If You Get Sick Again Which Cells Will Cause a Rapid Response
Information technology is non known how many infections are dealt with solely past the nonadaptive mechanisms of innate amnesty discussed in Chapter two; this is considering such infections are eliminated early on and produce piddling in the fashion of symptoms or pathology. Moreover, deficiencies in nonadaptive defenses are rare, and so it has seldom been possible to study their consequences. Innate immunity does, however, appear to be essential for constructive host defense, as shown by the progression of infection in mice that lack components of innate immunity just take an intact adaptive immune system (Fig. 10.half dozen). Adaptive immunity is besides essential, as shown by the immunodeficiency syndromes associated with failure of one or the other arm of the adaptive immune response (see Affiliate 11). Adaptive immunity is triggered when an infection eludes the innate defense mechanisms and generates a threshold dose of antigen (encounter Fig. 10.1). This antigen then initiates an adaptive immune response, which becomes effective merely after several days, the fourth dimension required for antigen- specific T cells and B cells to locate their specific strange antigen, to proliferate, and to differentiate into armed effector cells. In the earlier capacity of this book, we discussed the cells and molecules that mediate the adaptive allowed response, and the interactions between them. We are now ready to meet how each cell type is recruited in plow in the course of a primary adaptive allowed response to a pathogen, and how the effector lymphocytes and antibodies that are generated in response to antigen are dispersed to their sites of action. These clear the infection and protect against reinfection in the short term. A principal adaptive response also establishes a state of long-lasting protective immunity that is ultimately mediated by long-lived resting retentivity cells, to which we will return in the last part of this chapter.
Figure 10.six
The time class of infection in normal and immunodeficient mice and humans. The red curve shows the rapid growth of microorganisms in the absence of innate immunity, when macrophages (MAC) and polymorphonuclear leukocytes (PMN) are lacking. The green (more...)
10-3. The nonspecific responses of innate immunity are necessary for an adaptive immune response to be initiated
The institution of a focus of infection in tissues and the response of the innate allowed system to it produce changes in the immediate environment of the infection. In a bacterial infection, the first thing that usually happens is that the infected tissue becomes inflamed (meet Fig. ane.12). As we learnt in Chapter ii, this is initially the outcome of the activation of the resident macrophages by bacterial components such as lipopolysaccharide (LPS) interim through Toll-like receptors on the macrophage. The cytokines and chemokines secreted by the activated macrophages, particularly the cytokine tumor necrosis factor-α (TNF-α), induce numerous changes in the endothelial cells of nearby blood capillaries, a procedure known as endothelial prison cell activation. The cytokines cause the release of Weibel-Palade bodies from within the endothelial cells, which deliver P-selectin to the endothelial cell surface. Cytokines and chemokines also induce the synthesis and translation of RNA encoding E-selectin, which thus as well appears on the endothelial cell surface.
These 2 selectins cause leukocytes to adhere to and ringlet on the endothelial surface in big numbers. Amidst these will be polymorphonuclear leukocytes, mainly neutrophils, and monocytes. The cytokines besides induce the production of the adhesion molecule VCAM-1 on the endothelial cells, which binds to adhesion molecules on the leukocytes. This strengthens the interaction between leukocytes and endothelial cells, and aids the neutrophils and monocytes to enter the infected tissue in big numbers to form an inflammatory focus (see Fig. 2.36). As monocytes mature into tissue macrophages and become activated in their turn, more and more inflammatory cells are attracted into the infected tissue and the inflammatory response is maintained and reinforced. The inflammatory response tin can be idea of as putting up a flag on the endothelial cells to point the presence of infection, but every bit yet, the response is entirely nonspecific for the pathogen antigens.
A 2d crucial issue of infection is the activation of potential professional antigen-presenting cells—the dendritic cells—that reside in nigh tissues. These have up antigen in the infected tissues and, equally for macrophages, they are activated through innate allowed receptors that answer to common pathogen constituents. For example, the combination of LPS and lipopolysaccharide-bounden protein (LBP) bounden to the cell-surface receptors CD14 and the Toll-similar receptor TLR-iv induces the dendritic cells to mature into potent antigen-presenting cells. Activated dendritic cells increment their synthesis of MHC form 2 molecules and, about importantly, begin to express the co-stimulatory molecules CD80 and CD86 on their surface. As described in Chapter 8, these antigen-presenting cells are carried away from the infected tissue in lymph, forth with their antigen cargo, to enter secondary lymphoid tissues, in which they can initiate the adaptive immune response. They arrive in large numbers at the draining lymph nodes, or other nearby lymphoid tissue, attracted past the chemokines ELC, MIP-3β, and SLC that are produced past lymph node stromal and loftier vascular endothelial cells.
