Cells of the immune system

Immune responses are mediated by a variety of cells and the soluble molecules that these cells secrete (Fig. 1.1). Although the leukocytes are central to all immune responses, other cells in the tissues also participate, by signaling to the lymphocytes and responding to the cytokines (soluble intercellular signaling molecules) released by T cells and macrophages.

Fig. 1.1 Components of the immune system

The principal cells of the immune system and the mediators they produce are shown. Neutrophils, eosinophils, and basophils are collectively known as polymorphonuclear granulocytes (see Chapter 2). Cytotoxic cells include cytotoxic T lymphocytes (CTLs), natural killer (NK) cells (large granular lymphocytes [LGLs]), and eosinophils. Complement is made primarily by the liver, though there is some synthesis by mononuclear phagocytes. Note that each cell produces and secretes only a particular set of cytokines or inflammatory mediators.

Phagocytes internalize antigens and pathogens, and break them down

The most important long-lived phagocytic cells belong to the mononuclear phagocyte lineage. These cells are all derived from bone marrow stem cells, and their function is to engulf particles, including infectious agents, internalize them and destroy them. To do so, mononuclear phagocytes have surface receptors that allow them to recognize and bind to a wide variety of microbial macromolecules. They can then internalize and kill the micro-organism (Fig. 1.2). The process of phagocytosis describes the internalization (endocytosis) of large particles or microbes. The primitive responses of phagocytes are highly effective, and people with genetic defects in phagocytic cells often succumb to infections in infancy.

Fig. 1.2 Phagocytes internalize and kill invading organisms

Electron micrograph of a phagocyte from a tunicate (sea squirt) that has endocytosed three bacteria (B). (N, nucleus.)

(Courtesy of Dr AF Rowley.)

To intercept pathogens, mononuclear phagocytes are strategically placed where they will encounter them. For example, the Kupffer cells of the liver line the sinusoids along which blood flows, while the synovial A cells line the synovial cavity (Fig. 1.3).

Fig. 1.3 Cells of the mononuclear phagocyte lineage

Many organs contain cells belonging to the mononuclear phagocyte lineage. These cells are derived from blood monocytes and ultimately from stem cells in the bone marrow.

Leukocytes of the mononuclear phagocyte lineage are called monocytes. These cells migrate from the blood into the tissues, where they develop into tissue macrophages.

Polymorphonuclear neutrophils (often just called neutrophils or PMNs) are another important group of phagocytes. Neutrophils constitute the majority of the blood leukocytes and develop from the same early precursors as monocytes and macrophages. Like monocytes, neutrophils migrate into tissues, particularly at sites of inflammation, However, neutrophils are short-lived cells that phagocytose material, destroy it, and then die within a few days.

B cells and T cells are responsible for the specific recognition of antigens

Adaptive immune responses are mediated by a specialized group of leukocytes, the lymphocytes, which include T and B lymphocytes (T cells and B cells) that specifically recognize foreign material or antigens. All lymphocytes are derived from bone marrow stem cells, but T cells then develop in the thymus, while B cells develop in the bone marrow (in adult mammals).

These two classes of lymphocytes carry out very different protective functions:

• B cells are responsible for the production of antibodies that act against extracellular pathogens

• T cells are mainly concerned with cellular immune responses to intracellular pathogens, such as viruses. They also regulate the responses of B cells and the overall immune response.

B cells express specific antigen receptors (immunoglobulin molecules) on their cell surface during their development and, when mature, secrete soluble immunoglobulin molecules (also known as antibodies) into the extracellular fluids. Each B cell is genetically programmed to express a surface receptor which is specific for a particular antigen. If a B cell binds to its specific antigen, it will multiply and differentiate into plasma cells, which produce large amounts of the antibody, but in a secreted form.

