Immune system

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Immune system



Introduction


All living tissues are subject to the constant threat of invasion by disease-producing foreign agents and microorganisms (pathogens) i.e. bacteria, viruses, fungi, protozoa and multicellular parasites such as worms. These organisms may invade the body, multiply and destroy functional tissue, causing illness and potentially death. Three main lines of defense have consequently evolved:




Protective surface mechanisms


These provide the first line of defense and, while intact, provide excellent protection from many disease-causing organisms. However, pathogens may enter the body via breaches in the skin or mucosal linings of the gut, respiratory and genitourinary tracts. The skin, with its surface layer of keratin, constitutes an impenetrable barrier to most microorganisms, unless breached by injury such as abrasion or burning. The mucous surfaces of the body, such as the conjunctiva and oral cavity, are protected by a variety of antibacterial substances including defensins, short antimicrobial peptides that are found in surface mucus, and the enzyme lysozyme, which is secreted in tears and saliva. The respiratory tract is protected by a layer of surface mucus that is continuously removed by ciliary action and replaced by goblet cells. Maintenance of an acidic environment in the stomach, vagina and, to a lesser extent, the skin, inhibits the growth of pathogens in these sites. When such defenses fail and an infection takes hold, the two other main types of defense mechanism are activated.



The innate immune system


The innate immune response provides a rapid reaction to infections and, characteristically, the same magnitude of response each time the same pathogen is encountered (i.e. there is no learning in the innate system). The cells, proteins and peptides involved circulate in the blood of healthy individuals in sufficient amounts to overcome many trivial infections and contain more serious infections until an adaptive immune response can develop. The cellular components include neutrophils, eosinophils, basophils and macrophages, as well as tissue resident cells such as histiocytes and mast cells. The proteins and peptides of the innate response include complement, acute–phase proteins, chemokines and interleukins. The major functions of the most important components of the innate immune system are outlined in Table 11.1. The innate immune response causes a pathological condition known as inflammation, familiar to anyone who has ever had a cut finger. Acute inflammation is characterised by vascular changes including dilatation, enhanced permeability of capillaries and increased blood flow, resulting in the production of a fibrin-rich inflammatory exudate, thus bringing the proteins and cells required for early defence to the site of infection. Many of the cells and signalling molecules of the innate immune system are vital to the functioning of the adaptive immune system.




The adaptive immune system


The adaptive immune system is characterised by the ability to learn, so that second and subsequent encounters with a pathogen elicit a greater, more specific and faster response. This is the basis of lifelong immunity to certain infections after an initial infection or vaccination. The adaptive system builds on and is intimately associated with the innate immune system. Adaptive immunity depends on cell division to produce large numbers of lymphocytes with specificity for a particular pathogen (or antigen) and thus takes 3 to 5 days to develop a significant response. Lymphocytes are able to kill or disable pathogens either by a cellular response (T lymphocytes or T cells) or a humoral response (B lymphocytes or B cells) or, commonly, a combination of both. Adaptive immunity amplifies some of the mechanisms of the innate response. For instance, antibody, produced by B cells, coats bacteria (opsonisation) to facilitate phagocytosis by neutrophils and also directly activates the complement cascade. The adaptive immune response is also controlled by the innate response, as T lymphocytes require the services of antigen presenting cells (APCs) such as macrophages and dendritic cells for activation.



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FIG. 11.1 The organs of the immune system
The components of both the innate and adaptive systems are found throughout the body. The lymphocytes of the adaptive immune system are produced in the bone marrow from haematopoietic stem cells along with the cells of the innate system (see Ch. 3). As well as circulating in the blood, the cells of the adaptive immune system form specialised lymphoid tissues and also constitute a significant component of other tissues such as the gastrointestinal tract. The major lymphoid organs include:




• The thymus, situated in the anterior mediastinum, is the site of maturation of immature T lymphocytes.



• The bone marrow is not only the home of lymphocyte stem cells but is also the site of B lymphocyte maturation.



• The lymph nodes, found at the junctions of major lymphatic vessels, are the sites where both T and B lymphocytes may interact with antigen and APCs from the circulating lymph, leading to lymphocyte activation and cell division.



• The spleen, situated in the left upper quadrant of the abdomen, is the location where T and B lymphocytes may interact with blood-borne antigen and undergo stimulation and cell division.



• Mucosa-associated lymphoid tissue (MALT) includes the tonsils and adenoids in the oropharynx, Peyer’s patches and lymphoid aggregates of the small and large intestines, respectively, and a diffuse population of lymphocytes and plasma cells in the mucosae of the gastrointestinal, respiratory and genitourinary tracts. These specialised lymphoid tissues respond to antigens entering the body through these mucosae.


The thymus and bone marrow, where immature lymphocytes acquire the receptors to recognise antigen, are known as primary lymphoid organs. The spleen, lymph nodes and organised lymphoid tissues of MALT, where lymphocytes are activated in response to antigen, are the secondary lymphoid organs.