Once dendritic cells arrive in the lymphoid tissues, they appear to have reached their final destination. They somewhen die in these tissues, but before this their role is to activate antigen-specific naive T lymphocytes. Naive lymphocytes are continually passing through the lymph nodes, which they enter from the claret beyond the walls of high endothelial venules, as we will draw below. Those naive T cells that are able to recognize antigen on the surface of dendritic cells are activated and both divide and mature into effector cells that reenter the circulation. When there is a local infection, the changes induced past inflammation in the walls of nearby venules, as we will see later, induce these effector T cells to get out the blood vessel and migrate to the site of infection.
Thus the local release of cytokines and chemokines at the site of infection has far-reaching consequences. Likewise as recruiting neutrophils and macrophages, which are not specific for antigen, the changes induced in the claret vessel walls likewise enable newly activated effector T lymphocytes to enter infected tissue.
10-iv. An adaptive immune response is initiated when circulating T cells encounter their respective antigen in draining lymphoid tissues and go activated
The importance of the peripheral lymphoid organs in the initiation of adaptive immune responses was showtime shown by ingenious experiments in which a skin flap was isolated from the body wall and so that it had a claret apportionment just no lymphatic drainage. Antigen placed in the flap of skin did not arm-twist a T-prison cell response, showing that T cells do not become sensitized in the infected tissue itself. Nosotros now know that naive T lymphocytes are activated in the peripheral lymphoid organs by antigens brought in that location by dendritic cells. The allowed response to pathogens that enter through the skin rather than beyond mucosal surfaces is generally believed to occur in the lymph nodes, which are sites of intersection of two pathways of apportionment, those of the lymph and the claret (see Fig. i.8).
Equally described in Chapter 8, immature dendritic cells in tissues take up antigens and are stimulated by infection to migrate to draining lymph nodes. Antigens introduced directly into the bloodstream are picked upward by antigen-presenting cells in the spleen, and lymphocytes are activated in the splenic white pulp (see Fig. ane.ix). The trapping of antigen by antigen-presenting cells that migrate to these lymphoid tissues, and the continuous recirculation of naive T cells through these tissues, ensure that rare antigen-specific T cells volition see their specific antigen on an antigen-presenting cell surface. The unique compages of the peripheral lymphoid organs virtually guarantees contact of foreign antigen with specific T-cell receptors in the lymph nodes and spleen or in mucosa-associated lymphoid tissues (MALT) (see Fig. 1.10).
Naive T cells enter the lymphoid organs in essentially the aforementioned style every bit described in Affiliate 2 for the entry of phagocytes into sites of infection, except that selectin is expressed on the T cell rather than the endothelium. 50-selectin on naive T cells binds to sulfated carbohydrates on proteins such as the vascular addressins GlyCAM-1 and CD34. CD34 is expressed on endothelial cells in many tissues only is properly glycosylated for L-selectin bounden only on the high endothelial venule cells of lymph nodes (Fig. 10.7). Binding of Fifty-selectin causes the lymphocyte to scroll on the endothelial surface, and although the interaction is too weak to promote extravasation, it is critical for the lymphocyte to selectively home to the lymphoid organs. It is essential for the initiation of the stronger interactions that follow between the T cell and the high endothelium, which are mediated by molecules with a relatively broad tissue distribution.
Effigy 10.seven
Lymphocytes in the blood enter lymphoid tissue by crossing the walls of high endothelial venules. The first stride is the binding of L-selectin on the lymphocyte to sulfated carbohydrates of GlyCAM-1 and CD34 on the high endothelial cells. Local chemokines (more...)
Chemokines produced by the cells of the lymph node are also important for initiating strong adhesion. These chemokines bind to proteoglycan molecules in the extracellular matrix and high endothelial venule cell walls, and are recognized by receptors on the naive T jail cell (see Department 7-30). Stimulation by these locally-leap chemokines activates the adhesion molecule LFA-1 on the T jail cell, increasing its affinity for ICAM-2, which is expressed constitutively on all endothelial cells, and ICAM-1, which, in the absence of inflammation, is expressed only on the high endothelial venule cells of peripheral lymphoid tissues. The binding of LFA-1 to its ligands ICAM-1 and ICAM-2 has a major role in T-cell adhesion to and migration through the wall of the venule into the lymph node (encounter Fig. x.7).