Secreted antibody molecules are large glycoproteins found in the blood and tissue fluids. Because secreted antibody molecules are a soluble version of the original receptor molecule (antibody), they bind to the same antigen that initially activated the B cells. Antibodies are an essential component of an immune response, and, when bound to their cognate antigens, they help phagocytes to take up antigens, a process called opsonization (from the Latin, opsono, ‘to prepare victuals for’).

There are several different types of T cell, and they have a variety of functions (Fig 1.4):

• one group interacts with mononuclear phagocytes and helps them destroy intracellular pathogens – these are called type 1 helper T cells or TH1 cells;

• another group interacts with B cells and helps them to divide, differentiate, and make antibody – these are the type 2 helper T cells or TH2 cells;

• a third group of T cells is responsible for the destruction of host cells that have become infected by viruses or other intracellular pathogens – this kind of action is called cytotoxicity and these T cells are therefore called cytotoxic T lymphocytes (CTLs or TC cells).

Fig. 1.4 Functions of different types of lymphocyte

Macrophages present antigen to TH1 cells, which then activate the macrophages to destroy phagocytosed pathogens. B cells present antigen to TH2 cells, which activate the B cells, causing them to divide and differentiate. Cytotoxic T lymphocytes (CTLs) and large granular lymphocytes (LGLs) recognize and destroy virally infected cells.

A fourth group of T-cells, regulatory T cells or Tregs, help to control the development of immune responses, and limit reactions against self tissues.

In every case, the T cells recognize antigens present on the surface of other cells using a specific receptor – the T cell antigen receptor (TCR) – which is quite distinct from, but related in structure to, the antigen receptor (antibody) on B cells. T cells generate their effects either by releasing soluble proteins, called cytokines, which signal to other cells, or by direct cell–cell interactions.

Soluble mediators of immunity

A wide variety of molecules are involved in the development of immune responses, including antibodies, opsonins and complement system molecules. The serum concentration of a number of these proteins increases rapidly during infection and they are therefore called acute phase proteins.

One example of an acute phase protein is C reactive protein (CRP), so-called because of its ability to bind to the C protein of pneumococci; it promotes the uptake of pneumococci by phagocytes. Molecules such as antibody and CRP that promote phagocytosis are said to act as opsonins.

Another important group of molecules that can act as opsonins are components of the complement system.

Complement proteins mediate phagocytosis, control inflammation and interact with antibodies in immune defense

The complement system, a key component of innate immunity, is a group of about 20 serum proteins whose overall function is the control of inflammation (Fig. 1.5). The components interact with each other, and with other elements of the immune system. For example:

• a number of microorganisms spontaneously activate the complement system, via the so-called ‘alternative pathway’, which is an innate immune defense – this results in the microorganism being opsonized (i.e. coated by complement molecules, leading to its uptake by phagocytes);

• the complement system can also be activated by antibodies or by mannose binding lectin bound to the pathogen surface via the ‘classical pathway’.

Fig. 1.5 Functions of complement

Components of the complement system can lyse many bacterial species (1). Complement fragments released in this reaction attract phagocytes to the site of the reaction (2). Complement components opsonize the bacteria for phagocytosis (3). In addition to the responses shown here, activation of the complement system increases blood flow and vascular permeability at the site of activation. Activated components can also induce the release of inflammatory mediators from mast cells.

Complement activation is a cascade reaction, where one component acts enzymatically on the next component in the cascade to generate an enzyme, which mediates the following step in the reaction sequence, and so on. (The blood clotting system also works as an enzyme cascade.)

Activation of the complement system generates protein molecules or peptide fragments, which have the following effects:

• opsonization of microorganisms for uptake by phagocytes and eventual intracellular killing;

• attraction of phagocytes to sites of infection (chemotaxis);

• increased blood flow to the site of activation and increased permeability of capillaries to plasma molecules;

• damage to plasma membranes on cells, Gram-negative bacteria, enveloped viruses, or other organisms that have caused complement activation. This can result in lysis of the cell or virus and so reduce the infection;

• release of inflammatory mediators from mast cells.

