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Immunology is a particularly new area of study which has evolved rapidly with the discovery of new concepts since the late 1700s. Initially starting as a branch of microbiology, the field has been shown to be crucial in the understanding of disease, vaccinations and transplants. Though immunity is indirectly mentioned in ancient Greece and China (430 BC and 1000 AD respectively) the origin of the field of immunology is attributed to Edward Jenner who induced immunity against small pox via the process of variolation in 1798 (Kindt et al., 2007). Other important scientists contributing to the field include Louis Pasteur in the late 1800s establishing the rational development of (chicken cholera, anthrax and rabies) vaccines and further developing the 'germ theory of disease' and is regarded as the first experimental immunologist and 'Father of immunology' (Silverstein, 2009). Emil von Behring discovered antibodies (against diphtheria toxins) an important component of adaptive immunity whilst Eli Metchnikoff observed the phenomenon of phagocytosis, vital in innate immunity; both received Nobel prizes for their outstanding work in 1901 and 1908 respectively (Barrett, 1980).
Immunity which is derived from the Latin term immunitas meaning exemption, is defined as the 'body's ability to resist infection' (Abbas et al., 2007). The role of the immune system is to protect the body from numerous pathogens by acting as a defensive physical, biochemical and cellular barrier.
The immune system itself is made up of two main groups of organs: primary or generative organs which are responsible for the production and maturation of lymphocytes and secondary peripheral organs which concentrate antigens for the development of an immune response. The primary organs comprise of bone marrow and thymus gland; secondary include the spleen, lymph vessels/nodes and mucosa-associated lymphoid tissues (MALT) (Lentz and Feezor, 2003).
This system being so complex is made up of two distinct system pathways, innate and adaptive, each with different roles and cellular components which communicate with each other to protect the body. Innate immunity is the first line of defence which produces a very rapid response to stimuli whereas adaptive immunity though slower, provides immunological memory alongside a highly specific immune response (Kindt et al., 2007)
1.2 Adaptive Immunity
Adaptive immunity is the highly specific second line of defence of which there are two types: humoral and cell-mediated. Humoral immunity is mediated by B lymphocytes which recognise specific regions (epitopes) on circulating antigens and in response produce and release specific antibodies which adhere to and eliminate the extracellular antigens (Abbas et al., 2007). Cell-mediated immunity on the other hand is dependant upon T lymphocytes which when exposed to intracellular antigens (in antigen presenting cells) act in many ways. T helper lymphocytes release cytokines which activate B cells to produce antibodies, activate macrophages and other phagocytes to destroy ingested antigens (via phagocytosis) whereas cytotoxic T lymphocytes destroy infected cells (Kindt et al., 2007). The adaptive immune response which follows the innate response in an invasion is initially very slow, however due to the ability of providing an immunological memory, a rapid response occurs when the body is exposed to the same antigen twice which occurs by the generation of memory cells (Abbas and Janeway, 2000).
1.3 Innate Immunity
Innate immunity is the first line of defence against attacking microbes, providing an immediate rapid response within minutes of an encounter. The innate immune system which is present from birth is comprised of many physical, chemical and cellular components.
The physical defences comprising of skin and various internal mucosal membranes are very important as they are in contact with the external environment and therefore are the initial barriers that an invading pathogen must overcome (Kindt et al., 2007). These surfaces are made of intact tightly packed multilayered epithelial cells which, though efficient and strong in themselves, have specialised characteristics to assist in the prevention of microbes entering the body. The skins' upper most layer, the epidermis, is made of keratinised epithelial cells which are waterproof and the epithelial cells also secrete sebum which has anti-fungal properties. Internal mucosal epithelia found in the respiratory, gastrointestinal (GI) and genitourinary (GU) tracts are lined with mucus which traps microbes rendering it difficult for them to adhere to the cells. The presence of cilia in the respiratory tract efficiently expels these trapped microbes and dust particles out of the lungs (Abbas et al., 2007).
The protective chemical components of the innate system include the high concentrations of potent hydrochloric acid synthesised in the stomach, and lactic acid in vagina which prevent growth of many microbes and the presence of lysozymes in tears, saliva, sweat and nasal secretions which acts to digest bacterial cell walls (Murphy, et al., 2008; Wood, 2006).
Another very important biochemical mechanism in innate immunity is antimicrobial peptides (AMPs) which are generally synthesised by phagocytes and certain epithelial cells (in the skin and mucosal membranes) and effectively destroy microbial cell membrane. There are two main types of AMPs (cathelicidins and defensins), of which the more relevant defensins will be discussed in detail later (Eales, 2003). The physical and chemical barriers in the innate immune system are generally non-specific and non-immunologic; it is when these initial barriers are breached that the cellular components of the innate immune system are activated.
The most important action of innate immunity is phagocytosis which is the destruction of foreign organisms by cells that are generally termed phagocytes. These phagocytes include mononuclear phagocytes (MNP) such as monocytes and macrophages, polymorphonuclear neutrophilic leukocytes (PMN) or neutrophils and dendritic cells (DC) (see figure 1.1).
