Our bodies are constantly exposed to bacteria, fungi, and parasites. Many of these organisms are capable of causing severe disease should they be allowed access to the deeper tissues.

The simplest way for an organism to avoid infection or invasion by a foreign antigen is to prevent entry being gained into their body in the first place. Humans are no exception. In humans, the major physical barrier of defence is the skin, which, when intact, is virtually impermeable to most infectious agents (Roitt 1994). In addition, a large variety of microorganisms cannot survive long on the skin due to the low pH which results from the presence of lactic acid, and fatty acids in the sweat (Abbas et al. 1997).

Mucous secreted by the membranes lining the inner surfaces of the body acts as a protective barrier that blocks the adhesion of bacteria to epithelial cells. Other microbes become trapped in the mucous and are removed via the mechanical action of coughing, sneezing, or swallowing (Roitt 1994).

Many secreted body fluids contain bactericidal components such as acid in gastric juice, spermine and zinc in semen, and lactoperoxide in milk. The washing action of tears and saliva which both contain lysozyme is also a barrier to microbial invasion (Youmans 1980). Finally, the normal bacterial flora of the body acts as a form of microbial antagonism, which is effective in suppressing the growth of many pathologic bacteria and fungi (Sommers 1980).

Although all of the components of the immune system must function in a multifactorial interactive process in order to function effectively, the most crucial cell types involved are the leukocytes or white blood cells (WBCs), which form the mobile foot soldiers of the immune system (Fig. 15.1). Leukocytes normally account for about 1% of total blood volume. In normal circumstances the WBC number between 4000 and 11 000 per cubic millimetre of blood, with an average of 7000 (Marieb 1995; Guyton & Hall 1996).

Figure 15.1 The different types of white blood cells or leukocytes.

Leukocytes are grouped into two major categories, granulocytes and agranulocytes, based on their structural and chemical properties. Granulocytes contain highly specialised cytoplasmic granules. Agranulocytes lack any obvious intercellular granules. Granulocytes include neutrophils, basophils, and eosinophils. Agranulocytes include the T and B lymphocytes and non-T and non-B lymphocytes.

Neutrophils, or polymorphonuclear leukocytes, are derived from pleuripotent haematopoietic stem cells and eventually differentiate from myeloid cells in the bone marrow. Neutrophils are short-lived cells with a lifespan of hours to days, but are present in large numbers in the bone marrow, peripheral blood, and marginal pool, which is a reserve of cells adherent to the walls of postcapillary venules. These cells are crucial to the host defence against bacteria and some fungi. Neutrophils and monocytes can move from the bloodstream into the tissues by a process called diapedesis. In this process the leukocytes squeeze through tiny pores in the vessel walls by assuming the size and shape of the pores. Once in the tissues the cells move around by amoeboid-like motion (Guyton & Hall 1996).

Neutrophils become phagocytic upon encountering bacteria and bacterial killing is promoted by a process called respiratory burst, in which oxygen is metabolised to produce hydrogen peroxide, an oxidising, bleach-like substance which kills bacteria. Neutrophils can become actively phagocytic immediately upon confrontation with an antigen and do not have to experience a period of maturation as do other cells like monocytes which need to undergo activation processes to eventually mature into macrophages.

Eosinophils are filled with large, course granules that contain a variety of unique digestive enzymes. These cells exhibit chemotaxis to the sites of basophil and mast cell activation but are weak phagocytes for pathogens. These cells are mainly involved in attacking parasitic organisms too large to be phagocytised and are also probably involved in the deactivation of inflammatory substances released by mast cells and basophils to prevent widespread activity of these agents to other tissues not involved.

Basophils are the rarest white blood cells. They are morphologically very similar to the large mast cells that inhabit tissues exposed to the outside environment such as nasal passages and the lungs. Their cytoplasm contains large cytoplasmic granules containing histamine, heparin, bradykinin, slow-reacting substance of anaphylaxis, and serotonin. Histamine is an inflammatory chemical that acts as a vasodilator, which makes blood vessels ‘leaky’ and also attracts other WBC to the site of injury or inflammation. Heparin is a substance that reduces the ability of blood to clot.

