell sectionalisation, the number of memory cells for a given antigen is highly regulated, remaining practically constant during the memory phase.

Immunological memory tin exist measured experimentally in diverse ways. Adoptive transfer assays (seeAppendix I, Department A-42) of lymphocytes from animals immunized with simple, nonliving antigens accept been favored for such studies, as the antigen cannot proliferate. When an fauna is starting time immunized with a protein antigen, helper T-cell memory against that antigen appears abruptly and is at its maximal level after 5 days or so. Antigen-specific retentiveness B cells appear some days later, because B-cell activation cannot begin until armed helper T cells are available, and B cells must then enter a stage of proliferation and selection in lymphoid tissue. By one month after immunization, memory B cells are present at their maximal levels. These levels are and then maintained with trivial alteration for the lifetime of the animal. In these experiments, the beingness of memory cells is measured purely in terms of the transfer of specific responsiveness from an immunized, or 'primed,' animal to an irradiated, immunoincompetent and nonimmunized recipient. In the following sections, we will await in more detail at the changes that occur in lymphocytes afterwards antigen priming, and talk over the mechanisms that might account for these changes.

10-22. Both clonal expansion and clonal differentiation contribute to immunological memory in B cells

Immunological memory in B cells tin can be examined past isolating B cells from immunized mice and restimulating them with antigen in the presence of armed helper T cells specific for the aforementioned antigen. The response of these primed B cells can be compared with the master B-cell response seen on isolating B cells from unimmunized mice and stimulating them with antigen in the same style (Fig. x.24). By these means, it is possible to bear witness that antigen-specific memory B cells differ both quantitatively and qualitatively from naive B cells. B cells that can respond to antigen increase in frequency after priming past about 10- to 100-fold (run into Fig. ten.24) and produce antibody of higher average affinity than unprimed B lymphocytes; the affinity of that antibody continues to increase during the ongoing secondary and subsequent antibiotic responses (Fig. 10.25). The secondary antibody response is characterized in its first few days past the production of small amounts of IgM antibiotic and larger amounts of IgG antibody, with some IgA and IgE. These antibodies are produced by memory B cells that have already switched from IgM to these more mature isotypes and limited IgG, IgA, or IgE on their surface, also as a somewhat higher level of MHC class II molecules than is characteristic of naive B cells. Increased affinity for antigen and increased levels of MHC form Ii facilitate antigen uptake and presentation, and permit memory B cells to initiate their disquisitional interactions with armed helper T cells at lower doses of antigen. Unlike memory T cells, which can traffic to tissues owing to changes in cell-surface molecules that affect migration and homing, it is thought that memory B cells keep to recirculate through the same secondary lymphoid compartments that comprise naive B cells, principally the follicles of spleen, lymph node, and Peyer'south patch. Some retention B cells can also exist found in marginal zones, though it is non clear whether these represent a distinct subset of retentiveness B cells.

Effigy 10.24

The generation of secondary antibiotic responses from retention B cells is distinct from the generation of the master antibody response. These responses can be studied and compared by isolating B cells from immunized and unimmunized donor mice, and stimulating (more...)

Figure 10.25

The affinity likewise as the amount of antibody increases with repeated immunization. The upper panel shows the increase in the level of antibody with fourth dimension after primary, followed past secondary and third, immunization; the lower panel shows the increment (more...)

The stardom between master and secondary antibody responses is most clearly seen in those cases where the master response is dominated past antibodies that are closely related and evidence few if any somatic hypermutations. This occurs in inbred mouse strains in response to certain haptens that are recognized by a limited gear up of naive B cells. The antibodies produced are encoded by the same 5_H and V_L genes in all animals of the strain, suggesting that these variable regions have been selected during evolution for recognition of determinants on pathogens that happen to cross-react with some haptens. As a upshot of the uniformity of these main responses, changes in the antibody molecules produced in secondary responses to the aforementioned antigens are easy to observe. These differences include non only numerous somatic hypermutations in antibodies containing the ascendant variable regions but also the improver of antibodies containing V_H and V_L factor segments not detected in the main response. These are thought to derive from B cells that were activated at low frequency during the primary response, and thus not detected, merely that differentiated into retentiveness B cells.

