Cells And Tissues Of The Immune System

The immune system comprises a range of cells, tissues and chemicals that interact to overcome infection, repair tissue damage and maintain the integrity of the body. The immune response is affected by the food we eat, environmental, genetic, neurological and psychological influences. To understand how the immune system fights infection, you must be able to identify the cells involved and to associate the correct physical (phenotypic) and functional characteristics with them. These attributes (and many other aspects of the immune response) are described using specific terms that have precise meanings. So learning immunology is like learning a new language, once you have mastered the terminology and the basic structure, the rest falls into place quite easily!

The cells and tissues of the immune system provide part of the basic structure of immunology and these sections place special emphasis on introducing a number of relevant terms that you will come across again and again throughout this book. The purpose of this chapter is to introduce you to the terminology used to describe the cells involved in the immune response and to describe the physical organisation of the tissues within the body that comprise the immune system.

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1.1 Cells involved in the immune response

For many years, the immune response has been described as comprising the non-specific or innate response and the acquired or specific response. The innate

Immunology for Life Scientists, Second Edition. Lesley-Jane Eales. © 2003 John Wiley & Sons, Ltd: ISBN 0 470 84523 6 (HB); 0 470 84524 4 (PB)

Table 1.1 Standard adult white blood cell count

Cell Number (x10~9/L)

Neutrophils 2.0-7.5

Eosinophils 0.04-0.4

Basophils < 0.1

Monocytes 0.2-0.8

Lymphocytes 1.5-4.0

response occurs as a result of tissue damage caused by trauma or infections. It is a generalised response irrespective of the precipitating agent. By contrast, the specific immune response involves the precise recognition of particles that are foreign to the host's body (i.e. they are not normally present in the healthy body and are called non-self). These may be molecules on host cells, which have been altered in some way, or invading microorganisms. The cells involved in mediating these responses are found in the blood and in specialised tissues throughout the body (the lymphoid tissues). Although different types of cells tend to be associated with either the innate or specific immune response, the reality is that these responses are not discrete and some cells are key to both reactions. Thus, it is important to understand the characteristics and functions of the different cell types and how they may contribute to the immune response in general. The cells involved in immunity are the white blood cells, collectively known as leukocytes (Greek: leuko — white; cytes — cells). Table 1.1 introduces you to the different white blood cells by providing a summary of standard counts in the blood of a normal adult.

1.1.1 Cellular origins - the pluripotent stem cell

The mature cells of the immune system have a limited life span and therefore must be replaced continuously by new ones that arise from immature precursor cells in the bone marrow. These multiply and the daughter cells go through a series of changes and further divisions that result in cells with particular physical, chemical and functional characteristics, which are typical of the mature cells found in the blood or tissues. This process of arriving at the mature cell phenotype is known as differentiation.

The immature precursor cells themselves develop from progenitor cells that are thought to have a common origin - the pluripotent or common haemopoietic stem cell - found in the bone marrow. These cells are able to renew themselves by proliferation and are able to differentiate into progenitor cells. Thus, the process of blood cell production - haematopoiesis - comprises a complex sequence of events (including cell proliferation, differentiation and

Figure 1.1 Representation of the developmental lineage of immunologically active cells

The figure shows the development of immune cells from the pluripotent stem cell in the bone marrow. Dendritic cells have been shown to derive from myeloid- or lymphoid-like cells (indicated by the question marks) but it is unclear at what precise stage this differentiation takes place. Other cells are known to derive from the bone marrow but their precise route of differentiation is unclear.

Figure 1.1 Representation of the developmental lineage of immunologically active cells

The figure shows the development of immune cells from the pluripotent stem cell in the bone marrow. Dendritic cells have been shown to derive from myeloid- or lymphoid-like cells (indicated by the question marks) but it is unclear at what precise stage this differentiation takes place. Other cells are known to derive from the bone marrow but their precise route of differentiation is unclear.

maturation) controlled by a variety of soluble secreted factors (known as cytokines or lymphokines) and hormones. The developmental lineage of those cells described in this chapter is shown in Figure 1.1.

Cytokines are "cellular hormones''. They are peptides, which are produced by cells and act locally.

