Figure 1. Mechanisms of defence against infection. Natural barriers. These stop infectious agents entering the host or provide a hostile environment. Physical barriers to infection include the epithelia of the skin, lung and airways, and the gastro‐intestinal and urogenital tracts. Cells in these barriers may also secrete agents that kill infectious agents. Innate immunity. This is the first form of immunity induced by infectious agents. Cells and molecules such as phagocytes and complement can make rapid responses that may eradicate the infection. Adaptive immunity. Later adaptive responses may be generated if the infectious agent is not killed by innate immunity. Cells and molecules such as lymphocytes and antibodies take longer to become effective, but adaptive immunity can also lead to a state of long‐lasting resistance to re‐infection termed immunological memory (not shown).

Figure 2. Immune recognition. Innate immunity. PRRs directly or indirectly recognize conserved features of infectious agents called PAMPs. PRRs are widely expressed throughout the innate immune system. Adaptive immunity. The two main types of lymphocytes, B cells and T cells, have highly discriminatory receptors for microbial components or antigens, BCRs and TCRs respectively. These recognize antigens in totally different ways. BCRs can be secreted as soluble antibodies and bind to different types of antigen, such as carbohydrates on glycoproteins in their unfolded, native form. In contrast, TCRs generally recognize small peptides, generated by degradation of microbial proteins, in association with specialized presenting molecules (MHC molecules) on the surface of other cells (i.e. as peptide–MHC complexes).

Figure 3. Stages of immunity. Innate and adaptive immunity are closely interlinked. Specialized local (“alarm”) cells of innate immunity can sense the presence of infectious agents. Consequent inflammation enables blood‐borne innate effector cells and molecules to enter the tissue. (a) Dendritic cells (DC) at the site of infection sense the presence of an infectious agent and capture molecules (antigens) from it. (b) They migrate into secondary lymphoid tissues and activate lymphocytes that are specific for the infectious agent. (c) Some lymphocytes then make antibodies that circulate in blood to the site of infection and attack the infectious agent; other lymphocytes enter sites of infection and help or recruit other cells to kill the infectious agent, or directly kill infected cells.

Figure 4. Blood and lymph. Blood transports water, oxygen and small molecules that diffuse into extravascular tissues across endothelial cells of small blood vessels. Blood also carries leukocytes (white blood cells), but these cells, and larger molecules such as antibodies, can only enter tissues in large amounts at inflammatory sites (Figure 3). Extravascular fluid collects into lymphatic vessels and ultimately re‐enters blood. Lymph also transports cells from sites of infection into lymph nodes, enabling adaptive immunity to be triggered (Figure 3).

Figure 5. Primary and secondary lymphoid tissues. (a) Primary lymphoid tissues are sites where lymphocytes are produced. In adult humans and mice the main sites are the bone marrow and the thymus, where B cells and T cells, respectively, undergo most or all of their development. (b) Secondary lymphoid tissues or organs are sites where adaptive responses are induced and regulated. The main tissues are lymph nodes, the spleen and specialized MALTs such as the Peyer's patches in the small intestine. All have highly organized areas containing T cells and B cells. Lymphocytes recirculate between blood and lymph and can monitor different anatomical compartments for infection and mount appropriate responses.

Figure 6. Acute and chronic inflammation. (a) Acute inflammation. Infectious agents such as extracellular bacteria trigger inflammation that starts quickly and lasts a relatively short time. The main features are recruitment of cells and molecules such as neutrophils and complement, and the accumulation of extravascular fluid (oedema). (b) Chronic inflammation. Infectious agents that are not quickly eliminated and which trigger adaptive immune responses can lead to chronic inflammation that can last much longer. The main features are recruitment of blood monocytes, which become macrophages, and activated lymphocytes, especially T cells, and sometimes the development of long‐lasting granulomas.