ten-23. Repeated immunizations atomic number 82 to increasing affinity of antibiotic owing to somatic hypermutation and selection past antigen in germinal centers

Upon reexposure to the same antigen, a secondary allowed response volition ensue. In some ways, this resembles the primary immune response, with the initial proliferation of B cells and T cells at the interface between the T- and B-prison cell zones. The secondary response is characterized by early and vigorous generation of plasma cells, thus accounting for early profuse IgG product. Some B cells that take not yet undergone terminal differentiation tin migrate into the follicle and become germinal center B cells. There, these B cells enter a 2d proliferative phase, during which the Deoxyribonucleic acid encoding their immunoglobulin V domains again undergoes somatic hypermutation before the B cells differentiate into antibiotic-secreting plasma cells (see Section nine-vii).

The antibodies produced by plasma cells in the chief and early secondary response have an important part in driving analogousness maturation in the secondary response. In secondary and subsequent immune responses, any persisting antibodies produced past the B cells that differentiated in the principal response are immediately bachelor to bind the newly introduced antigen. Some of these antibodies divert antigen to phagocytes for degradation and disposal (run into Department 9-20). If in that location is sufficient preexisting antibody to clear or inactivate the pathogen, information technology is possible that no immune response will ensue. However, if there is a trace backlog of antigen, B cells whose receptors bind the antigen with sufficient avidity to compete with the preexisting antibody will take upwards the uncomplexed antigen, procedure it into peptide fragments, and present these peptides, bound to MHC class II molecules, to armed helper T cells surrounding and infiltrating the germinal centers (meet Section 9-8). Contact betwixt the B cells presenting antigenic peptides and armed helper T cells specific for the aforementioned peptide leads to an exchange of activating signals and the rapid proliferation of both activated antigen-specific B cells and helper T cells. Thus, only the higher-affinity memory B cells are efficiently stimulated in the secondary immune response. In this manner, the affinity of the antibody produced rises progressively, every bit but B cells with high-analogousness antigen receptors tin can bind antigen efficiently and be driven to proliferate by antigen-specific helper T cells (Fig. 10.26).

Figure 10.26

The mechanism of affinity maturation in an antibiotic response. At the beginning of a primary response, B cells with receptors of a wide variety of affinities (G_A), virtually of which volition bind antigen with low affinity, accept upwards antigen, present it to helper (more...)

10-24. Retentivity T cells are increased in frequency and have distinct activation requirements and prison cell-surface proteins that distinguish them from armed effector T cells

Because the T-cell receptor does not undergo isotype switching or affinity maturation, memory T cells have been far more difficult to characterize than memory B cells. Furthermore, it has proved hard to distinguish between effector T cells and memory T cells on the basis of their phenotype. Subsequently immunization, the number of T cells reactive to a given antigen increases markedly as effector T cells are produced, so falls back to persist at a level significantly (100- to 1000-fold) above the initial frequency for the residue of the animal's or person's life (Fig. 10.27). These cells carry prison cell-surface proteins more characteristic of armed effector cells than of naive T cells. However, they are long-lived cells with singled-out properties in terms of surface molecule expression, response to stimuli, and expression of genes that control cell survival. Therefore, they should be specifically designated memory T cells. In the example of B cells, the stardom between effector and memory cells is more obvious and has been recognized for some time considering effector B cells, as we saw in Chapter nine, are terminally differentiated plasma cells that have already been activated to secrete antibody until they die.

Figure x.27

Encounter with antigen generates effector T cells and long-lived memory T cells. On priming with antigen, a naive T cell divides and differentiates. Well-nigh of the progeny are relatively short-lived effector cells. Withal, some become long-lived memory (more...)