Cytokines signal between lymphocytes, phagocytes and other cells of the body

Cytokine is the general term for a large group of secreted molecules involved in signaling between cells during immune responses. All cytokines are proteins or glycoproteins. The different cytokines fall into a number of categories, and the principal subgroups of cytokines are outlined below.

Interferons (IFNs) are cytokines that are particularly important in limiting the spread of certain viral infections:

• one group of interferons (IFNα and IFNβ or type-1 interferons) is produced by cells that have become infected by a virus;

• another type, IFNγ, is released by activated TH1 cells.

IFNs induce a state of antiviral resistance in uninfected cells (Fig. 1.6). They are produced very early in infection and are important in delaying the spread of a virus until the adaptive immune response has developed.

Fig. 1.6 Interferons

Host cells that have been infected by virus secrete interferon-α (IFNα) and/or interferon-β (IFNβ). TH1 cells secrete interferon-γ (IFNγ) after activation by antigen. IFNs act on other host cells to induce resistance to viral infection. IFNγ has many other effects as well.

The interleukins (ILs) are a large group of cytokines produced mainly by T cells, though some are also produced by mononuclear phagocytes or by tissue cells. They have a variety of functions. Many interleukins cause other cells to divide and differentiate.

Colony stimulating factors (CSFs) are cytokines primarily involved in directing the division and differentiation of bone marrow stem cells, and the precursors of blood leukocytes. The CSFs partially control how many leukocytes of each type are released from the bone marrow. Some CSFs also promote subsequent differentiation of cells. For example, macrophage CSF (M-CSF) promotes the development of monocytes in bone marrow and macrophages in tissues.

Chemokines are a large group of chemotactic cytokines that direct the movement of leukocytes around the body, from the blood stream into the tissues and to the appropriate location within each tissue. Some chemokines also activate cells to carry out particular functions.

Tumor necrosis factors, TNFα and TNFβ, have a variety of functions, but are particularly important in mediating inflammation and cytotoxic reactions.

Transforming growth factors (e.g. TGFβ) are important in controlling cell division and tissue repair.

Each set of cells releases a particular blend of cytokines, depending on the type of cell and whether, and how, it has been activated. For example:

• TH1 cells release one set of cytokines, which promote TH1 cell interactions with mononuclear phagocytes;

• TH2 cells release a different set of cytokines, which activate B cells.

Some cytokines may be produced by all T cells, and some just by a specific subset.

Equally important is the expression of cytokine receptors. Only a cell that has the appropriate receptors can respond to a particular cytokine. For example the receptors for interferons are present on all nucleated cells in the body whereas other receptors are much more restricted in their distribution. In general, cytokine receptors are specific for their own individual cytokine, but this is not always so. In particular, many chemokine receptors respond to several different chemokines.

Effective immune responses vary depending on the pathogen

The primary function of the immune system is to prevent entry of and/or to eliminate infectious agents and minimize the damage they cause, ensuring that most infections in normal individuals are short-lived and leave little permanent damage. Pathogens, however come in many different forms, with various modes of transmission and reproductive cycles, so the immune system has evolved different ways of responding to each of them.

The exterior defenses of the body (Fig. 1.7) present an effective barrier to most organisms. Very few infectious agents can penetrate intact skin. In contrast, many infectious agents gain access to the body across the epithelia of the gastrointestinal or urogenital tracts; others, such as the virus responsible for the common cold, infect the respiratory epithelium of nasopharynx and lung; a small number of infectious agents infect the body only if they enter the blood directly (e.g. malaria and sleeping sickness).

Fig. 1.7 Exterior defenses

Most infectious agents are prevented from entering the body by physical and biochemical barriers. The body tolerates a number of commensal organisms, which compete effectively with many potential pathogens.