The agranulocytes, as stated above, include lymphocytes and monocytes. Monocytes are only agranulocytic before they mature to macrophages and become granulocytic in nature.

Monocytes are derived from myeloid precursor cells in the bone marrow, which migrate through the circulation to the tissues where they mature as macrophages. Monocytes have very little contribution to immunity until they have matured into macrophages. Often, in people who are actively fighting a serious infection, the numbers of monocytes in the blood will increase but have little involvement in the immunological processes until they are activated and mature into macrophages. Macrophages are highly mobile and are actively phagocytic. These cells have lifespans ranging from months to years depending on how often and to what severity they are called upon to fight antigens (Guyton & Hall 1996). These cells have three important immunological roles:

The macrophages are particularly concentrated in the lung and the liver where they are referred to as Kupffer cells, and the lining of the spleen sinusoids and lymph node medullary sinuses. They also occur in large concentrations in the glomerulus of the kidney where they are referred to as mesangial cells, in the brain where they are known as the microglial cells, and in bone where they form the class of cells called osteoclasts which engulf components of bone in the remodelling process.

When neutrophils and macrophages attack pathogens a number of them are also killed in the battle. The resulting necrotic tissue, dead macrophages, dead neutrophils, and tissue-fluid accumulation due to the process of inflammation, results in an interesting mixture referred to as pus. Generally, after a few days the pus is reabsorbed by the surrounding tissues and most of the evidence that it ever existed disappears. Occasionally, this process does not occur, and a pus-filled cavity called an abscess may form that needs to be mechanically drained before healing can occur.

Lymphocytes are the primary cells of the cellular immune response. These cells originally derive from pluripotent stem cells in the bone marrow and eventually differentiate into T cells, B cells, non-T cells, and non-B cells in the various lymphoid tissues of the body. Lymphocytes develop in the thymus and populate the germinal centres in the lymph nodes and spleen. Although there are large numbers of lymphocytes in the body very few are present normally in the peripheral blood. Usually the only lymphocytes present in the blood are those travelling to a specific lymphoid tissue or those travelling to the site of an infection. About 80% of the lymphocytes present in peripheral blood are T cells, which have many important functions including (Simon 1991):

There are three major populations of T cells that are antigen-bearing: helper T cells, cytotoxic T cells, and suppressor T cells. Both the helper and suppressor T cells are involved in the regulation aspect of the immune response, mainly the initiation and termination, respectively. Recent understanding of the structural differences in the membrane glycoproteins of these cells has led to a new classification system. CD4 or T4 cells express a specific glycoprotein structural receptor on their membranes specific for primary helper T cells. Two classes of helper T cells have also been distinguished and are referred to as Th1 and Th2 classes. These cells show different levels of activation and cytokine production that regulates the shift between cellular and humeral immunity processes (see below). The CD4 receptor moiety is the suspected attachment site for the HIV virus, which exclusively targets helper T cells. CD8 or T8 cells express a specific glycoprotein structural receptor on their membranes specific for both cytotoxic and suppresser T cells populations (Marieb 1995).

B lymphocytes develop in the bone marrow and undergo a secondary differentiation when exposed to an antigen to become non-dividing plasma cells which secrete immunoglobulins or antibodies. Plasma cells develop an elaborate intercellular rough endoplasmic reticulum which is capable of secreting huge amounts of antibody. Non-T, non-B cells do not carry the surface marker glycoproteins of either T or B cells. The major cell type of this class is the natural killer cells, which are capable of killing a large variety of non-specific targets without the presence of antibody or without the prior sensitisation of antibodies present (Simon 1991). These cells are augmented by interferons, which are a family of broad-spectrum antiviral agents synthesised by cells when they become infected with a viral agent (Heaney & Golde 1998).

