Principles of innate and adaptive immunity19 A lymph node () ere5roete marginal sinus tuated just behind the stomach node from the blo nod and is i ompose blood-bome pathogens.Lymphocytes enter and leave the spleen via blood and de vesse The spleen and disposes of blood cl of red pu When an immue se is ral areas of intense B-cell pr reas of white pu n nd an arteriole nphoid follicles occur at intervals along it and these contain mainly B cells Aso-called marginal zone su out which ite is o po cyti Chapter 8.Blood-bome microbes,soluble antigens,and antigen:antibody m the tis s an ges f p the ctly from cells from p eripheral tissues to the T-cell are eas ofly nh nodes dendritic cells in the marginal zones in the spleen migrate to the T-cell areas after taking up by the eff o the d here they are able to pret the s an Most pathogens enter the body through mucosal surfaces,and these are also er the exposed to a vast loado other poreh ntial an ntigens from the air food.and h venules not s n)and sive system of lymphoid tissues know enerally s the mucosal immune The light oh s emormucosgasoeaedswesoaNni.Colectweg,hemueoo recirculation from those in the othe peripheral lymphoid organs.The gut y of N.Ro inte Peyer's p tract.In Peyer's patches,which are the most important and highly organized of these tissues,the antigen is collected by specialized epithelial cells called
A lymph node cortical sinus -,.,."'-"<� secondary lymphoid follicle -1-+- . (with germinal center) afferent lymphatic vessel ._.,.c-\- primary lymphoid follicle (mostly B cells) .;-+- medullary cords (macrophages -f- and plasma cells) medullary sinus =o-'- artery vein efferent lymphatic vessel senescent /e;.L- - germinal center marginal sinus activated B cells are undergoing intense proliferation and differentiation into plasma cells. These mechanisms are described in detail in Chapter 10. In humans, the spleen is a fist -sized organ situated just behind the stomach (see Fig. 1.8). It has no direct connection with the lymphatic system; instead, it collects antigen from the blood and is involved in immune responses to blood-borne pathogens. Lymphocytes enter and leave the spleen via blood vessels. The spleen also collects and disposes of senescent red blood cells. Its organization is shown schematically in Fig. 1.19. The bulk of the spleen is composed of red pulp, which is the site of red blood cell disposal. The lymphocytes surround the arterioles running through the spleen, forming isolated areas of white pulp. The sheath of lymphocytes around an arteriole is called the periarteriolar lymphoid sheath (PALS) and contains mainlyT cells. Lymphoid follicles occur at intervals along it, and these contain mainly B cells. A so-called marginal zone surrounds the follicle; it has few T cells, is rich in macro phages, and has a resident, noncirculating population of B cells known as marginal zone B cells, about which little is known; they are discussed in Chapter 8. Blood-borne microbes, soluble antigens, and antigen:antibody complexes are filtered from the blood by macrophages and immature dendritic cells within the marginal zone. Like the migration of immature dendritic cells from peripheral tissues to the T-cell areas of lymph nodes, dendritic cells in the marginal zones in the spleen migrate to the T-cell areas after taking up antigen and becoming activated; here they are able to present the antigens they carry to T cells. Most pathogens enter the body through mucosal surfaces, and these are also exposed to a vast load of other potential antigens from the air, food, and the natural microbial flora of the body. Mucosal surfaces are protected by an ext ensive system of lymphoid tissues known generally as the mucosal immune system or mucosa-associated tissues (MALT). Collectively, the mucosal immune system is estimated to contain as many lymphocytes as all the rest of the body, and they form a specialized set of cells obeying somewhat different rules of recirculation from those in the other peripheral lymphoid organs. The gutassociated lymphoid tissues (GALT) include the tonsils, adenoids, appendix, and specialized structures in the small intestine called Peyer's patches, and they collect antigen from the epithelial surfaces of the gastrointestinal tract. In Peyer's patches, which are the most important and highly organized of these tissues, the antigen is collected by specialized epithelial cells called Principles of innate and adaptive immunity � Fig. 1.18 Organization of a lymph node. As shown in the diagram on the left, which shows a lymph node in longitudinal section, a lymph node consists of an outermost cortex and an inner medulla. The cortex is composed of an outer cortex of B cells organized into lymphoid follicles, and deep, or paracortical, areas made up mainly ofT cells and dendritic cells. When an immune response is under way, some of the follicles contain central areas of intense 8-cell proliferation called germinal centers and are known as secondary lymphoid follicles. These reactions are very dramatic, but eventually die out as senescent germinal centers. Lymph draining from the extracellular spaces of the body carries antigens in phagocytic dendritic cells and phagocytic macrophages from the tissues to the lymph node via the afferent lymphatics. These migrate directly from the sinuses into the cellular parts of the node. Lymph leaves by the efferent lymphatics in the medulla. The medulla consists of strings of macrophages and antibody-secreting plasma cells known as the medullary cords. Naive lymphocytes enter the node from the bloodstream through specialized postcapillary venules (not shown) and leave with the lymph through the efferent lymphatic. The light micrograph shows a transverse section through a lymph node, with prominent follicles containing germinal centers. Magnification x?. Photograph courtesy of N. Rooney