Once inside the body, the site of the infection and the nature of the pathogen largely determine which type of immune response will be induced – most importantly (Fig. 1.8) whether the pathogen is:

Fig. 1.8 Intracellular and extracellular pathogens

All infectious agents spread to infect new cells by passing through the body fluids or tissues. Many are intracellular pathogens and must infect cells of the body to divide and reproduce (e.g. viruses such as influenza viruses and malaria, which has two separate phases of division, either in cells of the liver or in erythrocytes). The mycobacteria that cause tuberculosis can divide outside cells or within macrophages. Some bacteria (e.g. streptococci, which produce sore throats and wound infections) generally divide outside cells and are therefore extracellular pathogens.

Many bacteria and larger parasites live in tissues, body fluids, or other extracellular spaces, and are susceptible to the multitude of immune defenses, such as antibodies (see Chapter 3) and complement (see Chapter 4), that are present in these areas. Because these components are present in the tissue fluids of the body (the ‘humors’ of ancient medicine), they have been classically referred to as humoral immunity.

Many organisms (e.g. viruses, some bacteria, some parasites) evade these formidable defenses by being intracellular pathogens and replicating within host cells. To clear these infections, the immune system has developed ways to specifically recognize and destroy infected cells. This is largely the job of cell-mediated immunity.

Intracellular pathogens cannot, however, wholly evade the extracellular defenses (see Fig. 1.8) because they must reach their host cells by moving through the blood and tissue fluids. As a result they are susceptible to humoral immunity during this portion of their life cycle.

Any immune response involves:

Innate immune responses are the same on each encounter with antigen

Broadly speaking, immune responses fall into two categories – those that become more powerful following repeated encounters with the same antigen (adaptive immune responses) and those that do not become more powerful following repeated encounters with the same antigen (innate immune responses).

Innate immune responses (see Chapters 6 and 7) can be thought of as simple though remarkably sophisticated systems present in all animals that are the first line of defense against pathogens and allow a rapid response to invasion.

Innate immune response systems range from external barriers (skin, mucous membranes, cilia, secretions, and tissue fluids containing antimicrobial agents; see Fig. 1.7) to sophisticated receptors capable of recognizing broad classes of pathogenic organisms, for example:

The innate defenses are closely interlinked with adaptive responses.

Adaptive immune responses display specificity and memory

In contrast to the innate immune response, which recognizes common molecular patterns (PAMPs), the adaptive immune system takes a highly discriminatory approach, with a very large repertoire of specific antigen receptors that can recognize virtually any component of a foreign invader (see Chapters 3 and 5). This use of highly specific antigen receptor molecules provides the following advantages:

These features underlie the phenomenon of specific immunity (e.g. diseases such as measles and diphtheria induce adaptive immune responses that generate life-long immunity).

Specific immunity can, very often, be induced by artificial means, allowing the development of vaccines (see Chapter 18).

Antigens initiate and direct adaptive immune responses

The immune system has evolved to recognize antigens, destroy them, and eliminate the source of their production – when antigen is eliminated, immune responses switch off.

Both T cell receptors and immunoglobulin molecules (antibodies) bind to their cognate antigens with a high degree of specificity. These two types of receptor molecules have striking structural relationships and are closely related evolutionarily, but bind to very different types of antigens and carry out quite different biological functions.

Antibody specifically binds to antigen

Soluble antibodies are a group of serum molecules closely related to and derived from the antigen receptors on B cells. All antibodies have the same basic Y-shaped structure, with two regions (variable regions) at the tips of the Y that bind to antigen. The stem of the Y is referred to as the constant region and is not involved in antigen binding (see Chapter 3).

The two variable regions contain identical antigen-binding sites that, in general, are specific for only one type of antigen. The amino acid sequences of the variable regions of different antibodies, however, vary greatly between different antibodies. The antibody molecules in the body therefore provide an extremely large repertoire of antigen-binding sites. The way in which this great diversity of antibody variable regions is generated is explained in Chapter 3.