Figure 7. Haematopoiesis. All blood cells are formed from haematopoietic stem cells. On division they form another stem cell (self renewal) and a more committed precursor for a blood cell. In turn, the CLP gives rise to different types of lymphocyte as well as natural killer (NK) cells, while the CMP can generate monocytes and macrophages, granulocytes, and other cell types. The production of different blood cells is regulated by different growth factors and is largely under feedback control.

Figure 8. Mechanisms of cell‐mediated immunity. There are three main ways in which cells can eliminate infectious agents or protect against infection. (a) Direct killing. Specialized phagocytes, mainly macrophages and neutrophils, can internalize microbes such as bacteria and destroy them intracellularly. (b) Killing of infected cells. NK cells and cytotoxic T cells can kill infected cells, preventing the replication and release of microbes such as viruses. (c) Maintaining natural barriers. Larger parasites, such as intestinal worms, cause damage to the epithelium, risking entry to the body. Cells such as eosinophils can help to repair the damage and, in some cases, may help to expel the organisms or kill it by secreting toxic substances.

Figure 9. Mechanisms of endocytosis. Phagocytosis. Phagocytes can internalize particles such as bacteria into vesicles called phagosomes. Pinocytosis. All cells engulf small quantities of fluids and their dissolved solutes. These are taken up in membrane‐bound vesicles called (primary) endosomes. In all cases, the primary endosomes or phagosomes then fuse with other intracellular vesicles called lysosomes to form secondary endosomes or phagolysosomes in which the internalized contents can be degraded. This can lead to killing of phagocytosed microbes.

Figure 10. Types of macrophages. Macrophages are plastic cells that can develop different specialized functions. Tissue‐resident macrophages are long‐lived cells present in connective tissues. In the steady state they are involved in homeostasis, helping to maintain the architecture of the tissue, and can also sense infectious agents and help to trigger inflammation (e.g. Figure 3). Inflammatory macrophages. Local inflammation recruits blood monocytes into tissues. In response to infectious agents these can become highly secretory cells that produce many innate effectors such as complement components. Activated macrophages. Innate and adaptive responses can help turn macrophages into potent anti‐microbial cells. Alternatively activated macrophages. Macrophages can also develop functions involved in wound repair and healing, and may help to dampen down the inflammation.

Figure 11. Killing by neutrophils. Neutrophils can kill microbes intracellularly and perhaps extracellularly. Intracellular killing. After phagocytosis of microbes the phagosomes fuse with cytoplasmic granules that contain or can produce anti‐microbial agents. The latter include reactive oxygen intermediates and other compounds that may be toxic to the microbes and proteases which may degrade them. Extracellular killing. These cells can also extrude neutrophil extracellular traps (NETs) composed of chromatin that are thought to trap extracellular microbes. The contents of other granules may subsequently discharge to release anti‐microbial agents and proteases to help kill them, although this is not yet proven.

Figure 12. Mediators produced by mast cells. Mast cells are present in all connective tissues. Mast cells have large cytoplasmic granules that store pre‐formed inflammatory mediators such as histamine and cytokines, and which are discharged when the mast cell is activated (degranulation). Activated mast cells also synthesize inflammatory mediators including lipid metabolites and other cytokines when activated. Mast cells can be activated by pathogen molecules or by molecules produced during acute inflammation. They can also be activated during allergic reactions such as hay fever.

Figure 13. Types of granulocytes. Granulocytes are leukocytes that contain different cytoplasmic granules with characteristic staining properties. All can be recruited to different sites of inflammation. Neutrophils are the most abundant leukocytes in blood. Large numbers can be recruited rapidly to sites of acute inflammation (Figure 6) and their production from the bone marrow can be greatly increased during some bacterial infections. They are highly active phagocytes (Figure 11). Eosinophils are normally present in low numbers, but can be recruited particularly into mucosal tissues. Larger numbers can be produced from the bone marrow during other types of infection, especially with large parasites against which they may provide resistance or defence, and in allergic responses such as asthma. Basophils are normally very rare in blood. They, too, can be recruited to inflammatory sites where they typically accompany eosinophils. They have very similar properties to mast cells but their roles in host defence are poorly understood.