T-cells that have arrived in the T-cell zone via the high endothelial venules browse the surface of the antigen-presenting dendritic cells for specific peptide:MHC complexes. If they do not recognize antigen, they eventually leave the lymph node via an efferent lymphatic vessel. This returns them to the blood so that they can recirculate through other lymph nodes. Rarely, a naive T cell recognizes its specific peptide:MHC complex on the surface of a dendritic prison cell. This signals the activation of LFA-1, causing the T jail cell to adhere strongly to the dendritic cell and cease migrating. Binding to the peptide:MHC complexes and co-stimulatory molecules on the dendritic cell surface stimulates the naive T cell to proliferate and differentiate, resulting in the production of an expanded population of armed, antigen-specific effector T cells (come across Fig. 8.4). The efficiency with which T cells screen each antigen-presenting prison cell in lymph nodes is very high, every bit can be seen by the rapid trapping of antigen-specific T cells in a single lymph node containing antigen: all of the antigen-specific T cells in a sheep were trapped in one lymph node inside 48 hours of antigen deposition (Fig. ten.8).
Figure 10.8
Trapping and activation of antigen-specific naive T cells in lymphoid tissue. Naive T cells entering the lymph node from the claret encounter many antigen-presenting dendritic cells in the lymph node cortex. T cells that do not recognize their specific (more...)
10-5. Cytokines made in the early phases of an infection influence the functional differentiation of CD4 T cells
The differentiation of naive CD4 T cells into the two major classes of CD4 effector T cell occurs during the initial response of these cells to antigen in the peripheral lymphoid tissues. This step, at which a naive CD4 T cell becomes either an armed THi cell or an armed TH2 cell, has a critical impact on the outcome of an adaptive allowed response, determining whether it will be dominated by macrophage activation or by antibody product.
The mechanisms that control this step in CD4 T-jail cell differentiation are not yet fully defined; yet, it is articulate that it can exist profoundly influenced past cytokines present during the initial proliferative stage of T-cell activation. Experiments in vitro accept shown that naive CD4 T cells initially stimulated in the presence of IL-12 and IFN-γ tend to develop into TH1 cells (Fig. x.9, left panels), in role considering IFN-γ inhibits the proliferation of THii cells. Equally IL-12, produced by dendritic cells and macrophages, and IFN-γ, produced past NK cells and CD8 T cells, predominate in the early on phase of the response to viruses and to some intracellular bacteria, such as Listeria species (meet Department 2-27), CD4 T-cell responses in these infections tend to be dominated by TH1 cells. By dissimilarity, CD4 T cells activated in the presence of IL-4, particularly when IL-half dozen is also present, tend to differentiate into THii cells. This is because IL-four and IL-6 promote the differentiation of TH2 cells, and IL-4 or IL-ten, either alone or in combination, can also inhibit the generation of TH1 cells.
Effigy 10.9
The differentiation of naive CD4 T cells into unlike subclasses of armed effector T cells is influenced past cytokines elicited by the pathogen. Many pathogens, particularly intracellular leaner and viruses, activate dendritic cells and NK cells to produce (more...)
One possible source of the IL-four needed to generate THtwo cells is a specialized subset of CD4 T cells that express the NK1.ane marker normally associated with NK cells; these cells are called NK 1.1 + T cells. They accept a nearly invariant α:β T-cell receptor; in fact, substantially the aforementioned receptor seems to be used in the NK 1.i+ T cells of mice and their counterparts in humans. Dissimilar that of other CD4 T cells, the development of the NK i.i+ T cells does not depend on the expression of MHC course Ii molecules. Instead, they recognize an MHC course IB molecule, CD1, which is non encoded within the MHC (encounter Section v-18). In mice there are two CD1 genes (CD1.1 and CD1.ii), whereas in humans there are five (CD1a-e), of which just CD1d is homologous to the murine CD1.1 and CD1.two. CD1 molecules are expressed by thymocytes, professional person antigen-presenting cells, and intestinal epithelium.
Although the exact function of CD1 molecules is non well defined, CD1b is known to present a bacterial lipid, mycolic acrid, to α:β T cells, whereas other CD1 molecules are recognized by γ:δ T cells. The activation of NK 1.1+ T cells is thought to depend on the expression of CD1 molecules induced in response to infection; whether all NK one.one+ T cells recognize a specific antigen presented by these CD1 molecules is non known, but some at least are able to recognize glycolipid antigens presented by CD1d. Upon activation, these NK 1.ane+ T cells secrete very large amounts of IL-iv and tin therefore raise the development of TH2 cells (Fig. x.9, right panels), which promotes the production of IgG1 (in mice) and IgE (in mice and humans) in subsequent humoral immune responses.
