The immune system 1

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7.2 Humoral immunity58
7.3 Cellular immunity61
7.4 Other components of the immune response63

Self-assessment: questions65
Self-assessment: answers67

7.1. Natural defences and immunity

Learning objectives
You should:

• distinguish innate from adaptive immunity
• name the cells important in innate and adaptive immunity and their main properties
• describe the morphological organisation of the immune system
• discuss the principles of specificity, memory, diversity and self-recognition.
The human body is constantly bombarded from the outside world by potentially harmful substances and microorganisms. To protect ourselves against these insults, we have evolved a sophisticated defence system composed of a complex web of cells and chemical mediators that interact to produce an integrated response. The defences can be divided into two main types:

• innate immunity – which has a general protective effect against a wide range of potential insults
• adaptive immunity – which is specific for particular foreign substances and microorganisms.
Together, the two arms of the immune system use a wide variety of different methods to distinguish between the components of the body, or ‘self’, from foreign invaders, or ‘non-self’. Non-self includes unacceptable changes within the body, such as a normal cell becoming neoplastic.
Many different cells take part in host defence; some are involved only in adaptive immune reactions whereas others play a part in innate immunity as well. The characteristics of some of these cells are discussed further in Chapter 9

Innate immunity

Natural (innate) immunity arose early in evolution. It is conferred by physical barriers and cellular responses that are not specific against any one particular insult, but provide an effective first line of defence. The most important types are give below.

Mechanical barriers

The intact skin and mucosal surfaces provide a physical barrier to microorganisms and foreign substances. Tight junctions between the cells and the continuous basement membrane are important components. The keratinised surface of the skin is particularly tough; only a minority of microorganisms can breach intact skin.

Secretion

The acidity of the gastric and vaginal secretions creates a hostile microenvironment which kills many organisms. Lysozyme, found in tears, has an antibacterial action. Paneth cells in the intestine secrete antibacterial proteins called defensins when stimulated by the presence of bacteria. Activation of the complement cascade by the alternative and mannose-binding lectin (MBL) pathways are also part of innate immunity (see Ch. 5).

Secretion and excretion currents

The flow of urine regularly flushes away any bacteria that ascend the urethra, helping to keep the bladder sterile. Bronchial mucus is constantly swept towards the pharynx, carrying with it any contaminating bacteria; when it reaches the pharynx it is coughed out or swallowed into the acid environment of the stomach. Tears have an analogous effect. Stasis of the normal flow of secretions or excretions is a potent cause of infection.

Phagocytes

Although neutrophils and macrophages participate in adaptive immune reactions and their activity is greatly enhanced when stimulated by specific immune responses, they have phagocytic and antimicrobial properties independent of the adaptive immune system. Thus, neutrophils and macrophages also contribute to innate immunity.

Mast cells and eosinophils

Like neutrophils and macrophages, mast cells and eosinophils participate in adaptive immune responses. However, they can also act independently of adaptive immunity. Mast cells (and the closely related basophils) release histamine, cytokines and other substances from their granules when stimulated, promoting inflammation (see Table 13, Ch. 8). Eosinophils secrete a range of substances that are toxic to microorganisms. The actions of mast cells and eosinophils seem to be particularly involved in defence against parasites, but they have other defensive roles and are also involved in allergic reactions.

Natural killer cells

Natural killer (NK) cells are lymphocytes that have the ability to lyse host cells, in particular virally infected cells and neoplastic cells. In this respect, they form part of innate immunity. In addition, NK cells take part in adaptive immunity by their ability to lyse cells opsonised with IgG (antibody-dependent cell-mediated cytotoxicity, see Section 7.4).

Pattern-recognition receptors

These receptors are found on many cells of the immune system and recognise a wide range of molecules found on bacteria, viruses and fungi. They represent a type of host defence found not only in animals but also in bacteria and plants. Binding of a pattern-recognition receptor triggers a response in an effector cell. An important group of pattern-recognition receptors comprises the toll-like receptors. For example, toll-like receptor 1 (TLR1) is expressed on macrophages, dendritic cells and B cells, and recognises a kind of lipopeptide found in bacteria.