Each antibody binds to a restricted part of the antigen called an epitope

Pathogens typically have many different antigens on their surface. Each antibody binds to an epitope, which is a restricted part of the antigen. A particular antigen can have several different epitopes or repeated epitopes (Fig. 1.9). Antibodies are specific for the epitopes rather than the whole antigen molecule.

Fig. 1.9 Antigens and epitopes

Antibodies recognize molecular shapes (epitopes) on the surface of antigens. Each antigen (Ag1, Ag2, Ag3) may have several epitopes recognized by different antibodies. Some antigens have repeated epitopes (Ag3).

Q. Many evolutionarily related proteins have conserved amino acid sequences. What consequences might this have in terms of the antigenicity of these proteins?

A. Related proteins (with a high degree of sequence similarity) may contain the same epitopes and therefore be recognized by the same antibodies.

Fc regions of antibodies act as adapters to link phagocytes to pathogens

The constant region of the antibody (the Fc region) can bind to Fc receptors on phagocytes, so acting as an adapter between the phagocyte and the pathogen (Fig. 1.10). Consequently, if antibody binds to a pathogen, it can link to a phagocyte and promote phagocytosis. The process in which specific binding of an antibody activates an innate immune defense (phagocytosis) is an important example of collaboration between the innate and adaptive immune responses.

Fig. 1.10 Antibody acts as an adapter that links a microbe to a phagocyte

The antibody binds to a region of an antigen (an epitope) on the microbe surface, using one of its antigen-binding sites. These sites are in the Fab regions of the antibody. The stem of the antibody, the Fc region, can attach to receptors on the surface of the phagocytes.

Other molecules (such as activated complement proteins) can also enhance phagocytosis when bound to microbial surfaces.

Binding and phagocytosis are most effective when more than one type of adapter molecule (opsonin) is present (Fig. 1.11). Note that antibody can act as an adapter in many other circumstances, not just phagocytosis.

Fig. 1.11 Opsonization

Phagocytes have some intrinsic ability to bind to bacteria and other microorganisms (1). This is much enhanced if the bacteria have been opsonized by complement C3b (2) or antibody (3), each of which cross-link the bacteria to receptors on the phagocyte. Antibody can also activate complement, and if antibody and C3b both opsonize the bacteria, binding is greatly enhanced (4).

Peptides from intracellular pathogens are displayed on the surface of infected cells

Antibodies patrol only extracellular spaces and so only recognize and target extracellular pathogens. Intracellular pathogens (such as viruses) can escape antibody-mediated responses once they are safely ensconced within a host cell. The adaptive immune system has therefore evolved a specific method of displaying portions of virtually all cell proteins on the surface of each nucleated cell in the body so they can be recognized by T cells.

For example, a cell infected with a virus will present fragments of viral proteins (peptides) on its surface that are recognizable by T cells. The antigenic peptides are transported to the cell surface and presented to the T cells by MHC molecules (a group of molecules encoded with the Major Histocompatibility Complex, see Chapter 5). T cells use their antigen-specific receptors (T cell receptors – TCRs) to recognize the antigenic peptide–MHC molecule complex (Fig. 1.12).

Fig. 1.12 T cell recognition of antigen

MHC molecules transport peptides to the surface of an infected cell where they are presented to T cells, which may recognize the MHC–peptide combination. If a cell is infected, MHC molecules present peptides derived from the pathogen, as well as the cell’s own proteins.

T cell responses require proper presentation of antigen by MHC molecules (antigen presentation). To activate T cell responses this must occur on the surface of specialized antigen-presenting cells (APCs), which internalize antigens by phagocytosis or endocytosis. Several different types of leukocyte can act as APCs, including dendritic cells, macrophages, and B cells.

APCs not only display antigenic peptide–MHC complexes on their surface, but also express co-stimulatory molecules that are essential for initiating immune responses (see Chapter 8). Co-stimulatory signals are upregulated by the presence of pathogens, which can be detected by the engagement of innate immune receptors that recognize PAMPs.