The differential capacity of pathogens to interact with dendritic cells, macrophages, NK cells, and NK 1.i+ T cells tin therefore influence the overall balance of cytokines nowadays early in the immune response, and thus determine whether TH1 or THtwo cells develop preferentially to bias the adaptive immune response toward a cellular or a humoral response. This can, in plow, determine whether the pathogen is eliminated or survives within the host; some pathogens may fifty-fifty take evolved to interact with the innate immune system so as to generate responses that are beneficial to them rather than to the host.
10-six. Distinct subsets of T cells can regulate the growth and effector functions of other T-prison cell subsets
The two subsets of CD4 T cells—TH1 and TH2—have very different functions: THtwo cells are the most constructive activators of B cells, especially in main responses, whereas THane cells are crucial for activating macrophages. It is also articulate that the two CD4 T-cell subsets tin regulate each other; one time one subset becomes ascendant, information technology is often hard to shift the response to the other subset. One reason for this is that cytokines from 1 type of CD4 T cell inhibit the activation of the other. Thus, IL-x, a product of TH2 cells, can inhibit the development of TH1 cells past acting on the antigen-presenting cell, whereas IFN-γ, a product of TH1 cells, can prevent the activation of TH2 cells (Fig. 10.10). If a particular CD4 T-cell subset is activated first or preferentially in a response, information technology tin can suppress the development of the other subset. The overall effect is that certain responses are dominated past either humoral (THtwo) or cell-mediated (TH1) immunity. However, nether many circumstances in vivo, there is a mixed TH1 and TH2 response.
Effigy 10.x
The two subsets of CD4 T cells each produce cytokines that tin can negatively regulate the other subset. THtwo cells brand IL-10, which acts on macrophages to inhibit TH1 activation, maybe by blocking macrophage IL-12 synthesis, and TGF-β, which acts (more than...)
This interplay of cytokines is of import in human affliction, but it has been explored at present mainly in certain mouse models, where such polarized responses are easier to written report. For instance, when BALB/c mice are experimentally infected with the protozoan parasite Leishmania, their CD4 T cells fail to differentiate into TH1 effector cells; instead, the mice preferentially make THii cells in response to this pathogen. These TH2 cells are unable to actuate macrophages to inhibit leishmanial growth, resulting in susceptibility to disease. Past contrast, C57BL/6 mice respond by producing TH1 cells that protect the host by activating infected macrophages to impale the Leishmania. The preferential activation of THii rather than TH1 cells in BALB/c mice tin can be reversed if IL-4 is blocked in the first days of infection past injecting anti-IL-4 antibiotic, just this handling is ineffective afterwards a calendar week or so of infection.
Because cytokines seem to regulate the remainder between TH1 and TH2 cells, one might expect that it would exist possible to shift this rest by administering appropriate cytokines. IL-2 and IFN-γ have been used to stimulate cell-mediated immunity in diseases such every bit lepromatous leprosy, and tin cause both a local resolution of the lesion and a systemic change in T-cell responses. IL-12, which is a potent inducer of TH1 cells, might be an even more attractive potential therapy.
CD8 T cells are also able to regulate the immune response by producing cytokines. Information technology has become clear recently that effector CD8 T cells can, in addition to their familiar cytolytic function, also respond to antigen past secreting cytokines typical of either THi or TH2 cells. Such CD8 T cells, called TC1 or TCii past analogy to the TH subsets, seem to be responsible for the evolution of leprosy in its lepromatous rather than its tuberculoid form, which we hash out in item in Chapter 11. Patients with the less subversive tuberculoid leprosy brand TCi cells, whose cytokines induce THane cells, which can activate macrophages to rid the body of its burden of leprosy bacilli. Patients with lepromatous leprosy have CD8 T cells that suppress the TH1 response by making IL-10 and TGF-β. Thus, the suppression of CD4 T cells by CD8 T cells that has been observed in various situations tin can be explained past their expression of different sets of cytokines.