The primary humoral responses occur when an antigen binds to the surface receptors of a B-lymphocytic cell, causing activation of a variety of second and third messengers that eventually result in the activation and replication of cellular DNA to initiate synthesis of antibodies or immunoglobulins (Igs). The activation of surface receptors causes the B lymphocyte to multiply into a series of clones that mature into plasma cells capable of secreting antibodies (Igs) against the antigen (Fig. 15.5). Some of these B lymphocytes become memory cells, which are capable of storing the memory of the assaulting antigen in case re-exposure occurs in the future. This results in the secondary humoral response, which involves the IgM antibodies and is much more vigorous and rapid than the primary response. The antibodies produced combine with the specific antigen that stimulated their production and form an antigen–antibody complex that allows other cells such as macrophages, natural killer cells, and neutrophils to recognise and destroy the antigen-bearing complex.

Figure 15.5 The role of cytokines in B cell activation. The differentiation of a B cell (following interaction with a Th cell via presentation of antigen associated with HLA class II) involves an increase with metabolic activity and size, giving rise to a lymphoblast which undergoes mitosis and finally matures into an antibody-secreting plasma cell (P). Cytokines secreted by Th cells (and other cells) act on the B cell at different stages of differentiation. This is illustrated with IL-4 and IL-6, but other cytokines may also be involved: e.g. IL-1 and BCGF-I (B cell growth factor) promote early activation; IL-2, BCGF-II, and IFN-γ stimulate replication; IL-2 and IFN-α promote maturation to plasma cells.

Antigens

The antibody molecule or immunoglobulin (Ig) is composed of two identical heavy and two identical light chain peptides held together by interchain disulfide bonds (Figs 15.6 and 15.7). Five classes of antibody have been identified, each with a variety of subgroups also identified. These classes of antibody are IgG, IgA, IgM, IgE, and IgD.

Figure 15.6 Immunoglobulin chains and the fragments formed by proteolytic digestion. N, amino terminus; C, carboxy terminus.

Figure 15.7 The basic components of an immunoglobulin molecule.

IgG

This immunoglobulin is the most abundant immunoglobulin of the internal body fluids, especially in extravascular fluid where it combats microorganisms and their toxins. When IgG complexes with a bacteria or antigen the classic complement cascade is triggered, which results in chemotactic attraction of polymorphonuclear (PMN) cells, which then can adhere to the bacteria or antigen through surface receptors that recognise segments of the IgG antibody, called constant regions, and stimulate the PMN cell to ingest the bacteria through the process of phagocytosis.

Receptors for IgG constant regions are present on monocytes, neutrophils, eosinophils, platelets, and B lymphocytes. When IgG antibody binds to the B cells, receptor down-regulation of cellular responsiveness occurs, which leads to the decreased production of antibody in a negative feedback fashion.

IgG is the only antibody that can cross the human placenta such that it provides a major line of defence for the first few weeks of the baby’s life (Fig. 15.8).

Figure 15.8 The structure of immunoglobulins IgG, IgD, IgA, and IgE.

IgA

This antibody only appears in the seromucous secretions such as saliva, tears, nasal fluids, sweat, colostrum, and secretions of the lung, gastrointestinal, and genitourinary tracts, where it has the job of defending the body against attack by microorganisms. IgA is synthesised by plasma cells, and functions by inhibiting the adherence of coated microorganisms to the surface of mucosal cells, thereby preventing entry into the body tissues. IgA can also activate the alternative (not classic) complement pathway (Fig.15.8).

IgM

This antibody is formed as a pentamer of IgG molecules and is the largest of all the immunoglobulins. For this reason it is very effective at agglutinating bacteria and initiating the classic complement pathway (Fig. 15.9).

Figure 15.9 The structure of the immunoglobulin IgM.

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