Figure 14. Mechanisms of cellular cytotoxicity. NK cells and cytotoxic T cells can kill infected cells by inducing apoptosis in a process called cellular cytotoxicity. Granule‐dependent mechanisms. Pre‐existing (NK cells) or newly generated (CTLs) granules store molecules which can trigger apoptosis. These include perforin that can polymerize to form pores in target cell membranes and enables molecules such as granzymes to enter the cytosol where they trigger apoptosis. Granule‐independent mechanisms. Cytotoxic T cells and NK cells can also express cell surface molecules such as Fas ligand which, when it bind to Fas on the target cell, initiates apoptosis in the target cell.

Figure 15. Different types of T cells. αβ T cells. In humans and mice these are the predominant T cells. They express highly diversified antigen receptors (αβ TCR); they pass repeatedly through all secondary lymphoid tissues (recirculation). γδ T cells. In foetal mice, different waves of non‐conventional T cells with much less diversified antigen receptors (γδ TCR) populate epithelia; they are produced before αβ T cells. NKT cells. These are very specialized T cells that represent another developmental pathway. Some invariant NKT (iNKT) cells express αβ TCR, but with very little diversity.

Figure 16. Subsets of conventional αβ T cells. Two main αβ T cell subsets are produced in the thymus: CD4 and CD8 T cells. Each can acquire specialized (polarized) functions during immune responses. CD4 T cells. These may develop into T _h1, T _h2 or T _h17 cells depending on the type of infection. They regulate the functions of other cell types or help to recruit and orchestrate different effector mechanisms, some of which are indicated. CD4 T cells can also develop into T _reg cells that can suppress immune responses. CD8 T cells. These cells can develop into cytotoxic cells (CTLs) and may also adopt polarized functions somewhat resembling those of CD4 T cells although these are less well understood.

Figure 17. Different types of B cells. Different types of B cell develop during foetal and neonatal life (cf. Figure 15 for T cells). All can develop into plasma cells and make antibodies. They may respond to different types of antigen. Follicular B cells. The predominant, conventional, B cells in humans and mice have highly diversified antigen receptors (BCRs) and pass repeatedly through all secondary lymphoid tissues (recirculation). B‐1 cells. In mice, non‐conventional B cells with much less diversified BCRs populate the peritoneal and pleural cavities; they are first produced before conventional B cells. Marginal zone B cells. These are sessile cells in splenic marginal zone that represent an alternative pathway of development to follicular B cells.

Figure 18. Effector and memory lymphocyte responses. Primary responses. In response to a new infection, effector lymphocytes are produced after a lag (when the cells are being activated and expanded) and their numbers slowly decrease as the microbe is cleared. A population of memory lymphocytes then appears and persists, often for a lifetime. Secondary responses. If the same infection occurs again, memory lymphocytes can rapidly develop into effector cells and help to clear the infection more efficiently. They then revert back to memory cells (or are replaced by new ones) and can respond again similarly if the infection happens at any time in the future. These principles apply for both T cell and B cell responses. The efficiency of secondary responses is seen even more clearly in antibody responses, since more appropriate types of antibodies of higher affinity can be produced, compared to those secreted in a primary response (not shown; see Chapter 6.)

Figure 19. Functions of “classical” dendritic cells. Classical DCs are found in nearly all peripheral tissues; in skin epidermis they are called Langerhans cells. (1) When infection occurs, these cells internalize and degrade microbial antigens to forms that can be recognized by T cells (peptide–MHC complexes). (2) Sensing of the pathogen through PRRs also causes them to increase expression of specialized costimulatory molecules that are needed to activate T cells. (3) They then migrate into secondary lymphoid tissues (e.g. from skin to draining lymph nodes via afferent lymph). (4) These migratory DCs can now activate antigen‐specific T cells, triggering adaptive immunity. Lymph nodes additionally contain a distinct population of resident DCs that play less understood roles in T cell activation or regulation than the migratory DCs.