A major problem in experiments aimed at establishing the existence of retentivity T cells is that nigh assays for T-prison cell effector office take several days, during which the putative memory T cells are reinduced to armed effector cell condition. Thus, these assays do not distinguish preexisting effector cells from retentiveness T cells. This problem does not apply to cytotoxic T cells, withal, as cytotoxic effector T cells tin program a target prison cell for lysis in 5 minutes. Memory CD8 T cells demand to be reactivated to become cytotoxic, simply they can practice so without undergoing Dna synthesis, as shown past studies carried out in the presence of mitotic inhibitors. Recently, it has become possible to runway particular clones of antigen-specific CD8 T cells by staining them with tetrameric MHC:peptide complexes (seeAppendix I, Section A-28). It has been found that the number of antigen-specific CD8 T cells increases dramatically during an infection, and then drops by upward to 100-fold; nevertheless, this last level is distinctly higher than before priming. These cells continue to express some markers characteristic of activated cells, similar CD44, simply stop expressing other activation markers, like CD69. In addition, they express more Bcl-ii, a protein that promotes cell survival and may be responsible for the long one-half-life of memory CD8 cells. These cells are more sensitive to restimulation past antigen than are naive cells, and more apace and more vigorously produce cytokines such as IFN-γ in response to such stimulation.

The issue is more difficult to address for CD4 T-cell responses, and the identification of memory CD4 T cells rests largely, simply not entirely, on the existence of a long-lived population of cells that have surface characteristics of activated armed effector T cells (Fig. ten.28) just that are singled-out from them in that they require additional restimulation earlier acting on target cells. Changes in three cell-surface proteins—L-selectin, CD44, and CD45—are peculiarly significant after exposure to antigen. 50-selectin is lost on almost retention CD4 T cells, whereas CD44 levels are increased on all memory T cells; these changes contribute to directing the migration of retentiveness T cells from the claret into the tissues rather than directly into lymphoid tissues. The isoform of CD45 changes because of alternative splicing of exons that encode the extracellular domain of CD45 (Fig. 10.29), leading to isoforms that associate with the T-jail cell receptor and facilitate antigen recognition. These changes are characteristic of cells that accept been activated to become armed effector T cells (encounter Section 8-12), yet some of the cells on which these changes have occurred have many characteristics of resting CD4 T cells, suggesting that they correspond memory CD4 T cells. Only after reexposure to antigen on an antigen-presenting cell practice they accomplish armed effector T-cell status, and learn all the characteristics of armed T_H2 or T_H1 cells, secreting IL-four and IL-v, or IFN-γ and TNF-β, respectively.

Figure 10.28

Many cell-surface molecules accept altered expression on memory T cells. This is seen nearly conspicuously in the example of CD45, where there is a modify in the isoforms expressed (run across Fig. 10.29). Many of these changes are also seen on cells that accept been activated (more...)

Figure 10.29

Memory CD4 T cells express altered CD45 isoforms that regulate the interaction of the T-cell receptor with its co-receptors. CD45 is a transmembrane tyrosine phosphatase with 3 variable exons (A, B, and C) that encode part of its external domain. (more...)

Information technology thus seems reasonable to designate these cells as retentiveness CD4 T cells, and to surmise that naive CD4 T cells can differentiate into armed effector T cells or into memory T cells that can later on be activated to effector condition. Recent experiments show that CD4 cells can differentiate into two types of retentivity cell, with distinct activation characteristics. One type are called effector retentivity cells because they can rapidly mature into effector CD4 T cells and secrete large amounts of IFN-γ, IL-4, and IL-5 early after restimulation. These cells lack the chemokine receptor CCR7 simply express high levels of β-1 and β-2 integrins, as well equally receptors for inflammatory chemokines. This contour suggests these effector memory cells are specialized for quickly entering inflamed tissues. The other blazon are called central memory cells. They express CCR7 and thus would be expected to recirculate more easily to T zones of secondary lymphoid tissues, as do naive T cells. These central retention cells are very sensitive to T-prison cell receptor cantankerous-linking and quickly upregulate CD40L in response to information technology; even so, they accept longer to differentiate into effector cells and thus practice not secrete as much cytokine equally do effector memory cells early on after restimulation. Interestingly, CD8 T cells tin also be divided into analogous key and effector retentiveness subsets.

Every bit with memory CD8 T cells, the field volition soon be revolutionized past direct staining of CD4 T cells with peptide:MHC class II oligomers (seeAppendix I, Section A-28). This technique allows 1 not only to identify antigen-specific CD4 T cells but likewise, using intracellular cytokine staining (seeAppendix I, Section A-27), to determine whether they are T_H1 or T_H2 cells. These improvements in the identification and phenotyping of CD4 T cells volition chop-chop increase our knowledge of these hitherto mysterious cells, and could contribute valuable information on naive, retentivity, and effector CD4 T cells.