10-7. The nature and amount of antigenic peptide can besides affect the differentiation of CD4 T cells
Another factor that influences the differentiation of CD4 T cells into distinct effector subsets is the amount and exact sequence of the antigenic peptide that initiates the response. Large amounts of peptide that achieve a loftier density on the surface of antigen-presenting cells tend to stimulate TH1 cell responses, whereas low-density presentation tends to arm-twist TH2 cell responses. Moreover, peptides that collaborate strongly with the T-cell receptor tend to stimulate THone-like responses, whereas peptides that demark weakly tend to stimulate TH2-similar responses (Fig. 10.11).
Effigy ten.11
The nature and amount of ligand presented to a CD4 T jail cell during primary stimulation can make up one's mind its functional phenotype. CD4 T cells presented with low levels of a ligand that binds the T-cell receptor poorly differentiate preferentially into TH2 (more...)
This deviation could be very important in several circumstances. For instance, allergy is acquired by the production of IgE antibiotic, which, as we learned in Chapter 9, requires high levels of IL-4 but does not occur in the presence of IFN-γ, a potent inhibitor of IL-4-driven class switching to IgE. Antigens that elicit IgE-mediated allergy are generally delivered in infinitesimal doses, and they arm-twist THtwo cells that brand IL-4 and no IFN-γ. It is too relevant that allergens do not elicit any of the known innate immune responses, which produce cytokines that tend to bias CD4 T-jail cell differentiation toward TH1 cells. Finally, allergens are delivered to humans in minute doses across a sparse mucosa, such as that of the lung. Something about this route of sensitization allows even potent generators of TH1 responses like Leishmania major to induce THtwo responses.
Most protein antigens that arm-twist CD4 T-cell responses stimulate the production of both THi and TH2 cells. This reflects the presence in nigh proteins of several different peptide sequences that can bind to MHC class 2 molecules and be presented to CD4 T cells. Some of these peptides are likely to bind to MHC course II molecules with loftier affinity, and consequently will be nowadays at high density on the antigen-presenting cell, whereas others are likely to bind MHC class Ii molecules with depression affinity and exist present only at depression density. Naive T cells specific for peptide antigens that have loftier affinity for MHC molecules are therefore likely to come across a loftier density of their ligand, whereas others might just encounter a low density, and these differences could affect the subsequent response of the T cell. Indeed, it can exist shown experimentally that some peptides in a protein tend to elicit the production of THii cells, whereas other peptides tend to elicit THane cells.
x-8. Armed effector T cells are guided to sites of infection by chemokines and newly expressed adhesion molecules
The full activation of naive T cells takes four–five days and is accompanied by marked changes in the homing behavior of these cells. Armed effector cytotoxic CD8 T cells must travel from the lymph node, or other peripheral lymphoid tissue in which they have been activated, to attack and destroy infected cells. Armed effector CD4 TH1 cells must also get out the lymphoid tissues to activate macrophages at the site of infection. Almost of the antigen-specific armed effector T cells cease production of L-selectin, which mediates homing to the lymph nodes, while the expression of other adhesion molecules is increased (Fig. x.12). One of import change is a marked increase in the expression of the integrin α4:β1, also known as VLA-4. This binds to the VCAM-1 molecule that is induced on activated endothelial prison cell surfaces and initiates the extravasation of the effector T cells. Thus if the innate immune response has already activated the endothelium at the site of infection, as described in Section 10-iii, effector T cells will rapidly be recruited. At the early phase of the immune response, only a few of the effector T cells that enter the infected tissues volition be expected to be specific for pathogen, as any effector T jail cell specific for any antigen will also be able to enter. However, specificity of the reaction is maintained, every bit but those effector T cells that recognize pathogen antigens will bear out their office, destroying infected cells or specifically activating pathogen-loaded macrophages. By the summit of an adaptive immune response, virtually of the recruited T cells will exist specific for the infecting pathogen, as after several days of clonal expansion and differentiation these cells predominate in numbers.
Figure 10.12
Armed effector T cells change their surface molecules, allowing them to home to sites of infection. Naive T cells home to lymph nodes through the binding of 50-selectin to sulfated carbohydrates displayed past various proteins, such every bit CD34 and GlyCAM-1 (more than...)
Differential expression of adhesion molecules can direct dissimilar subsets of armed effector T cells to specific sites. Some, for case, migrate to the lamina propria of the gut, which involves the binding of both L-selectin and the α4:β7 integrin expressed on the T cell to divide sites on MAdCAM-1. T cells that abode to the epithelium of the gut limited a novel integrin called αe:βvii and bind to the E-cadherin expressed on epithelial cells. Cells that home to the skin, in contrast, express the cutaneous lymphocyte antigen (CLA), a glycosylated isoform of P-selectin glycolipid-one, and bind to E-selectin. As nosotros will discuss afterward in this chapter, the peripheral immune system is compartmentalized such that different populations of lymphocytes drift through different lymphoid compartments and—after activation—through the different tissues they serve. The selective expression of different homing receptors that bind to tissue-specific 'addressins' is the mechanism by which this is accomplished.