Most immune responses to infectious organisms are made up of a variety of innate and adaptive components:

The two major phases of any immune response are antigen recognition and a reaction to eradicate the antigen.

Antigen activates specific clones of lymphocytes

In adaptive immune responses, lymphocytes are responsible for immune recognition, and this is achieved by clonal selection. Each lymphocyte is genetically programmed to be capable of recognizing just one particular antigen. However, the immune system as a whole can specifically recognize many thousands of antigens, so the lymphocytes that recognize any particular antigen are only a tiny proportion of the total.

How then is an adequate immune response to an infectious agent generated? The answer is that, when an antigen binds to the few lymphocytes that can recognize it, they are induced to proliferate rapidly. Within a few days there is a sufficient number to mount an adequate immune response. In other words, the antigen selects and activates the specific clones to which it binds (Fig. 1.13), a process called clonal selection. This operates for both B cells and T cells.

Fig. 1.13 B cell clonal selection

Each B cell expresses just one antibody (i.e. with specificity for a single particular antigen), which it uses as its antigen receptor. Antigen binds only to those B cells with the specific antibody (number 2 in this example), driving these cells to divide and differentiate into plasma cells and memory cells, all having the same specificity as the original B cell. Thus an antigen selects just the clones of B cells that can react against it.

How can the immune system ‘know’ which specific antibodies will be needed during an individual’s lifetime? It does not know. The immune system generates antibodies (and T cell receptors) that can recognize an enormous range of antigens even before it encounters them. Many of these specificities, which are generated more or less at random (see Chapters 3 and 5), will never be called upon to protect the individual against infection.

Lymphocytes that have been stimulated, by binding to their specific antigen, take the first steps towards cell division. They:

Even when the infection has been overcome, some of the newly produced lymphocytes remain, available for restimulation if the antigen is ever encountered again. These cells are called memory cells, because they are generated by past encounters with particular antigens. Memory cells confer lasting immunity to a particular pathogen.

Antigen elimination involves effector systems

There are numerous ways in which the immune system can destroy pathogens, each being suited to a given type of infection at a particular stage of its life cycle. These defense mechanisms are often referred to as effector systems.

Phagocytosis is promoted by opsonins

More often antibody activates complement or acts as an opsonin to promote ingestion by phagocytes. Phagocytes that have bound to an opsonized microbe, engulf it by extending pseudopodia around it. These fuse and the microorganism is internalized (endocytosed) in a phagosome. Granules and lysosomes fuse with the phagosome, pouring enzymes into the resulting phagolysosome, to digest the contents (Fig. 1.14).

Fig. 1.14 Phagocytosis

Phagocytes attach to microorganisms using cell surface receptors for microbial products or via antibody or complement C3b. Pseudopods extend around the microorganism and fuse to form a phagosome. Killing mechanisms are activated and lysosomes fuse with the phagosomes, releasing digestive enzymes that break down the microbe. Undigested microbial products may be released to the outside.

Phagocytes have several ways of dealing with internalized opsonized microbes in phagosomes. For example:

• macrophages reduce molecular oxygen to form microbicidal reactive oxygen intermediates (ROIs), which are secreted into the phagosome;

• neutrophils contain lactoferrin, which chelates iron and prevents some bacteria from obtaining this vital nutrient.

Termination of immune responses limits damage to host tissues

Although it is important to initiate immune responses quickly, it is also critical to terminate them appropriately once the threat has ended.

To clear the offending pathogen immune responses are often massive, with:

These responses, if left unchecked, can also damage host tissues.

A number of mechanisms are employed to dampen or terminate immune responses. One is a passive process – that is, simple clearance of antigen should lead to a diminution of immune responses.

Antigen elimination can be a slow process, however, so the immune system also employs a variety of active mechanisms to downregulate responses, as discussed in Chapter 11.