When a pathogen enters the body and causes tissue damage or infection one of the first actions is that a tissue macrophage recognises the pathogen as being foreign, becomes activated and as consequence releases cytokines and chemokines such as interleukins (IL), interferons (IFN) and tumour necrosis factors (TNF). These polypeptides further activate other macrophages and recruit granulocytic (basophils and eosinophils) and phagocytic cells to the site of infection (amongst other roles) (Eales, 2003).
Phagocytosis itself is initiated when phagocytes identify the invading organism as being foreign (or non-self) by the presence of pathogen-associated molecular patterns (PAMPs) such as bacterial lipopolysaccharides (LPS) on microbial cell surfaces; PAMPs are detected via various transmembrane pattern recognition receptors (PRR) on the cellular surface of phagocytes (Takeuchi and Akira, 2010). Once recognised as foreign, the microbe is adhered to cell surface receptors, surrounded by cellular projections called pseudopodia and subsequently internalised into the phagocyte in a vesicle called a phagosome. After ingestion, the phagosomes fuse with lysosomes which contain proteolytic enzymes and AMPs such as defensins that degrade the bacterial cell wall and membrane into cellular debris (Kindt et al., 2007; Abbas et al., 2007). Other methods of destroying the ingested microbe are the production of oxygen free radicals (via NADPH oxidase) and toxic nitric oxides (in PMNs); the phagocytosed material is then egested from the cell. Phagocytosis can be also enhanced by the binding of antibodies or complement factor (plasma proteins) C3b to foreign antigen, a process known as opsonisation (Wood, 2006).
Another important cell participating in the innate immune response is the natural killer (NK) cell which is neither a granulocyte nor a phagocyte. NK cells derived, like lymphocytes, from lymphoid progenitor cells (figure 1.1), induce apoptosis in virus infected cells and many tumour cells and release cytokines such as IFN-γ which stimulate macrophages to phagocytose microbes (Abbas et al., 2007).
If the innate immune system is evaded, the second phase of immunity (adaptive immune response) is required to efficiently eradicate any remaining foreign organisms; this is induced by dendritic cells (DC). Immature DCs (iDCs) present in skin (Langerhans cells) and mucosal epithelia are in close proximity to the external environment and so more readily ingest invading pathogens. Once activated into mature DCs (mDCs) (and thus antigen-presenting cells), they travel to lymph nodes and interact with naïve T lymphocytes causing them to mature and initiate a powerful specific immune response (Abbas and Janeway, 2000).
Many cells are responsible for innate immunity; the ones of particular relevance to this study are monocytes and macrophages
Figure 1.1 - Haematopoiesis. Haemopoetic stem cells give rise to all the cell lineages of the blood and immune system (Kindt et al., 2007).
Monocytes, which correspond to approximately 10% of leukocytes in humans, are developed from haemopoietic stem cells (HSC) in the bone marrow. These cells differentiate further into many progenitor cell lines, of which the common myeloid progenitor, after multiple stages gives rise to precursor cells (monoblasts and promonocytes) and consequently monocytes (figure 1.1) (Auffray et al., 2009). Morphologically monocytes (figure 1.2) possess typical features which include an irregular cell and nuclear shape, large, often kidney-shaped, nucleus which takes up most of the cellular space (i.e. high nucleus-cytoplasm ratio), presence of small vesicles and azurophilic granules and a diameter of 10-20μm (Ziegler-Heitbrock, 2000).
Once differentiated, monocytes remain in the blood circulation for 1-3 days before migrating (usually in response to cytokines, chemokines and inflammatory signals) to organs and tissues where they develop into macrophages. Cells that do not differentiate further into macrophages or travel to tissues in response to inflammation, infection or invading organisms, undergo spontaneous apoptosis and are subsequently phagocytosed by macrophages (Heindreich, 1999). Monocytes, macrophages and their precursor cells are all part of the MNP system and their synthesis from HSCs, is strongly dependant on the release of macrophage-colony stimulating factor (M-CSF or CSF-1), a type of growth factor (Auffray et al., 2009).
Apart from acting as a precursor for macrophages, other monocyte roles include phagocytosis of foreign bodies (organisms and toxins), secretion of inflammatory cytokines such as TNF-α and antigen presentation to lymphocytes and thus activation of adaptive immunity, due to the expression of major histocompatibility complex (MHC) class II molecules on extracellular surfaces (Parihar et al., 2010; Auffray et al., 2009).