Not all infections trigger innate allowed responses that actuate local endothelial cells, and it is not so clear how armed effector T cells are guided to the sites of infection in these cases. However, activated T cells seem to enter all tissues in very small numbers, perhaps via adhesive interactions such as the binding of P-selectin to P-selectin glycolipid-1, and could thus encounter their antigens fifty-fifty in the absenteeism of a previous inflammatory response.
Effector T cells that recognize pathogen antigens in the tissues produce cytokines such every bit TNF-α, which activates endothelial cells to express E-selectin, VCAM-i, and ICAM-1, and chemokines such as RANTES (encounter Fig. 2.33), which can and then act on effector T cells to activate their adhesion molecules. The increased levels of VCAM-i and ICAM-1 on endothelial cells bind VLA-4 and LFA-1, respectively, on armed effector T cells, recruiting more of these cells into tissues that contain the antigen. At the same fourth dimension, monocytes and polymorphonuclear leukocytes are recruited to these sites by adhesion to E-selectin. TNF-α and IFN-γ released by the activated T cells as well human action synergistically to change the shape of endothelial cells, assuasive increased claret flow, increased vascular permeability, and increased emigration of leukocytes, fluid, and protein into a site of infection.
Thus one or a few specific effector T cells encountering antigen in a tissue can initiate a potent local inflammatory response that recruits both a greater number of specific armed effector cells and many more nonspecific inflammatory cells to that site. By contrast, effector T cells that enter the tissues simply do non recognize their antigen are rapidly lost. They either enter afferent lymph in the tissues and render to the bloodstream, or undergo apoptosis. Near of the T cells in the afferent lymph that drains tissues are retentiveness or effector T cells, which characteristically express the CD45RO isoform of the jail cell-surface molecule CD45 and lack 50-selectin. Effector T cells and memory T cells have a similar phenotype, equally we volition discuss later, and both seem to be committed to migration through potential sites of infection. Likewise as allowing effector T cells to clear all sites of infection, this pattern of migration allows them to contribute, along with retentivity cells, to protecting the host confronting reinfection with the same pathogen (encounter Sections 10-11 and 10-12).
10-9. Antibody responses develop in lymphoid tissues under the direction of armed helper T cells
Migration out of lymphoid tissues is conspicuously important for the effector actions of armed CD8 cytotoxic T cells and armed THi cells. Nonetheless, the most important functions of helper CD4 T cells, predominantly TH2 cells, depend on their interactions with B cells, and these interactions occur in the lymphoid tissues themselves. B cells specific for a protein antigen cannot be activated to proliferate, class germinal centers, or differentiate into plasma cells until they run across a helper T cell that is specific for one of the peptides derived from that antigen. Humoral allowed responses to protein antigens thus cannot occur until subsequently antigen-specific helper T cells have been generated.
One of the near interesting questions in immunology is how 2 antigen-specific lymphocytes—the naive antigen-bounden B cell and the armed helper T cell—find one some other to initiate a T-cell dependent antibody response. Equally we learned in Chapter 9, the likely respond lies in the migratory path of B cells through the lymphoid tissues and the presence of armed helper T cells on that path (Fig. x.xiii).
Figure x.13
The specialized regions of lymphoid tissue provide an environment where antigen-specific naive B cells tin can interact with armed helper T cells specific for the aforementioned antigen. The initial come across of antigen-specific naive B cells with the advisable helper (more...)
If B cells bounden their specific antigen in the T-cell zone of peripheral lymphoid organs receive specific signals from armed helper T cells, they proliferate in the T-cell areas (see Fig. x.13, 2d panel). In the absence of T-cell signals, these antigen-specific B cells die within 24 hours of arriving in the T-cell zone.