1.1.2 Cells principally involved in the innate immune response

Polymorphonuclear leukocytes

The polymorphonuclear leukocytes (PMNs) are a group of cells that have two major features in common; their nuclei demonstrate a wide range (poly) of different shapes (morpho) and they all have distinct granules in their cytoplasm. The presence of these granules has led to their being known as granulocytes, although this is slightly confusing since some other cells also have granules in their cytoplasm. To be a granulocyte, a cell must have both granules and the typical lobulate nucleus.

The polymorphs derive from the myeloid progenitor cell, which is found in the bone marrow. This cell goes through a series of replication and differentiation processes giving rise to differentiated daughter cells with distinct characteristics. This process is regulated by cytokines, particular cytokines favouring the production of neutrophils, eosinophils, basophils or mast cells. A summary of the characteristics of these cells is shown in Table 1.2.

Neutrophils

Normally, 60-70% of white blood cells are granulocytes and about 90% of these are neutrophils, which provide protection from a variety of microorganisms and are arguably the most important white blood cells in eliminating non-viral infections. They are relatively large cells (about 10-20 mm in diameter) and despite their important function, are relatively short-lived (about 2-3 days).

Neutrophils are the most common white blood cell. The primary function of these cells is to remove microorganisms by a process known as phagocytosis (a phenomenon which may be compared to the uptake of particulate matter by an amoeba).

Table 1.2 Summary of the characteristics of the polymorphonuclear leukocytes

Name

Characteristics

Polymorphonuclear leukocytes Irregularly shaped nuclei; granular cytoplasm (also known as granulocytes)

Neutrophils Eosinophils

Basophils Mast cells

Pale blue staining, granular cytoplasm; actively phagocytic

Granular cytoplasm stains red with eosin; slightly phagocytic but most important role is in allergy and resistance to parasitic infections

Large, dark blue staining granules; blood borne;

important in allergy; granules contain chemicals which have dramatic effects on muscles and blood vessels

Similar staining to basophils only larger granules, usually not seen in blood, only tissues

The granular appearance of polymorphs is due to their cytoplasmic inclusions. At least four types of granules have been identified in neutrophils that emerge at different stages of the cell's development. These are the primary (azurophilic) granules (lysosomes), which contain acid hydrolases, myeloperoxidase and lysozyme; secondary (specific) granules, which contain lactoferrin and lysozyme but lack myeloperoxidase; tertiary granules that contain gelatinase; and secretory vesicles, which act as intracellular stores of molecules usually found anchored in the cell membrane where they act as receptors for other molecules.

Neutrophils are produced in the bone marrow whence mature cells pass into the circulation. In the major vessels these cells are in constant flow. However, in the capillary beds these cells become temporarily stationary (owing to their lack of deformability), without being attached to the endothelial cells that line the blood vessels. When there is local tissue damage as a result of trauma or infection, neutrophils become activated and emigrate from the capillaries and post-capillary venules into the tissues in response to gradients of particular chemicals known as chemotaxins and chemokines (chemotactic cytokines). This directed migration is known as chemotaxis. During this process, the cells may discharge the contents of their granules (degranulation). This may affect nearby cells or extracellular bacteria and may increase cell membrane-associated events (such as chemotaxis and the respiratory burst) by increased expression of particular membrane proteins. This whole process is described in detail in the section on innate immunity.

The respiratory burst is an ATP-dependent chemical reaction, which consumes oxygen and results in the production of highly reactive chemicals (e.g. reactive oxygen and nitrogen species) that are capable of destroying microorganisms.

Eosinophils

Eosinophils, like neutrophils, are produced in the bone marrow, which retains a reserve of mature cells. The majority of eosinophils are found in the tissues of the body and comprise only 4% of the white cells in the blood. Their life span is about 13 days and they are about 8 mm in diameter. Differentiation of precursors in the bone marrow is influenced by the cytokines interleukin 3 (IL-3) and granulocyte-monocyte colony-stimulating factor (GM-CSF). In addition, interleukin 5 (IL-5) specifically promotes the expansion of eosinophil (and basophil) numbers. The release of mature eosinophils from the bone marrow reserves is promoted by both IL-5 and the chemokine known as eotaxin.