Adaptive immunity

Adaptive immunity is specific to the foreign substance which invokes it and becomes quicker and more intense with subsequent exposure to it. Thus the adaptive immune response ‘remembers’ previous challenges with the same substance and can mount a heightened and more rapid response. Adaptive immunity is only seen in higher vertebrates such as mammals.

Cells of the adaptive immune system

Central to the adaptive immune response are two types of lymphocyte, called B cells and T cells. Both these cell types possess membrane receptors which can bind to foreign material (antigen). This triggers a series of intracellular events in the lymphocyte which leads to its activation, multiplication and enhanced ability to destroy or neutralise the antigen. By definition, adaptive immunity (as opposed to innate immunity) involves the antigen-specific receptors on B cells and T cells.
Both types of lymphocyte are derived from precursor cells in the bone marrow. B cell maturation occurs in the bone marrow itself, whereas T cells migrate to the thymus for maturation. B and T cells have distinct functions, but they are interdependent and rely on cooperation with each other and other cells of the immune system.

B cells

The B cell surface receptor is a type of antibody molecule, namely monomeric IgM. When the appropriate antigen binds to the receptor, the B cell is activated. It multiplies and the offspring ultimately mature into plasma cells, which synthesise and secrete large amounts of antibody into the extracellular fluid; this antibody has the same specificity as the B cell receptor, allowing disposal of the antigen that stimulated it. This process is known as humoral immunity; it is especially important in defence against extracellular bacteria.

T cells

These have a surface antigen recognition system known as the T cell receptor, which is similar to the antibody molecule. There are discrete subsets of T cells which, when triggered by antigen-receptor binding, have functions as diverse as killing cells, coordinating B and T cell responses and stopping the immune response. T cells are particularly involved with the immune response to intracellular organisms (e.g. viruses and certain bacteria such as Mycobacterium tuberculosis). This process is known as cellular immunity.

Organisation of the adaptive immune system

In order to optimise the combined functions of surveillance of the body’s tissues for antigen and production of a coordinated immune response, the cells of the adaptive immune response are organised into structured lymphoid tissues, namely lymph nodes, thymus, mucosa-associated lymphoid tissue and spleen. Lymphocytes are also found in the bone marrow.
The bone marrow and the thymus are sometimes known as primary lymphoid organs, where lymphocytes are produced and mature (B cells in bone marrow, T cells in thymus), whereas the peripheral lymph nodes and other lymphoid sites are called secondary organs, where lymphocytes live and recognise antigens and initiate the immune response. The spleen is primarily involved in clearing the blood of unwanted antigens, while the lymph nodes are responsible for clearing the lymphatic fluid. The mucosal surfaces represent potential portals of entry for microbes, and the mucosa-associated lymphoid tissue forms an important part of the body’s defences. This lymphoid tissue is often concentrated into distinct structures such as the tonsils in the throat, the Peyer patches in the intestine, and the lymphoid tissue of the appendix.

Properties of the immune response

Specificity

The response is specific. Most antigens are foreign macromolecules or microbes that are made up of large numbers of differently shaped structural components (usually proteins or carbohydrates). Some of these components will be recognised by a receptor on the membrane of a restricted number of lymphocytes. Only these few lymphocytes can, therefore, initially respond to the foreign substance. The smallest components recognisable by B cell and T cell receptors are called epitopes or determinants. Some molecules (haptens) are too small to be recognised by themselves, but will be recognised if they are bound to a larger molecule.

Memory

The immune response has memory. Exposure to a previously encountered antigen results in a quicker and larger response. This is, at least in part, through the generation of memory cells during the first challenge with antigen. Memory cells are long-lived cells that have the antigen receptor on their surface and on a subsequent occasion can proliferate quickly to mount a response.