About 5 days later master immunization, principal foci of proliferating B cells appear in the T-cell areas, which correlates with the time needed for helper T cells to differentiate. Some of the B cells activated in the primary focus may migrate to the medullary cords of the lymph node, or to those parts of the red lurid that are next to the T-jail cell zones of the spleen, where they get plasma cells and secrete specific antibody for a few days (meet Fig. 10.13, third panel). Others drift to the follicle (run into Fig. x.13, fourth panel), where they proliferate further, forming a germinal center in which they undergo somatic hypermutation (come across Sections 4-9 and nine-7). The antibodies secreted past B cells differentiating early in the response not only provide early on protection; they may likewise be important in trapping antigen in the form of antigen:antibody complexes on the surface of the local follicular dendritic cells.The antigen: antibody complexes, which get coated with fragments of C3, are held past complement fragment receptors (CR1, CR2, and CR3) as well equally past a nonphagocytic Fc receptor on the follicular dendritic cells. Antigen can be retained in lymphoid follicles in this course for very long periods. The office of this antigen is unclear, simply it is likely that it regulates the long-term antibody response.
The proliferation, somatic hypermutation, and selection that occur in the germinal centers during a primary antibody response take been described in Chapter 9. The adhesion and chemokine molecules that govern the migratory behavior of B cells are likely to be very of import to this process just, as however, picayune is known of their nature or of the ligands to which they bind. The chemokine/receptor pair BLC/CXCR5, which controls B-jail cell migration into the follicle, may be important, specially for B cells homing to the germinal eye. Another chemokine receptor, CCR7, which is strongly expressed on T cells and weakly expressed on B cells, may play a office in temporarily directing B cells to the interface with the T-prison cell zone. The ligands for CCR7—MIP-3β and SLC—are highly expressed in the T zone (encounter Section 7-xxx) and could concenter B cells that have regulated their CCR7 receptor upward.
x-ten. Antibody responses are sustained in medullary cords and bone marrow
The B cells activated in primary foci migrate either to side by side follicles or to local extrafollicular sites of proliferation. B cells abound exponentially in these sites for 2–3 days and undergo vi to vii jail cell divisions before the progeny come out of the cell bike and course antibody-producing plasma cells in situ (Fig. 10.14, upper panel). Well-nigh of these plasma cells have a life-span of 2–iii days, afterward which they undergo apoptosis. Most x% of plasma cells in these extrafollicular sites live longer; their origin and ultimate fate are unknown. The B cells that migrate to the primary follicles to form germinal centers undergo isotype switching and affinity maturation before either becoming memory cells or leaving the germinal centre to become relatively long-lived antibody-producing cells (see Sections 9-six to 9-eight).
Figure ten.fourteen
Plasma cells are dispersed in medullary cords and bone marrow. In these sites they secrete antibiotic at high rates directly into the blood for distribution to the balance of the body. In the upper micrograph, plasma cells in lymph node medullary cords are (more...)
These B cells leave germinal centers every bit plasmablasts (pre-plasma cells). Plasmablasts originating in the follicles of Peyer'southward patches and mesenteric lymph nodes migrate via lymph to the blood and then enter the lamina propria of the gut and other epithelial surfaces. Those originating in peripheral lymph node or splenic follicles migrate to the bone marrow (Fig. ten.14, lower panel). In these distant sites of antibody production, the plasmablasts differentiate into plasma cells that mostly have a life-span of months to years. These are thought to provide the antibody that tin terminal in the blood for years after an initial immune response. Whether this supply of plasma cells is replenished by the continual just occasional differentiation of memory cells is not yet known. Studies of responses to nonreplicating antigens show that germinal centers are present for just 3–4 weeks after initial antigen exposure. Modest numbers of B cells, all the same, continue to proliferate in the follicles for months. These may be the precursors of antigen-specific plasma cells in the mucosa and bone marrow throughout the subsequent months and years.
ten-11. The effector mechanisms used to clear an infection depend on the infectious amanuensis
A primary adaptive immune response usually serves to clear the primary infection from the body and in most cases provides protection against reinfection with the same pathogen. Notwithstanding, as nosotros volition discuss farther in Chapter xi, some pathogens evade complete clearance and persist for the life of the host, for case, Leishmania, toxoplasma, and canker viruses. Figure 10.xv summarizes the different types of infection in humans and the ways in which they can be eliminated or held in check by a chief adaptive allowed response. It as well indicates the mechanisms involved in amnesty to reinfection, or protective amnesty, against these pathogens. Inducing protective amnesty is the goal of vaccine development and to achieve this it is necessary to induce an adaptive allowed response that has both the antigen-specificity and the appropriate functional elements to combat the item pathogen concerned. Protective immunity consists of two components—immune reactants, such as antibody or effector T cells generated in the initial infection or by vaccination, and long-lived immunological memory (Fig. 10.16), which we volition consider in the last office of this affiliate. The type of antibody or effector T jail cell that offers protection depends on the infectious strategy and lifestyle of the pathogen. Constructive amnesty confronting polio virus, for example, requires preexisting antibiotic, because the virus rapidly infects motor neurons and destroys them unless it is immediately neutralized by antibody and prevented from spreading inside the torso. Specific IgA on epithelial surfaces can besides neutralize the virus before information technology enters the trunk. Thus, protective immunity can involve effector mechanisms (IgA in this case) that practice non operate in the elimination of the main infection (come across Fig. ten.15).