20 Chapter 1:Basic Concepts in Immunology The soleen red pulo section of white pulp B-cell coron enlar nen 99 nt of di blo ces in the e section.with two portion ersesection and longt he fol eath (PALS)mac at b de up of t cells he zone come ins es a The MZ, aowheads,entdarenoe microfold or M cells(Fig.1.20).The lymphocytes form a follicle consisting a large dome of B lymphocytes su I by smaller number blood and leave through efferent lymphatics.Effector lymphocytes generated hreeopatohereaeheoleheeaPbtatcatelandintouteblood out their effector actions
� Chapter 1: Basic Concepts in Immunology The spleen capsule red pulp white pulp RP Transverse section of white pulp trabecular artery .,�r-+-+-+- o->,-+-+-+- B-cell corona -+-'<-+-+< .-+-+-+- germinal center -+-"""'rT-'t-+ marginal zone -+-�·' Fig. 1.19 Organization of the lymphoid tissues of the spleen. The schematic at top left shows that the spleen consists of red pulp (pink areas), which is a site of red blood cell destruction, interspersed with the lymphoid white pulp. An enlargement of a small section of a human spleen (top right) shows the arrangement of discrete areas of white pulp (yellow and blue) around central arterioles. Most of the white pulp is shown in transverse section, with two portions in longitudinal section. The bottom two schematics show enlargements of a transverse section (lower center) and longitudinal section (lower right) of white pulp. Surrounding the central arteriole is the periarteriolar lymphoid sheath (PALS), made up of T cells. Lymphocytes and antigen-loaded dendritic cells come together here. The follicles consist mainly of B cells; in secondary follicles a germinal center is surrounded by a 8-cell corona. The follicles are surrounded by a so-called marginal zone of lymphocytes. In each area of white o-+-11- perifollicular -1->,o -+-+- zone periarteriolar -+-�,.,., '-,f-+- lymphoid sheath central arteriole -+-� pulp, blood carrying both lymphocytes and antigen flows from a trabecular artery into a central arteriole. From this arteriole smaller blood vessels fan out, eventually terminating in a specialized zone in the human spleen called the perifollicular zone (PFZ), which surrounds each marginal zone. Cells and antigen then pass into the white pulp through open blood-filled spaces in the perifollicular zone. The light micrograph at bottom left shows a transverse section of white pulp of human spleen immunostained for mature B cells. Both follicle and PALS are surrounded by the perifollicular zone. The follicular arteriole emerges in the PALS (arrowhead at bottom), traverses the follicle, goes through the marginal zone and opens into the perifollicular zone (upper arrowheads). Co, follicular 8-cell corona; GC, germinal center; MZ, marginal zone; RP, red pulp; arrowheads, central arteriole. Photograph courtesy of N.M. Milicevic. microfold or M cells (Fig. 1.20). The lymphocytes form a follicle consisting of a large central dome of B lymphocytes surrounded by smaller numbers ofT lymphocytes. Dendritic cells resident within the Peyer's patch present the antigen to T lymphocytes. Lymphocytes enter Peyer's patches from the blood and leave through efferent lymphatics. Effector lymphocytes generated in Peyer's patches travel through the lymphatic system and into the bloodstream, from where they are disseminated back into mucosal tissues to carry out their effector actions. Similar but more diffuse aggregates of lymphocytes are present in the respiratory tract and other mucosa: nasal-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT) are present in the respiratory
Principles of innate and adaptive immunity 21 Peyer's patches are covered by an epithelial layer containing spe lized cells called M cells,which have characteristic membrane ruffles thelial dom tract.like the pever's patches.these mucosal lymphoid tissues are also over Fig.1.20 Organization of a Peyer's laid by M cells,through which inhaled microbes and antigens that become a pever's nitecture.They nt a een the as the s en to migrator small lymphocytes,thus inducing adaptive immune respor s.The periph antigen continue to recirculate. une responses,the edly depending on whether or not infection is present.The diffuse mucosa may appe as the a the orga B-cell fouicle ore and as B lymphocytes proliferate to form germinal centers(se eFig1.18 lymph node enlarges,a phenomenon familiarly known as h Finally,specialized populations of lymphocytes can be found distributed the b on mic grapn o er al ll as the has thelial lir of th a.s epithelia,and,in mice but not in humans,the epidermis.These lymphoc normal epithell ma Ieayedhomtheanigenreceporhenanigen2bnbondhose 1-16 Lymphocyte activation requires additional signal ae articles Peripheral lymphoid tissues p oromote the interaction between antigen-bear cation o ing APCs and lymphocytes,but antigen alone is not sufficient c,23.000.So mmunol.Aev.1997.156:145-166. adapemuDeepom5g mphocytes require other sign deliv ecom tory molecules (s e Section 1-8) For naive I cells an activate nature of these signals in detail in Chapter 7
