Figure 1. Surface areas of skin and mucosal tissues. Mucosal tissues have many times the surface area of the skin. In adult humans the respiratory tract has a surface area of roughly the size of a tennis court and the gastro‐intestinal (G‐I) tract of a football pitch. These surfaces are also much thinner, often only one cell thick. It is not surprising that most infections start at mucosal surfaces.

Figure 2. Structure of skin showing defence barriers. The epidermis varies in thickness in different parts of the body, but is always several cells thick and the outer layers are always keratinized, forming a mechanical barrier to infection. Sebaceous glands discharge their contents, including anti‐microbial molecules, into the hair follicle and thence onto the surface of the skin. Both the epidermis and the dermis contain classical dendritic cells (DCs), Langerhans cells and dermal dendritic cells, respectively involved in the initiation of adaptive immunity. The dermis also contains macrophages and mast cells that can sense infectious agents that have breached the outermost layers.

Figure 3. Mucosal tissues I: respiratory tract. The upper respiratory tract (trachea and bronchi) is lined by ciliated epithelial cells – the cilia beat coherently to move secretions towards the mouth. The alveoli, where gas exchange occurs, are lined by flat, squamous epithelium. They contain alveolar macrophages that may have a defence function, but also clear inhaled particles. Other cells in the alveoli secrete molecules such as surfactants which are lubricants but may also have anti‐microbial effects, acting as pattern‐recognition receptors (PRRs), see Chapter . Some IgA may be produced as natural antibodies before adaptive immunity is triggered and may help to provide an extra layer of defence against infection of the epithelia.

Figure 4. Mucosal tissues II: intestine. The intestine is lined by a single layer of epithelial cells. In the small intestine villi and crypts are present. The large intestine has a smooth surface, but contains many deep tubular glands. Within the epithelium, goblet cells secrete mucus that is a lubricant, but also has mechanical barrier functions. In the crypts of the small intestine, specialized Paneth cells secrete a variety of anti‐microbial peptides such as defensins. The lamina propria of the intestine contains macrophages and mucosal mast cells, classical DCs, usually eosinophils (not shown), and plasma cells that typically secrete IgA that is transported into the lumen. Peristalsis serves to propel the intestinal contents towards the anus.

Figure 5. Acute inflammation in the skin. Acute inflammation induces vascular changes: dilatation of arterioles and venules and increased permeability of venules. This increases overall blood flow to the area, but also slows the flow in venules, increasing the probability of leukocytes attaching to the endothelium. Changes in the expression of venule adhesion molecules permit the recruitment of neutrophils and monocytes into the inflamed tissue. The increased permeability, due to gaps forming between endothelial cells, permits exudation of water and solutes including macromolecules such as antibodies and complement. The water causes swelling – oedema, one of the main features of acute inflammation; another is often pain.

Figure 6. Initiation of acute inflammation. Acute inflammation can be induced by sterile trauma or infection. Sterile trauma involving damage to blood vessels activates blood platelets and the coagulation cascade. It may also damage mast cells. All of these can release mediators (some examples are shown) that induce the vascular changes typical of acute inflammation. In infections, alarm cells such as epithelia, macrophages and mast cells can recognize pathogens via pattern recognition receptors (PRRs) which stimulate the release of inflammatory mediators. The skin and gut are illustrated, but these principles apply to epithelial tissues in general.

Figure 7. Vascular changes in acute inflammation. Inflammatory mediators such as histamine act on venule smooth muscle to cause dilatation, leading to slowing of blood flow. Mediators also act on endothelial cells, leading to the breakdown of tight junctions – forming gaps that permit the exudation of blood plasma containing macromolecules such as antibodies, complement and coagulation factors. Changes in adhesion molecule expression also lead to leukocyte recruitment (see Figure 8).

Figure 8. Leukocyte recruitment in acute inflammation. (1) Leukocytes, particularly neutrophils, use selectins to form loose adhesions to carbohydrate ligands on venule endothelium and they roll along the endothelium. (2) This permits them to interact with chemokines bound to endothelial surface molecules. (3) The chemokines stimulate neutrophil integrins to increase their affinity, permitting strong adhesion to their ligands on the endothelium. (4) Neutrophils migrate to junctions between endothelial cells and cross the endothelium into extravascular tissues. (5) Chemotactic factors then draw the neutrophils to the site of infection. The underlying alarm cells are responsible for producing the chemokines and inducing the endothelial ligands (vascular addressins) in this process.

Figure 9. Leukocyte function in inflammation. In acute inflammation caused by pyogenic bacteria, neutrophils are the most important bactericidal cells. Recruited (inflammatory) macrophages are important in removing the damaged tissues and regulating the healing response. In chronic inflammation, recruited (activated) macrophages are crucial for killing intracellular bacteria such as mycobacteria following their activation interferon (IFN)‐γ from NK cells or T cells. Macrophages also both cause tissue damage and are responsible for regulating healing and repair.