Figure 20. Examples of molecules involved in immune responses. Recognition of infectious agents. PRRs are expressed by many different types of cell, particularly innate cells, and enable them to recognize different classes of infectious agent. Antigen receptors (TCRs and BCRs) are expressed only by lymphocytes and enable them to recognize specific components of infectious agents. Endocytic receptors. These facilitate uptake of molecules and particles which are sometimes coated with other immune components (e.g. antibodies or complement). Communication molecules. Cytokine receptors bind cytokines that are produced by the same or other cells and change cellular functions. Some cytokines, called chemokines, generally alter cell migration after binding to chemokine receptors. Cell‐positioning molecules. These are needed for cells to migrate to and from normal or inflamed tissues, or to adhere to and communicate with other cells. Signalling molecules. Binding of ligands to receptors typically triggers biochemical cascades within the cell involving intracellular signalling molecules. These form pathways that ultimately change the behaviour of the cell (e.g. movement) or change gene expression so the cell can acquire new roles in immunity.

Figure 21. The “post code” principle for leukocyte extravasation. Leukocytes from blood must enter specific tissues and organs (extravasation) to mount immune responses during infection (peripheral tissues in innate responses and secondary lymphoid tissues in adaptive responses). The combination of different types of molecule expressed by vascular endothelial cells resembles a post code (ZIP code) that can be read by the leukocyte. (1) Selectins. Selectins, through weak binding to their carbohydrate ligands, mediate transient attachment and rolling of leukocytes along the endothelium. (2) Chemokine receptors. Chemokines produced at sites of inflammation are transported across the endothelium to the luminal side where they are displayed for recognition by leukocytes with corresponding receptors. (3) Integrins. Intracellular signalling from chemokine receptors leads to activation of integrins, which can now bind strongly to counter‐receptors on the endothelial cells, leading to firm attachment. (4) Molecules involved in transmigration. Other types of molecule (not shown) enable the leukocyte to cross between or directly through the endothelial cells to enter extravascular tissues.

Figure 22. Types and locations of pattern recognition receptors. PRRs are localized in different cellular compartments. Widely expressed components of different classes of infectious agent act as agonists for different PRRs and stimulate different cellular responses (e.g. phagocytosis, degranulation, cytokine secretion). Plasma membrane PRRs. These PRRs include some TLRs, C‐type lectin receptors and scavenger receptors. Typically they are involved responses to bacteria, fungi or protozoa. Endosomal PRRs. Some TLRs are expressed on endosomal membranes. Typically they respond to nucleic acids (RNA, DNA) from viruses and bacteria. Cytoplasmic PRRs. These include RNA helicases, which for example recognize nucleic acids of viruses, and NOD‐like receptors which recognize components of bacteria that may have escaped into the cytoplasm. Many PRRs signal to the nucleus to change gene expression, but others modulate other cell functions by acting on cytoplasmic components (such as actin, leading to changes in cell shape (not shown).

Figure 23. Rearrangement of antigen receptor genes. BCRs and TCRs are comprised of two different molecules – immunoglobulin (Ig) heavy (H) and light (L) chains, and TCR α and β chains respectively. Each chain consists of variable and constant regions. Each chain is encoded in a particular region (locus) of a different chromosome but, in germline DNA, the receptor genes are not present as functional genes. In lymphocytes, functional antigen receptor genes are assembled by rearrangement of gene segments. IgH and TCR β genes. There are three groups of gene segments: V, D and J in the variable region locus. Largely at random, one D segment joins to one J segment and the DJ segment then joins to a V segment. This encodes the variable (V) region of the IgH chain or the TCR β chain respectively. IgL and TCR α genes. A similar principle applies but D segments are absent. One V segment joins to one J segment, and the assembled VJ segment encodes the V region of the IgL chain or the TCR a chain. C (constant) region segments. Downstream of the V, D and/or J segments, there are one or more C region segments. The newly assembled VDJ or VJ segments become juxtaposed to the closest C region segment and a functional gene is created. In the case of the IgH locus there are several different C regions enabling different types of BCR to be assembled with the same V region; these can be secreted as antibodies with different corresponding functions but with the same antigen specificity.