Immune responses to extracellular and intracellular pathogens differ

In dealing with extracellular pathogens, the immune system aims to destroy the pathogen itself and neutralize its products.

In dealing with intracellular pathogens, the immune system has two options:

Because many pathogens have both intracellular and extracellular phases of infection, different mechanisms are usually effective at different times. For example, the polio virus travels from the gut, through the blood stream to infect nerve cells in the spinal cord. Antibody is particularly effective at blocking the early phase of infection while the virus is in the blood stream, but to clear an established infection CTLs must kill any cell that has become infected.

Consequently, antibody is important in limiting the spread of infection and preventing reinfection with the same virus, while CTLs are essential to deal with infected cells (Fig. 1.15). These factors play an important part in the development of effective vaccines.

Fig. 1.15 Reaction to extracellular and intracellular pathogens

Different immunological systems are effective against different types of infection, here illustrated as a virus infection. Antibodies and complement can block the extracellular phase of the life cycle and promote phagocytosis of the virus. Interferons produced by infected cells signal to uninfected cells to induce a state of antiviral resistance. Viruses can multiply only within living cells; cytotoxic T lymphocytes (CTLs) recognize and destroy the infected cells.

Leukocytes enter inflamed tissue by crossing venular endothelium

The process of leukocyte migration is controlled by chemokines (a particular class of cytokines) on the surface of venular endothelium in inflamed tissues. Chemokines activate the circulating leukocytes causing them to bind to the endothelium and initiate migration across the endothelium (Fig. 1.17).

Fig. 1.17 Three phases in neutrophil migration across endothelium

A neutrophil adheres to the endothelium in a venule (1). It extends its pseudopodium between the endothelial cells and migrates towards the basement membrane (2). After the neutrophil has crossed into the tissue, the endothelium reseals behind (3). The entire process is referred to as diapedesis.

(Courtesy of Dr I Jovis.)

Once in the tissues, the leukocytes migrate towards the site of infection by a process of chemical attraction known as chemotaxis. For example, phagocytes will actively migrate up concentration gradients of certain (chemotactic) molecules.

A particularly active chemotactic molecule is C5a, which is a fragment of one of the complement components (Fig. 1.18) that attracts both neutrophils and monocytes. When purified C5a is applied to the base of a blister in vivo, neutrophils can be seen sticking to the endothelium of nearby venules shortly afterwards. The cells then squeeze between the endothelial cells and move through the basement membrane of the microvessels to reach the tissues. This process is described more fully in Chapter 6.

Fig. 1.18 Chemotaxis

At a site of inflammation, tissue damage and complement activation cause the release of chemotactic peptides (e.g. chemokines and C5a), which diffuse to the adjoining venules and signal to circulating phagocytes. Activated cells migrate across the vessel wall and move up a concentration gradient of chemotactic molecules towards the site of inflammation.

Inappropriate reaction to self antigens – autoimmunity

Normally the immune system recognizes all foreign antigens and reacts against them, while recognizing the body’s own tissues as ‘self’ and making no reaction against them. The mechanisms by which this discrimination between ‘self’ and ‘non-self’ is established are described in Chapter 19.

When the immune system reacts against ‘self’ components, the result is an autoimmune disease (see Chapter 20), for example rheumatoid arthritis or pernicious anemia.

Ineffective immune response – immunodeficiency

If any elements of the immune system are defective, the individual may not be able to fight infections adequately, resulting in immunodeficiency. Some immunodeficiency conditions:

Overactive immune response – hypersensitivity

Sometimes immune reactions are out of all proportion to the damage that may be caused by a pathogen. The immune system may also mount a reaction to a harmless antigen, such as a food molecule. Such immune reactions (hypersensitivity) may cause more damage than the pathogen or antigen (see Chapters 23–26). For example, molecules on the surface of pollen grains are recognized as antigens by particular individuals, leading to the symptoms of hay fever or asthma.