Figure 10. Systemic effects of inflammation. Cells in inflamed tissues release pro‐inflammatory mediators into the blood. These can act on distant organs such as the brain to cause fever, malaise and loss of appetite, and on the liver to increase synthesis of defence‐related proteins such as complement components. They also act on the bone marrow to cause release of stored leukocytes and to increase the production of leukocytes from stem cells. They act on muscle and adipose tissue to increase catabolism, generating energy. The latter is crucial; to increase body temperature by only 1 °C requires as much energy as an adult walking 35–40 km.

Figure 11. Healing of a sterile wound. (1) A blood clot forms at the site of the wound. Local inflammation stimulates the activity of macrophages to release growth factors for fibroblasts, as do activated platelets in the clot. (2) These factors induce the recruitment and division of the fibroblasts and stimulate them to make collagen and other connective tissue molecules. (3) Other factors stimulate the in‐growth of blood and lymphatic vessels (angiogenesis). (4) Epithelial cells divide to cover the wound and eventually the site of the wound is represented by a small, collagenous scar.

Figure 12. Healing of an infected wound. If a wound is infected by pyogenic bacteria there is increased local inflammation and increased recruitment of neutrophils. (2) This may lead to increased tissue liquefaction and the formation of pus. (3) The healing process is delayed, there is increased collagen formation and increased scarring. (cf. Figure 11.

Figure 13. Disease caused by an excessive healing response – cirrhosis. If the liver suffers long‐term damage (e.g. from chronic infection with hepatitis viruses or excessive alcohol consumption), there is a continual healing response with large‐scale deposition of collagen. The collagen surrounds and encloses groups of regenerating hepatocytes, preventing them from restoring normal cell numbers and function. The end result is a shrunken, fibrotic liver that cannot function effectively, leading to liver failure.

Figure 14. Anatomical organization of innate and adaptive immune systems. Alarm cells of the innate system are widely dispersed throughout the body. Their local activation by infection serves to recruit effector cells and molecules to the site of infection. The adaptive system is based largely in secondary lymphoid tissues that are relatively distant from the site of initial infection. Antigens from the infecting organisms (typically carried by DCs) and signals from the innate system are transported into the secondary lymphoid organs to initiate and regulate the adaptive response. Effector mechanisms such as antibodies and activated T cells can then be transported or migrate back to the inflamed site of infection to mediate elimination of the microbe.

Figure 15. Tissue monitoring in adaptive immunity. Most peripheral tissues and solid organs are monitored by lymph nodes which are connected to these sites by afferent lymphatics. The blood is monitored by the spleen. The intestine and some other mucosal tissues have secondary lymphoid organs embedded in their walls that monitor the lumen; in the small intestine these are Peyer's patches. Theses tissues also drain to lymph nodes. Naïve lymphocytes continually migrate to, and recirculate between all these secondary lymphoid organs, monitoring them for the presence of microbial and other antigens.

Figure 16. Lymph node structure. Lymph nodes receive lymph from peripheral tissues through several afferent lymphatics that drain into the subcapsular sinus. Cells and molecules in the lymph are delivered to different specialized areas of the node. Cortical B cell follicles contain recirculating B cells and resident follicular dendritic cells (FDCs). The paracortex contains recirculating T cells and classical DCs, some of which have entered from the lymph. This area also contains high endothelial venules (HEV) which are the sites where recirculating T and B cells enter from the blood. The medulla contains sinuses that are lined with macrophages which have a filtering function. Lymph leaves the node via the efferent lymphatic(s) and is eventually drained back into the blood.

Figure 17. High‐endothelial venules. These post‐capillary venules have cuboidal endothelial cells that express adhesion molecules complementary to lymphocyte surface molecules, permitting lymphocytes to attach and migrate between the endothelial cells into the node. HEVs are present in lymph nodes and mucosal secondary lymphoid tissues such as Peyer's patches, but not the spleen. HEVs are very efficient, extracting around 30% of lymphocytes that enter a node from the arterial blood during each passage through it.

Figure 18. Cellular and molecular streams in a lymph node (steady state). Afferent lymph brings soluble molecules and migratory DCs from peripheral tissues into the node. The DCs enter the T cell paracortex and molecules are delivered to different areas of the nodes. Naïve B and T cells enter the paracortex from the blood via HEVs (not shown). T cells interact with DCs in the paracortex and then leave via efferent lymph. B cells migrate to the follicle before they too enter efferent lymph and thence back to the blood (not shown). The continuous passage of lymphocytes into and out of lymph nodes and other secondary lymphoid tissues is known as lymphocyte recirculation.

Figure 19. Antigen delivery to lymph nodes. Antigens in peripheral tissues may be acquired by classical DCs and be transported by them to T cell areas in the node. Soluble antigens enter via afferent lymph and some enter connective tissue conduits which penetrate both B cell follicles and T cell areas. Resident DCs in the T cell areas can acquire antigens from the conduits. The functions of these different forms of antigen delivery are not yet fully understood (see Box 3.3 How DC Activate T cells in Lymph Nodes of Mice ).