Figure 24. Functions of B cell antigen receptors. All B cells express membrane‐bound BCRs. Antigen recognition. BCRs recognize structural features on antigens known as conformational determinants or B cell epitopes. These are three‐dimensional surfaces of folded microbial proteins, carbohydrates or glycolipids, for example. Intracellular signalling. BCRs are associated with a molecular complex, CD79, which triggers intracellular signalling following antigen recognition. These signals can help to activate a naïve B cell, after which it may develop into a plasma cell that secretes its BCRs as antibodies. Antigen internalization. Antigens bound to BCRs can be internalized and degraded. Peptides from protein antigens can be expressed as peptide–MHC complexes at the cell surface, enabling T cells to recognize the B cells and change their functions (e.g. to instruct them to make different types of antibodies).

Figure 25. Structure and function of T cell receptors. Conventional T cells express plasma membrane αβ TCRs; these are structurally related to immunoglobulin molecules, but functionally very different. Antigen recognition. αβ TCRs do not recognize whole proteins. Small peptides are produced by degradation of microbial proteins present in different cellular components. These peptides then bind to MHC molecules that transport them to the cell surface. Conventional αβ TCRs can then recognize these peptide–MHC complexes (but not either alone). The peptide represents a sequential determinant or (in association with an MHC molecule) a T cell epitope. Intracellular signalling. TCRs are associated with a molecular complex, CD3, which triggers intracellular signalling when TCR recognition occurs. These signals, to which CD8 molecules (or CD4 molecules; not shown) also contribute, represent signal 1 that is necessary for T cell responses to occur, but which is usually not alone sufficient for naïve T cells to become activated.

Figure 26. Costimulation of lymphocytes. For naïve T and B cells, antigen recognition through TCRs and BCRs respectively (Signal 1), is not normally sufficient to induce full activation. Instead, they need additional signals (Signal 2) to provide costimulation. For T cells the most important are provided when B7 molecules (CD80, 86), typically expressed by activated DCs, bind to CD28 on T cells; additional signals can be provided by CD40 and CD40 ligand interactions. For B cells, binding of CD40 ligand on activated CD4 T cells to CD40 on the B cell is one of the most important for production of antibodies against protein antigens; other signals that are delivered when an activated complement component binds to a complex containing CD19 greatly enhance B cell responses. Cells that do not receive sufficient costimulation do not undergo full activation and may become unresponsive (anergy) or die. This can result in antigen‐specific unresponsiveness and tolerance.

Figure 27. Types of classical MHC molecules. Classical MHC molecules bind peptides and these complexes are recognized by “conventional” αβ T cells. MHC class I molecules contain a heavy chain, non‐covalently associated with an invariant molecule, β ₂‐microglobulin. In contrast, MHC class II molecules are heterodimers composed of α and β chains (not to be confused with the molecules that comprise the TCRs). Both types of classical MHC molecules contain an antigen‐binding groove that can potentially bind many different peptides (one at a time). They are also highly polymorphic, differing from each other mostly in the amino acid residues that form the antigen‐binding groove which thus determine the precise nature of the peptides that can be bound.