Diversity

The response is diverse. The number of different antigen-specific lymphocytes is vast. We have millions of lymphocytes, each bearing a receptor recognising a slightly different shaped or structured antigenic determinant. When exposed to a particular antigen, e.g. a bacterium, the lymphocyte with the appropriate receptor is selected from this vast available pool and stimulated to multiply. This process is called clonal selection.
The diversity of the system results from the variability in the structure of the lymphocyte surface receptor. The basic structure of the T cell receptor and the immunoglobulin molecule are similar, both being members of the immunoglobulin ‘superfamily’. The enormous diversity of B cell and T cell receptors is due to random rearrangement of a small number of genes within the cell allowing the generation of many different receptors. The result is considerable diversity in the variable region of the antibody molecules and T cell receptors. Molecular techniques such as Southern blot analysis (see Ch. 2) have shown that the portions of DNA containing the immunoglobulin gene are of a different size in B cells and cells that do not produce antibody. This can be explained by the genes being far apart in ‘ordinary’ cells, but close together in B cells. Therefore, B cells must be able to rearrange these genes during their development. This is done in a precise order (e.g. the first rearrangement involves the heavy chains).

Recognition of self

The immune system can distinguish between self and non-self. Thus, under normal circumstances, lymphocytes recognise and respond to molecules that they perceive as foreign but apparently ignore the millions of potential antigens present in normal human tissues and organs. This non-response to our own tissues by our own lymphocytes is known as tolerance and is partly achieved by the early deletion (by apoptosis) of potentially self-reacting cells. If cells reacting with self escape from these control measures, autoimmune disease occurs and our own tissues are damaged and destroyed (see Ch. 8).

7.2. Humoral immunity

Learning objectives
You should:

• describe the humoral immune reaction and the role of antigen-presenting cells
• describe the structure and function of immunoglobulin
• name the classes of immunoglobulin and state their distinguishing properties.

The B cell response

Antibodies are synthesised by B cells; they are then either secreted into the tissue fluids for combination with antigen or are inserted into the B cell membrane to act as receptors. If a human is exposed to an antigen, a number of B cells may each recognise a different epitope of the antigen by means of their surface antibody (immunoglobulin) receptors. The proliferation of different B cells with different antibodies being produced by the resultant plasma cells is called a polyclonal response.

Antibody structure

The basic structure of an antibody is shown in Figure 18. In its simplest form, an antibody is composed of two identical light chains and two identical heavy chains. The molecular weight is about 150 000. The light chains are joined to the heavy chains and the heavy chains to each other by covalent disulphide bonds. Overall, the antibody molecule has a ‘Y’ shape, with movement of the arms possible at the hinge. Light chains and heavy chains can be further subdivided into domains, each approximately 110 amino acid residues long. There are four domains per heavy chain and two per light chain. The amino acid sequence in the N-terminal domain of both the light and heavy chains is very variable – the so-called variable region – and it is here that antigen binding occurs. The remaining domains are relatively constant. The different types of immunoglobulin are classified according the Fc region, which is responsible for the actions of the antibody. For example, IgG and IgM opsonise bacteria to which they are bound (because phagocytes have receptors for IgG and IgM Fc regions), and IgE uses its Fc portion to attach to the surface of mast cells and basophils. There are different classes of antibody, which have different functions (Table 9), but they all are based on the simple prototype.
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Table 9 Classes and functions of antibodies
Antibody class Functions
IgM First class of antibody, produced before IgG supervenes
Pentamer with 10 antigen-binding sites Intravascular: cannot cross placenta
Activates complement and agglutinates foreign substances
IgG Four subclasses
Can attach to phagocytic cells via Fc fragment (opsonisation)
Found in tissues and can cross placenta
Activates complement
IgA Main antibody in secretions and excretions and in urine and gut contents
Two subclasses: can dimerise (molecular weight 320 000) and has an additional secretory piece – this prevents digestion