10-25. In immune individuals, secondary and subsequent responses are mediated solely past memory lymphocytes and not by naive lymphocytes

In the normal course of an infection, a pathogen showtime proliferates to a level sufficient to arm-twist an adaptive immune response and and so stimulates the production of antibodies and effector T cells that eliminate the pathogen from the body. Most of the armed effector T cells so die, and antibody levels gradually decline later the pathogen is eliminated, because the antigens that elicited the response are no longer nowadays at the level needed to sustain information technology. Nosotros tin think of this as feedback inhibition of the response. Memory T and B cells remain, nevertheless, and maintain a heightened ability to mount a response to a recurrence of infection with the same pathogen.

The antibody and retentiveness T cells remaining in an immunized individual also prevent the activation of naive B and T cells by the same antigen. Such a response would exist wasteful, given the presence of retentiveness cells that tin reply much more speedily. The suppression of naive lymphocyte activation can exist shown by passively transferring antibody or memory T cells to naive recipients; when the recipient is then immunized, naive lymphocytes practise not reply to the original antigen, but responses to other antigens are unaffected. This has been put to practical use to foreclose the response of Rh^- mothers to their Rh⁺ children; if anti-Rh antibody is given to the female parent before she reacts to her child's reddish blood cells, her response will be inhibited. The mechanism of this suppression is likely to involve the antibiotic-mediated clearance and destruction of the child's blood-red blood cells, thus preventing naive B cells and T cells from mounting an immune response. Memory B-cell responses are not inhibited past antibody confronting the antigen, so the Rh^- mothers at risk must be identified and treated earlier a response has occurred. This is considering retentiveness B cells are much more sensitive, because of their high affinity and alterations in their B-cell receptor signaling requirements, to smaller amounts of antigen that cannot exist efficiently cleared by the passive anti-Rh antibiotic. The ability of retentiveness B cells to be activated to produce antibody even when exposed to preexisting antibody also allows secondary antibiotic responses to occur in individuals who are already immune.

Adoptive transfer of immune T cells (seeAppendix I, Section A-42) to naive syngeneic mice also prevents the activation of naive T cells by antigen. This has been shown most conspicuously for cytotoxic T cells. It is possible that, once reactivated, the retention CD8 T cells regain cytotoxic action sufficiently rapidly to kill the antigen-presenting cells that are required to actuate naive CD8 T cells, thereby inhibiting the latter's activation.

These mechanisms might also explain the phenomenon known equally original antigenic sin. This term was coined to describe the tendency of people to make antibodies only to epitopes expressed on the commencement influenza virus variant to which they are exposed, fifty-fifty in subsequent infections with variants that bear boosted, highly immunogenic, epitopes (Fig. 10.thirty). Antibodies against the original virus will tend to suppress responses of naive B cells specific for the new epitopes. This might benefit the host by using only those B cells that can respond most rapidly and effectively to the virus. This pattern is broken only if the person is exposed to an flu virus that lacks all epitopes seen in the original infection, as at present no preexisting antibodies demark the virus and naive B cells are able to respond.

Figure 10.30

When individuals who take already been infected with one variant of influenza virus are infected with a second variant they make antibodies only to epitopes that were present on the initial virus. A kid infected for the beginning fourth dimension with an influenza (more...)

Summary

Protective immunity confronting reinfection is one of the most important consequences of adaptive amnesty operating through the clonal selection of lymphocytes. Protective immunity depends not merely on preformed antibody and armed effector T cells, merely well-nigh chiefly on the institution of a population of lymphocytes that mediate long-lived immunological memory. The capacity of these cells to respond rapidly to restimulation with the same antigen can be transferred to naive recipients by primed B and T cells. The precise changes that distinguish naive, effector, and memory lymphocytes are at present being characterized and, with the advent of receptor-specific reagents, the relative contributions of clonal expansion and differentiation to the memory phenotype are rapidly existence clarified. Memory B cells can also be distinguished by changes in their immunoglobulin genes because of isotype switching and somatic hypermutation, and secondary and subsequent immune responses are characterized by antibodies with increasing affinity for the antigen.

longoriasking1984.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/books/NBK27158/