Figure 28. Antigen recognition by CD4 and CD8 T cells. Conventional αβ T cells express either CD4 or CD8. CD4 T cells recognize peptide–MHC class II complexes. Their CD4 molecules bind to conserved regions of MHC class II molecules, helping their TCRs to recognize peptide–MHC class II complexes. The peptides bound to MHC class II molecules are derived from “exogenous” antigens from the extracellular milieu (e.g. microbial components that have been endocytosed). Only a few specialized cell types express MHC class II molecules constitutively. Activated CD4 T cells are often known as helper T cells. CD8 T cells recognize peptide–MHC class I molecules. The CD8 molecules bind to conserved regions of MHC class I molecules and perform an analogous function to CD4 molecules (Section 5.3.4) in permitting T cell recognition. However peptides bound to MHC class I molecules are typically derived from “endogenous” antigens from the intracellular milieu (e.g. components of infecting viruses in the cytoplasm). Almost all cell types express MHC class I molecules. Fully activated CD8 T cells are generally known as cytotoxic T lymphocytes (CTLs).

Figure 29. Examples of cytokine functions. All immune (and many other) cell types can produce cytokines, which represent the main method of communication between cells that are not in direct contact with each other. Cytokines are proteins that act on other cells to alter their properties and functions. They can act on the cell that produces them (autocrine), on local cells (paracrine) or distantly (systemically – endocrine). They can be involved in activation or inhibition of cell functions. Some general functions of cytokines that play particularly important roles in innate and adaptive immunity or which help link these two arms are indicated. These are, however, gross over‐simplifications. Not shown is another class of specialized cytokines, chemokines, that play important roles in regulating cell migration and localization, and which can be produced by all cell types indicated.

Figure 30. Activation and functions of complement. The complement system comprises many different proteins, some of which form a proteolytic cascade that becomes activated during innate and adaptive responses. Complement can be activated by three different routes. Typically the lectin pathway is triggered directly by some microbial structures, the classical pathway is triggered by some types of antibodies, and the alternative pathway acts as an amplification loop for the former two. Convergence at C3. Activation of complement by any of these pathways leads to activation of the central C3 component, after which the pathways are identical. Functions of complement. Complement activation has four main outcomes. (i) Binding of complement components to the surface of microbes can opsonize them, promoting phagocytosis via complement receptors. (ii) Small complement fragments help to trigger local inflammatory responses. (iii). Activation can help to solubilize or eliminate large antibody–antigen immune complexes. (iv). The late complement components can assemble into pores in microbial membranes and (in some cases) kill them.

Figure 31. Some functions of antibodies. Antibodies are of different classes: IgD, IgM, IgG, IgA and IgE. These all comprise the typical immunoglobulin monomer (a “Y”‐shaped molecule), but in some cases they can form multimers, particularly IgA and IgM. Some classes, such as some types of IgG, are important opsonins, binding to microbes and targetting them to phagocytes through specific FcRs. Several classes, such as IgA in the gut, can bind to microbes and inhibit their attachment to host cells; by thus preventing infection they neutralize the microbe. Particular classes, including IgM, are very efficient at activating complement, thus indirectly leading to opsonization or inflammatory responses (mediated by activated complement components).

Figure 32. An example of an intracellular signalling pathway. A number of cytokine receptors signal through the JAK–STAT pathway. These receptors are associated with tyrosine kinases called JAKs. Binding of a cytokine leads to dimerization of the receptors and juxtaposition of the JAKs which phosphorylate and activate each other. This enables STATs to bind (they have SH2 domains which recognize phosphorylated tyrosines). The JAKs phosphorylate the STATs, which then translocate as a dimer to the nucleus, bind DNA and act as transcription factors to change gene expression. This is a very simple signalling pathway that does not involve other molecules as adaptors or scaffolds to help link or localize different components of the pathway.