Principles of innate and adaptive immunity � Peyer's patches are covered by an epithelial layer containing specialized cells called M cells, which have characteristic membrane ruffles tract. Like the Peyer's patches, these mucosal lymphoid tissues are also overlaid by M cells, through which inhaled microbes and antigens that become trapped in the mucous covering of the respiratory tract can pass. The mucosal immune system is discussed in Chapter 12. Although very different in appearance, the lymph nodes, spleen, and mucosaassociated lymphoid tissues all share the same basic architecture. They all operate on the same principle, trapping antigens and antigen-presenting cells from sites of infection and enabling them to present antigen to migratory small lymphocytes, thus inducing adaptive immune responses. The peripheral lymphoid tissues also provide sustaining signals to lymphocytes that do not encounter their specific antigen immediately, so that they survive and continue to recirculate. Because they are involved in initiating adaptive immune responses, the peripheral lymphoid tissues are not static structures but vary quite markedly, depending on whether or not infection is present. The diffuse mucosal lymphoid tissues may appear in response to infection and then disappear, whereas the architecture of the organized tissues changes in a more defined way during an infection. For example, the B-cell follicles of the lymph nodes expand as B lymphocytes proliferate to form germinal centers (see Fig. 1.18), and the entire lymph node enlarges, a phenomenon familiarly known as swollen glands. Finally, specialized populations of lymphocytes can be found distributed throughout particular sites in the body rather than being found in organized lymphoid tissues. Such sites include the liver and the lamina propria of the gut, as well as the base of the epithelial lining of the gut, reproductive epithelia, and, in mice but not in humans, the epidermis. These lymphocyte populations seem to have an important role in protecting these tissues from infection, and are described further in Chapters 8 and 12. 1-16 Lymphocyte activation requires additional signals beyond those relayed from the antigen receptor when antigen binds. Peripheral lymphoid tissues promote the interaction between antigen-bearing APCs and lymphocytes, but antigen alone is not sufficient to initiate an adaptive immune response. Lymphocytes require other signals to become activated and to acquire effector functions. These signals are delivered to lymphocytes by another cell through cell-surface molecules known generally as co-stimulatory molecules (see Section 1-8). For naive T cells, an activated dendritic cell usually delivers these signals, but for naive B cells, the second signal is delivered by an activated helper T cell (Fig. 1.21). We discuss the nature of these signals in detail in Chapter 7. Fig. 1.20 Organization of a Peyer's patch in the gut mucosa. As the diagram on the left shows, a Peyer's patch contains numerous 8-cell follicles with germinal centers. T cells occupy the areas between follicles, the T-cell dependent areas. The layer between the surface epithelium and the follicles is known as the subepithelial dome, and is rich in dendritic cells, T cells, and B cells. Peyer's patches have no afferent lymphatics and the antigen enters directly from the gut across a specialized epithelium made up of so-called microfold (M) cells. Although this tissue looks very different from other lymphoid organs, the basic divisions are maintained. As in the lymph nodes, lymphocytes enter Peyer's patches from the blood across the walls of high endothelial venules (not shown), and leave via the efferent lymphatic. T he light micrograph in panel a shows a section through a Peyer's patch in the gut wall of the mouse. The Peyer's patch can be seen lying beneath the epithelial tissues. GC, germinal center; TDA, T-cell dependent area. Panel b is a scanning electron micrograph of the follicle-associated epithelium boxed in panel a, showing the M cells, which lack the microvilli and the mucus layer present on normal epithelial cells. Each M cell appears as a sunken area on the epithelial surface. Panel c is a higher-magnification view of the boxed area in panel b, showing the characteristic ruffled surface of an M cell. M cells are the portal of entry for many pathogens and other particles. Panel a, hematoxylin and eosin stain; magnification x1 00; panel b, x5000; panel c, x23,000. Source: Mowat, A., Viney, J.: lmmunol. Rev. 1997, 156:145-166
Chapter 1:Basic Concepts in Immunology The induction of co-stimulatory molecules is important in initiating an adap- tive mmune response because contact with antigen without accompanying ing them,leading either to clonal deletion or an inactive state known as by cells that be whose expression is regulated by innate immunity. cells.These three specialized antigen-presenting cells of the immune system are illustrated in Fig.1.22.Dendritic cells are the most important of the three effector activities.These circumstances are discussed in Chapters 9 and 10. 1-17 memory. tally he a be very small,certainly not enough to mount a response against a pathogen. o generate nugen-spe ctor lymph an ith these finally dif rentiate into effector cells.On recognizing its specific anti new proteins are synthesized.Within a few hours,the cell looks completely different and is known as a lymphoblast. are able to dupli two to four tim a clone of aroun d 1000 daughter cells of i entical specificity.The n dif. effector cells are cytotoxicT cells able to destroy infected cells,or helper T mpnocyte AaonegP8hs7mdacnatio ceiving a signal through their nd ch as t ually de ed by an activat cell nd presented by Pe6aTe Po