Figure 10.fifteen
Different effector mechanisms are used to clear master infections with dissimilar pathogens and to protect against subsequent reinfection. The pathogens are listed in order of increasing complexity, and the defense mechanisms used to clear a primary infection (more...)
Figure 10.xvi
Protective immunity consists of preformed immune reactants and immunological retentivity. Antibody levels and effector T-cell activeness gradually decline after an infection is cleared. An early on reinfection is apace cleared by these immune reactants. In that location (more...)
Preformed reactants can besides allow the immune organization to respond more rapidly and efficiently to a second exposure to a pathogen. Thus, when opsonizing antibodies such equally IgG1 are present (come across Section 9-12), opsonization and phagocytosis of pathogens will be more than efficient. If specific IgE is nowadays, so pathogens will also exist able to activate mast cells, rapidly initiating an inflammatory response through the release of histamine and leukotrienes.
10-12. Resolution of an infection is accompanied past the decease of about of the effector cells and the generation of memory cells
When an infection is effectively repelled by the adaptive immune system, 2 things occur. The first is the removal of most of the effector cells, equally part of the restoration of tissue integrity. The allowed organization has well-adult mechanisms for getting rid of cells that have outlasted their usefulness. Most unwanted effector cells die by apoptosis, a procedure used past all multicellular eukaryotic organisms to remove unwanted cells.
The actions of effector cells remove the specific stimulus that originally recruited them. In the absence of this stimulus, they then undergo 'death by fail,' removing themselves by apoptosis. The dying cells are chop-chop cleared by macrophages, which recognize the membrane lipid phosphatidylserine. This lipid is unremarkably found only on the inner surface of the plasma membrane, but in apoptotic cells it rapidly redistributes to the outer surface, where information technology tin can exist recognized by specific receptors on phagocytes. Thus, not just does the catastrophe of infection atomic number 82 to the removal of the pathogen, it also leads to the loss of most of the pathogen-specific effector cells.
However, some of the effector cells are retained, and these provide the raw material for memory T-cell and B-cell responses. These are crucially important to the operation of the adaptive allowed system, every bit we volition argue in Chapter 15. The memory T cells, which we volition consider at the terminate of this chapter, are retained nearly forever. However, the mechanisms underlying the decision to induce apoptosis in the bulk of effector cells and retain only a few are not known. It seems likely that the reply volition lie in the cytokines produced by the environment or by the T cells themselves.
Summary
The adaptive immune response is required for effective protection of the host against pathogenic microorganisms. The response of the innate immune organisation to pathogens helps initiate the adaptive immune response, as interactions with these pathogens pb to the product of cytokines and the activation of dendritic cells to activated antigen-presenting prison cell status. The antigens of the pathogen are transported to local lymphoid organs by these migrating antigen-presenting cells and presented to antigen-specific naive T cells that continuously recirculate through the lymphoid organs. T-prison cell priming and the differentiation of armed effector T cells occur here on the surface of antigen-loaded dendritic cells, and the armed effector T cells either leave the lymphoid organ to outcome cell-mediated amnesty in sites of infection in the tissues, or remain in the lymphoid organ to participate in humoral amnesty by activating antigen-binding B cells. Which response occurs is determined past the differentiation of CD4 T cells into TH1 or THtwo cells, which is in turn determined by the cytokines produced in the early on nonadaptive phase. CD4 T-cell differentiation is also affected past ill-divers characteristics of the activating antigen and past its overall affluence. CD8 T cells play an of import role in protective immunity, peculiarly in protecting the host against infection by viruses and intracellular infections by Listeria and other microbial pathogens that accept special means for entering the host cell's cytoplasm. Ideally, the adaptive immune response eliminates the infectious amanuensis and provides the host with a state of protective amnesty confronting reinfection with the same pathogen.
Source: https://www.ncbi.nlm.nih.gov/books/NBK27125/
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