Lymphocytes


Lymphocytes comprise some 20% to 50% of white cells in the circulation. Most circulating lymphocytes measure 6 to 9 µm (i.e. about the same size as erythrocytes) and are called small lymphocytes. About 3% are large lymphocytes, measuring 9 to 20 µm. The light and electron microscopic features of lymphocytes are described in Fig. 3.17. Briefly, small lymphocytes have a round to ovoid nucleus occupying about 90% of the cell volume, with a thin rim of basophilic (bluish) cytoplasm.


Lymphocytes constantly patrol the body, circulating in the blood, lymph and other extracellular fluids and pausing in the organised lymphoid tissues. Secondary lymphoid organs are arranged to optimise the chances of an antigen meeting a potentially reactive lymphocyte and facilitating lymphocyte activation. If an antigen binds to a lymphocyte surface receptor, the lymphocyte will be activated and a specific response to that antigen is triggered. Obviously, the immune response must be tightly controlled so as to be active when there is a potentially serious infection, but not react against harmless components of everyday life such as food proteins or even against normal components of the body (autoimmunity).


The effectiveness of the adaptive immune system in recognising the huge range of pathogenic organisms found in nature depends upon the unique ability of lymphocytes to produce an equally huge range of antigen receptors i.e. the B cell receptor (BCR), comprising surface immunoglobulin (sIg) plus accessory molecules for B cells and the T cell receptor (TCR) for T cells. The ability of antibody to bind to antigen is determined by the physico-chemical properties of the antibody. Put simply, the shape and electrical charge of the binding site of the antibody must be complementary to the antigen, and the closer the fit of binding site to antigen, the stronger the bond formed and the greater the likelihood of the lymphocyte being stimulated. The TCR binds to antigen by similar reciprocity of shape and charge but it must also bind to the major histocompatibility complex (MHC) (see Figs 11.2 and 11.3). During maturation of lymphocytes, alternate components of the antigen-binding part of the antigen receptor genes are spliced together (rearranged) in a random fashion. Thus a huge range of possible antigen specificities are generated before the lymphocytes have a chance to meet external antigen.



The role of T lymphocytes


T cells have a number of effector and regulatory functions. Immature T lymphocytes migrate from the bone marrow to the thymus where they develop into mature T lymphocytes. The process of maturation includes proliferation, rearrangement of TCR genes, and acquisition of the surface receptors and accessory molecules of the mature T cell. At this stage, T cells with the ability to react with ‘self-antigens’ (normal body components) are removed by apoptosis, creating a state of self-tolerance. Mature T cells then populate the secondary lymphoid organs and, from there, continuously recirculate via the bloodstream in the quest for antigen.


T lymphocytes may develop into one of the functional subsets detailed below. These subsets develop from naïve T cells, depending on the mixture of cytokines and interleukins to which they are exposed, and can be identified in the laboratory by means of their surface receptors and accessory molecules.


The best known subsets of T cells include:



• T helper cells (TH cells). These T lymphocytes ‘help’ other cells to perform their effector functions by secreting a variety of mediators known as interleukins. TH cells thus provide ‘help’ to B cells, cytotoxic T cells (see below) and macrophages. TH cells can be subdivided into subgroups with different functions. TH1 cells tend to promote a cell-mediated reaction, important for defence against viruses and intracellular pathogens. TH2 cells are important for humoral (antibody mediated) responses and TH17 modify and augment certain types of acute inflammation. TH cells express the surface markers CD2, CD3 and CD4.


• Cytotoxic T cells (TC cells). These lymphocytes are able to kill virus-infected and some cancer cells. They require interaction with TH cells to become activated and proliferate to form clones of effector cells. TC cells express CD2, CD3 and CD8.


• Regulatory T cells (TREG). These cells suppress immune responsiveness to self-antigens (autoimmunity) and switch off the response when antigen is removed. These cells usually express CD4 and FOXP3.


• Memory T cells develop from activated T cells to provide a ‘rapid reaction force’ for a subsequent encounter with the same antigen. This is the basis of persisting immunity after infection with some organisms and also the basis of vaccination.


• γδ T cells are a subset of T cells where the TCR is a heterodimer consisting of one γ chain and one δ chain, rather than the usual heterodimer of one α and one β chain. These cells populate the epithelium of the gastrointestinal tract and are CD8 positive.



The role of B lymphocytes


B lymphocytes are derived from precursors in the bone marrow and also mature there. Stimulated B cells mature into plasma cells that synthesise large amounts of antibody (immunoglobulin). Immunoglobulins fall into five different structural classes (IgG, IgA, IgD, IgM and IgE) and are secreted into and circulate in the blood. Immunoglobulin molecules are also anchored in the plasma membrane of B cells, with the antigen-binding region exposed to the external environment. This surface immunoglobulin is the antigen receptor for B lymphocytes (part of the BCR), and when it binds antigen the B cell is activated, generally with the ‘help’ of a TH cell responding to the same antigen.


Once activated, the B cell undergoes mitotic division to produce a clone of cells able to synthesise immunoglobulin of the same antigen specificity. Most of the B cells of such a clone mature into plasma cells. When an antigen is encountered for the first time, this is described as the primary immune response. A few cells from the same clone mature to become memory B cells, small long-lived circulating lymphocytes that are able to respond quickly to any subsequent challenge with the same antigen. Antibody production during this secondary immune response occurs much more rapidly, is of much greater magnitude and produces IgG rather than IgM. This phenomenon explains the lifetime immunity that follows many common infections; it is also the general principle on which vaccination is based. Antibodies neutralise or destroy invading organisms by a number of methods (see Fig. 11.2).