Figure 20. Lymphocyte recruitment. Naïve B and T cells are continually entering lymph nodes from the blood. If a B or T cell does not recognize antigen in the node it leaves again after a few hours. If, however, antigen is recognized, the lymphocyte is retained in the node and may become activated. This recruitment of lymphocytes from the recirculating pool represents a method of rapidly increasing the numbers of antigen‐specific lymphocytes at the secondary lymphoid tissue where they are needed to make a response. After activation, the clones of antigen‐specific lymphocytes are expanded rapidly by proliferation (clonal expansion).

Figure 21. Influences on naïve CD4 T cell differentiation. A naïve T cell, when activated, can adopt one of several distinct differentiation pathways, and which pathway is adopted depends on external signals received by the T cell in the node. Signals, which could be cell‐bound or soluble, may derive from a number of different sources. Migrating DCs are a major source of such signals, but the roles of other potential sources are not well‐understood; some of these potential sources are illustrated.

Figure 22. Migration of activated CD4 T cells. Some activated CD4 T cells migrate to B cell follicles and help B cells generate antibody responses. Others remain in the T cell area and give help to CD8 T cells. Some effector CD4 T cells leave the node in efferent lymph and enter the blood from where they migrate to peripheral sites of inflammation. Here, depending on how they have differentiated, they may activate cells such as macrophages or help to recruit the different types of granulocyte needed to deal with different types of infection.

Figure 23. T cell‐dependent B cell activation. (1) Following antigen presentation by DCs in the T cell area, (2) activated CD4 T cells migrate to the edge of B cell follicles and (3) interact with antigen‐specific B cells. (4) The B T cells migrate into the follicles, and the B cell starts to divide, forming a germinal centre. (5) Activated B lymphoblasts leave the germinal centre – some become plasma cells, secreting antibody either in the medulla of the node itself (these tend to be short‐lived cells) (6a) or after migration to other sites such as spleen and bone marrow (bone marrow plasma cells may be very long‐lived) (6b). Other activated B cells do not become plasma cells, but differentiate to become memory cells.

Figure 24. Germinal centres. Germinal centres form in B cell follicles during TD antibody responses. They consist of dark areas where B cell are dividing very rapidly and undergoing somatic hypermutation, and light areas where B cell undergo isotype switching. B cells migrate between the two areas. FDCs serve as antigen repositories for the differentiating B cells to help select those of higher affinity for the antigen.

Figure 25. Peyer's patches. Peyer's patches are secondary lymphoid organs present in the wall of the small intestine, related structures are present in some other mucosal tissues. They do not possess afferent lymphatics. Instead, antigen is transported from the intestinal lumen by specialized epithelial cells called M cells. DCs and other cells lie under the M cells and acquire antigens from them. Peyer's patches contain B and T cell areas where these cells can be activated. The activated lymphocytes then leave the patches via efferent lymph and pass through mesenteric lymph nodes before eventually entering the blood. B cells activated in Peyer's patches usually switch to producing IgA and migrate to many mucosal tissues. Peyer's patches are particularly involved in IgA responses to intestinal antigens.

Figure 26. Spleen. The spleen is a secondary lymphoid organ monitoring blood‐borne antigens. The white pulp is the lymphoid area, containing T and B cell areas as in other tissues. It also possesses a marginal zone that contains specialized macrophages and resident, non‐recirculating B cells that respond to TI antigens. The red pulp of the spleen contains plasma cells, but also macrophages that are involved in housekeeping functions such as the removal of old RBCs. In some circumstances the spleen may become a primary haematopoietic organ (Section 5.1).

Figure 27. Haematopoiesis. In adult mammals, the bone marrow is the major haematopoietic organ. Multipotent (pluripotent) stem cells divide to give another stem cell and a differentiating precursor cell which becomes committed to one of several lineages. Common lymphoid precursors (CLP) give rise to B and T cells, as well as NK cells and some DCs. The common myeloid precursor (CMP) gives rise to all the other leukocytes including monocytes and macrophages, different types of granulocytes, other DCs but not megakaryocytes (the source of platelets) and erythrocytes. For simplicity, mast cells are shown as being myeloid cells, although they may develop from a distinct progenitor.

Figure 28. Thymus. The thymus is the organ in which T cells differentiate. Early T cell precursors enter from the bone marrow and divide to populate the thymic cortex with thymocytes. If a thymocyte recognizes MHC molecules on cortical epithelial cells it survives (positive selection); otherwise it undergoes apoptosis. Surviving thymocytes enter the medulla and those that recognize self peptides on medullary epithelial cells (MECs) or DCs apoptose (negative selection). The surviving thymocytes leave the thymus and become peripheral T cells. Positive and negative selection respectively ensure that TCRs recognize antigens appropriately (peptides bound to MHC molecules, rather than either alone) and are generally unable to recognize normal cells (i.e. are not autoreactive).