In early development, their nuclei are bilobed but with maturation, they can become multilobed like other polymorphs. Like neutrophils, they contain intracellular granules, although those in eosinophils are quite distinct. The primary granules contain Charcot-Leiden crystal protein and the characteristic secondary granules contain a crystalline core of major basic protein (MBP) and a matrix of eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO). The cells also contain lipid bodies that are the site of lipid mediator synthesis. The major basic protein is highly toxic to multicellular parasites. Although eosinophils are able to phagocytose, it is not their main function and these organisms are too large. Thus, the membranes surrounding the eosinophil granules fuse with the cell membrane and the contents are released outside the eosinophil. The toxic granule proteins help to destroy and eliminate the parasites. This process is dependent upon adhesion of the eosinophil to the parasite. This attachment is mediated via molecules on the surface of the eosinophil called b-integrins.

b-Integrins are adhesion molecules that are found on the surface of many cells and whose expression can be increased or decreased by local chemical influences such as cytokines.

In addition to their anti-parasitic activity, eosinophils participate in a number of other immunological reactions, including allergy. They are able to produce a range of cytokines (e.g. IL-2, interferon gamma (IFNg), IL-4, IL-5 and IL-10) that may enhance or decrease their own function (autocrine action) or that of a range of other cells (paracrine action). Additionally, eosinophils synthesise prostaglandins and leukotrienes from lipids found in the cell membrane. These molecules stimulate a process known as inflammation. Activation of eosinophils is dependent upon adhesion but also on electrical charge. Negatively charged molecules such as heparin, mucins and sialic acid may decrease activation, whilst it may be increased by positively charged molecules such as the basic granule protein.

Inflammation is a complex series of cellular and biochemical reactions that occur in response to tissue damage.

Basophils and mast cells

Both mast cells and basophils originate from haematopoietic stem cells in the bone marrow. Their progenitor cells are expanded in number through the influence of IL-3. Although these cells share many characteristics, their differentiation pathways are quite distinct (Figure 1.2). Basophils complete their differentiation in the bone marrow under the influence of IL-3 and the cytokine transforming growth factor b (TGFb). Then they enter the circulation where they comprise <0.2% of white blood cells. Mast cell differentiation is due to the presence of stem cell factor (SCF; the ligand for Kit, a product of the c-kit proto-oncogene). They leave the bone marrow as precursors and after migrating to the tissues, proliferate and differentiate into mature mast cells.

Like other granulocytes, the nucleus of the circulating basophil is deeply lobed. However, those of mast cells in the tissues are rounded. As mentioned earlier, basophils are largely found in the circulation but enter the tissues in response to the release of chemotaxins and chemokines during inflammation.

Both cell types play a role in allergic reactions, inflammation, host responses to parasites and cancers, blood vessel generation (angiogenesis) and tissue remodelling. They are the only cells on whose membranes large amounts of a high-affinity receptor for a molecule known as immunoglobulin E (IgE) are expressed naturally (constitutively), and that store histamine in their secretory granules. These molecules play an important role in allergic and inflammatory responses respectively.

There are two main types of mast cell distinguished by the contents of their intracellular granules. Those with tryptase, chymase, carboxypeptidase and cathepsin are called MCTC and are found largely in the normal skin and submucosa of the small bowel. Those with only tryptase are referred to as MCt cells and are found in the normal airway. In addition, mast cells in different tissues may exhibit different activities in response to stimulators other than IgE. Mast cells have been shown to have different types of chemokine receptors on their surface. Since the binding of chemokines to these receptors stimulates mast cell migration into the tissues, this may explain how different types of mast cell are recruited to different tissue sites.

Activation of basophils and mast cells may be due to the cross-linking of IgE bound to the IgE receptors on their surface (IgsR; Figure 1.3). In addition, molecules produced as a result of inflammation such as C3a and C5a, eosinophil-derived major basic protein and neuropeptides may activate some mast cells and basophils.

Once activated, both basophils and mast cells release a variety of substances that can enhance inflammation and influence other cells. These can be divided into those preformed mediators stored in the secretory granules and those that are freshly generated upon activation. The former include histamine, proteoglycans and proteases; the latter include arachidonic acid metabolites, cytokines and chemokines (Table 1.3).

Pluilpotent stem cell +

Myeloid progenitor cells

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