In recent years evidence has strongly indicated that monocytes demonstrate heterogeneity in phenotype and function in humans contrary to previous belief, and monocytes can therefore be divided into two main subsets, 'classical' and 'non-classical', according to the expression or lack of cluster of differentiation (CD) molecules 14 and 16 on their cellular surfaces (Ziegler-Heitbrock, 2000). Classical monocytes, which are representative of 80-90% of monocytes, express very highly for CD14 only (i.e. CD14++ CD16-) whilst non-classical monocytes express a combination of both CD14 and CD16 (Auffray et al., 2009). The non-classical subset of monocytes, which represent the remaining 10% of monocytes, can be further divided into the cells that co-express CD16 alongside CD14 at reduced levels (CD14+ CD16+) and high levels (CD14++ CD16+) (Parihar et al., 2009).
The two types of monocytes have also been known to have differing functions: CD14++ monocytes have been shown to have very high phagocytic activity and produce high levels of cytokines such as IL-10 (in vitro) when provoked with bacterial LPS stimulation. CD16+ monocytes in contrast have been shown to produce inflammatory cytokines such as TNF-α in response to LPS, proliferate in acute inflammations and infections and thus have been termed 'pro-inflammatory' monocytes (Auffray et al., 2009).
Figure 1.2 - Monocyte and macrophage morphology and the obvious structural differences between the two. Macrophages (b) are much greater in size, cell surface is more villous with many pseudopodia and contain more organelles and lysosomes than monocytes (a) (Kindt et al., 2007).
Macrophages are derived from monocytes which travel to tissues and undergo maturation and thus are also a part of the MNP system. Morphologically macrophages increase greatly in size, approximately five to ten times the size of monocytes, acquire more organelles which are increasingly complex compared to the simple organelles present in monocytes, and contain a higher number of lysosomes therefore synthesise and secrete higher concentrations of lysozymes and other hydrolytic enzymes (figure 1.2). In addition after maturing, macrophages are more specialised as they gain an improved phagocytic capability and release a diverse range of chemical regulators such as chemokines and cytokines (Kindt et al., 2007).
In contrast to monocytes macrophages have a longer and more stable lifespan which can span from weeks to many months and is thought to be due to their resistance against numerous toxins (Parihar et al., 2009; Heindreich, 1999).
Macrophages not only show complexity in structure, but function too; their assorted roles include: secreting growth factors, inflammatory mediators, cytokines and chemokines such as TNF-α, IL-1, IL-6 in response to external stimuli to recruit other cells to infected site, releasing enzymes, reactive oxygen and nitrogen species, AMPs such as defensins in response to invading organisms and recognising PAMPs on foreign bodies via PRR and subsequently engulfing them in a process called phagocytosis. Alongside foreign organisms and toxins, macrophages are also responsible for phagocytosing cellular debris, infected cells and apoptotic bodies therefore clearing and removing old cells (Abbas et al., 2007; Duffield, 2003; Martinez et al., 2009); macrophages thereby also contribute to maintaining tissue homeostasis as phagocytosis of old tissue leads to proliferation of parenchymal cells, promoting repair and tissue remodelling (i.e. scar formation) (Duffield, 2003). Macrophages also act as antigen presenting cells and can thus initiate the secondary adaptive immune response.
Macrophages can be resident to one specific tissue or organ or can travel to various tissues, where they are needed in time of infection, invasion and inflammation, by amoeboid movement. Actin filaments and microtubules facilitate pseudopodia formation which is essential for movement and phagocytosis (Stvrtinová et al., 1995).
There are two groups of macrophages: fixed/resident and inflammatory macrophages. Resident macrophages remain fixed in their specific local tissue and include: Kupffer cells in the liver, mesangial cells in the kidney, histiocytes in connective tissue, osteoclasts in bone, alveolar macrophages in lung alveoli, splenic macrophages in the spleen and microglia macrophages in the brain and central nervous system (Kindt et al., 2007; Gordon and Taylor, 2005). These fixed macrophages that reside in tissues, adapt their abilities to suit their local microenvironment which can be seen in alveolar macrophages which express MHC II and scavenger receptors more highly than other macrophages which assist in the removal of airborne microorganisms (Gordon and Taylor, 2005). Inflammatory macrophages are also located in tissues, but unlike resident macrophages they can travel freely by amoeboid movement to sites of pathogenic invasion where they are needed for defence; they are also present in exudates (Kindt et al., 2007; Stvrtinová et al., 1995).
To induce an immune response macrophages must be activated; this occurs when stimulated by stimuli such as PAMPS on invading pathogens e.g. bacterial LPS, LBP (lipopolysaccharide binding protein) or internally released chemicals such as IFN-γ and TNF-α. Once activated, this increases their phagocytic ability to engulf foreign organisms and triggers the release of an array of pro-inflammatory mediators such as TNF-α, IL-6, IL-1β which can lead to vasodilation, MCP-1 which induces an increase in endothelial permeability and chemoattractant chemokines to recruit more cells, such as PMNs, activated T lymphocytes and NK cells, to the site of inflammation (Gordon and Taylor, 2005; Duffield, 2003).
Monocytes and macrophages are very important in providing an innate immune response against invading pathogens; a potent invoker of this response is bacterial LPS.