� Chapter 1: Basic Concepts in Immunology Fig. 1.21 Two signals are required for lymphocyte activation. In addition to receiving a signal through their antigen receptor (signal1), mature naive lymphocytes must also receive a second signal (signal 2) to become activated. For T cells (left panel), this second signal is delivered by an antigen-presenting cell such as the dendritic cell shown here. For B cells (right panel), the second signal is usually delivered by an activated T cell, which recognizes antigenic peptides taken up, processed, and presented by the B cell on its surface. The induction of co-stimulatory molecules is important in initiating an adaptive immune response because contact with antigen without accompanying co-stimulatory molecules inactivates naive lymphocytes rather than activating them, leading either to clonal deletion or an inactive state known as anergy. We return to this topic in Chapter 8. Thus, we need to add a final postulate to the clonal selection theory. A naive lymphocyte can only be activated by cells that bear not only specific antigen but also co-stimulatory molecules, whose expression is regulated by innate immunity. Macro phages and B cells can also present foreign antigens on their surface and can be induced to express co-stimulatory molecules and thus can activate T cells. These three specialized antigen-presenting cells of the immune system are illustrated in Fig. 1.22. Dendritic cells are the most important of the three in initiating the adaptive immune response, whereas the others function as antigen-presenting cells at later stages, when T cells have acquired particular effector activities. These circumstances are discussed in Chapters 9 and 10. 1-17 Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory. The great diversity of lymphocyte receptors means that there will usually be at least a few that can bind to a given foreign antigen. However, this number will be very small, certainly not enough to mount a response against a pathogen. To generate sufficient antigen-specific effector lymphocytes to fight an infection, a lymphocyte with an appropriate receptor specificity is activated first to proliferate. Only when a large clone of identical cells has been produced do these finally differentiate into effector cells. On recognizing its specific antigen on an activated antigen-presenting cell, a naive lymphocyte stops migrating, the volume of the nucleus and cytoplasm increases, and new mRNAs and new proteins are synthesized. Within a few hours, the cell looks completely different and is known as a lymphoblast. Dividing lymphoblasts are able to duplicate themselves two to four times every 24 hours for 3-5 days, so that a single naive lymphocyte can produce a clone of around 1000 daughter cells of identical specificity. These then differentiate into effector cells. In the case of B cells, the differentiated effector cells are the plasma cells, which secrete antibody; in the case ofT cells, the effector cells are cytotoxic T cells able to destroy infected cells, or helper T cells that activate other cells of the immune system. Effector lymphocytes do not recirculate like naive lymphocytes. Some effector T cells detect sites of Antigen-receptor binding and co-stimulation ofT cell by dendritic cell dendritic cell T lymphocyte Proliferation and differentiation ofT cell to acquire effector function Antigen-receptor binding and activation of B cell by T cell T lymphocyte B lymphocyte Proliferation and differentiation of B cell to acquire effector function
Principles of innate and adaptive immunity 23 Dendritic cell Macrophag 收静 Fig.1.2 The nting are sho ens,esp been co light m ope (se nd row:th e them to i alize large amountso ca (bottom row).Mature man (N.Rooney (.S.Knight (d and immature tissue dendritic cells that interact with many distinc
Principles of innate and adaptive immunity � =========�==nd =ri=t==� c =ll========�� �� ==========M=a=c=ro=p=ha=g=e========�� ��=========B=I=ym= p= h=oo=�= e========� d e Fig. 1.22 The antigen-presenting cells. The three types of antigen-presenting cells are shown in the form in which they are depicted throughout this book (top row), as they appear in the light microscope (second row; the relevant cell is indicated by an arrow), by transmission electron microscopy (third row) and by scanning electron microscopy (bottom row). Mature dendritic cells are found in lymphoid tissues and are derived from immature tissue dendritic cells that interact with many distinct types of pathogens. Macrophages are specialized to internalize extracellular pathogens, especially after they have been coated with antibody, and to present their antigens. B cells have antigenspecific receptors that enable them to internalize large amounts of specific antigen, process it, and present it. Photographs courtesy of R.M. Steinman (a), N. Rooney (b, c, e, f), S. Knight (d, g), and P.F. Heap (h, i)