Figure 33. Some mechanisms of tolerance induction. As B cells and T cells generate their respective antigen receptors largely at random (Figure 23) many have a high risk of recognizing components of the host itself (e.g. structural components of tissues or other cells of the body) – such receptors are termed autoreactive. Generally speaking, during lymphocyte development, cells with autoreactive receptors are killed through the induction of apoptosis (clonal deletion) or rendered unresponsive (anergy). Both apply to B cells developing in the bone marrow; the former particularly applies to T cells developing in the thymus. In addition, B cells can try to make another receptor that is not autoreactive (receptor editing). The remaining cells mature, expressing receptors are generally not able to recognize self components – hence they are tolerant – but they can potentially recognize foreign antigens should they be encountered in the future.

Figure 34. Infection, disease and tissue damage. (1) In healthy (normal) individuals with functional immunity, many non‐pathogenic microbes are eliminated without causing disease, subclinically. (2) In immunodeficient individuals these same microbes may cause disease (Section 6.3). (3) In normal individuals infected with some pathogenic microbes, secretion of toxic molecules or other mechanisms can cause disease. (4) In some normal individuals, the immune response to the microbe is the actual cause of clinical disease – collateral damage.

Figure 35. Autoimmune diseases and immune‐related sensitivities. Disease can result from activation of adaptive immune responses against otherwise harmless (“intrinsic”) components of the body itself or against non‐infectious (“extrinsic”) foreign agents from the environment. The effector mechanisms causing the tissue damage may be mediated by antibodies of different types, large immune complexes, T cells that aberrantly activate macrophages or cytotoxic T cells, or a combination of these. Symptoms can be mild (e.g. skin rashes) to life‐threatening (e.g. anaphylaxis following a wasp sting in a sensitized individual). The clinical pattern of disease usually reflects the distribution of the antigen being recognized and may be localized to particular organs or become widespread throughout the body (systemic).

Figure 36. Alloreactivity. Transplants between non‐identical members of the same species (allografts) are rejected with surprising vigour because a very high frequency of T cells from any individual can recognize MHC molecules of a genetically different (allogeneic) individual. This very high frequency represents cross‐reactive recognition; a T cell that can potentially recognize a foreign (e.g. microbial) peptide bound to a self peptide–MHC may also recognize an allogeneic MHC molecule(s) binding a different peptide(s).

Figure 37. Immune evasion by tumours. Malignant tumours (cancers) are clones of cells that have very high mutation rates. This means that many of them will express mutant proteins that can give rise to peptides not present in normal cells, which may be potentially antigenic. These peptides may induce an adaptive response to the tumour. The high mutation rate also means that new tumour variants are continually forming and, inevitably, some of these will be able to evade or avoid the immune response. (They may, for example, lose a tumour antigen, decrease MHC expression, secrete anti‐inflammatory cytokines or induce regulatory instead of effector T cells). These mutant subclones will have a selective advantage and will outgrow the parental clone. Thus, over time the tumour will develop multiple means of avoiding the immune response and a cancer may develop. This is a good example of Darwinian selection in action within an individual organism.

Figure 38. Resistance to infection. Resistance to infection can be acquired passively or actively, through natural or artificial means. For example, passive immunity may be acquired naturally by a foetus or neonate through transfer of maternal antibodies across the placenta or in milk. It may also be delivered artificially, such as by giving pooled human immunoglobulin to antibody‐deficient patients. Active immunity generally follows naturally after recovery from an infection. It may also be stimulated artificially during vaccination with a vaccine designed to induce a protective response.

Figure 39. Therapeutic antibodies. The development of monoclonal antibody technology has enabled the production of large quantities of homogenous antibodies with a defined antigenic specificity that can be used therapeutically to treat human disease. A major problem with such antibodies is that they are foreign proteins (they are typically produced in mice). The immune responses induced against them (e.g. the production of anti‐antibodies) can lead to their very rapid destruction. To avoid this, genetic engineering has been used to create antibodies in which the only non‐human parts are the hypervariable regions that form the antigen‐binding site itself and hence are much less immunogenic. These can be used, for example, to block the activity of pro‐inflammatory cytokines such as TNF‐α in some autoimmune diseases, or to target molecules expressed selectively by tumour cells in certain cancers.