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FIG. 11.2 The basics of the immune response (illustration opposite)
This diagram outlines the key steps in the adaptive immune response, i.e. recognition of antigen, activation of the response, generation of effector mechanism and destruction or inactivation of the antigen.
Recognition of antigen
T and B cells carry antigen receptors on their surface, the T cell receptor (TCR) and B cell receptor (BCR). The BRC consists of surface immunoglobulin plus certain accessory molecules. Random rearrangement of the genes for the variable region of the receptor molecules gives rise to receptors with a truly staggering range of antigen binding sites. Each individual T or B cell has specificity for only one antigen, but the entire population is very varied.
Activation of the immune system
Initiation of an immune response first requires contact between antigen Ag and surface receptors on mature lymphocytes. There are several mechanisms of activation:




1. Activation of T cells is dependent on antigen presenting cells APC. The antigen is taken up by an APC (e.g. macrophage, B lymphocyte, dendritic cell, Langerhans cell of skin) and broken down to short peptides (see Fig. 11.3). Processed antigen PA is then bound to a major histocompatibility complex molecule MHC, and the MHC-peptide complex is incorporated into the cell membrane so that the bound antigenic peptide is exposed to the extracellular fluid. Contact with a mature T cell bearing a T cell receptor with appropriate specificity activates the T cell. The type of response depends on whether the peptide is presented bound to MHC class I or II. Antigenic peptides bound to class II MHC molecules induce a T helper cell TH response needed to activate B cells B and cytotoxic T cells TC. B cell receptors (sIg) or TC receptor must also bind to the antigen for activation to occur. TH cells secrete a variety of interleukins IL that mediate activation, clonal expansion and maturation of the B or cytotoxic T cell response.



2. Antigen synthesised within a body cell (e.g. tumour cell, virus-infected cell) is presented on the APC plasma membrane bound to a class I MHC protein where it is recognised by cytotoxic T cells TC. Cytotoxic T cells are able to kill the abnormal cells directly. TH activation is also required for a TC response to be mounted.



3. B lymphocytes interact with unprocessed antigens. They recognise antigen by means of the BCR (surface immunoglobulin, sIg). In most cases, the unprocessed antigen is presented to the B cell on the surface of an APC such as a follicular dendritic cell in a lymphoid follicle. The majority of antigens can only activate a B cell if there is ‘help’ from an activated T helper cell TH. Activation without T cell help will occur if sIg binds to a protein or polysaccharide antigen with a repeating chemical structure (e.g. the polysaccharide coat of the bacterium Pneumococcus). Such antigens are often known as T cell–independent antigens. Few naturally occurring antigens are of this type (not illustrated).


Generation of effector mechanisms




1. Production of antibodies by plasma cells. Mechanisms of antibody-mediated antigen elimination are as follows:




2. Cell-mediated cytotoxicity is the destruction by apoptosis of abnormal cells by cytotoxic T cells, natural killer (NK) cells or antibody dependent cytotoxic cells.



3. Certain types of organism, such as Mycobacterium tuberculosis, the cause of tuberculosis, activate T helper cells (TH1) to secrete cytokines that in turn activate macrophages. Activated macrophages are more effective at killing phagocytosed organisms. This is the mechanism of type IV hypersensitivity (chronic granulomatous inflammation) (not illustrated).


Termination of the immune response
There are a number of mechanisms for switching off the immune response when the need for it has been removed. These include removal of antigen, the short life span of plasma cells, the activities of regulatory T cells and a variety of other mechanisms that downregulate the activity of T and B cells. It is vital that the immune response is terminated when no longer needed to prevent damage to normal tissue from an overenthusiastic immune response. These mechanisms are also important in the prevention of autoimmunity.
Immunological memory
When activated lymphocytes undergo clonal expansion during an immune response, some of the cells so generated mature to become memory T and B cells. These lymphocytes have a similar appearance to naïve lymphocytes but are able to produce a faster and more effective response to a smaller quantity of antigen. This is known as a secondary immune response and is the basis of lifelong immunity after certain infections and of vaccination.



Ag antigen APC antigen presenting cell B B lymphocyte BCR B cell receptor IL interleukins MAC membrane attack complex MHC major histocompatibility complex PA processed antigen TC cytotoxic T lymphocyte TCR T cell receptor TH helper T lymphocyte



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FIG. 11.3 Lymphocytes and antigen presenting cells (illustration (b) opposite)
(a) Schematic diagram (b) EM ×18 000
Antigen presenting cells APC are vital for the activation of lymphocytes to produce an adaptive immune response. They include macrophages, dendritic cells and B lymphocytes. Dendritic cells patrol the body surfaces and phagocytose invading pathogens. Dendritic cells are versatile and potent APCs. Some appear to be resident in the lymph node while others, carrying antigen from peripheral tissues, migrate in the lymph to the regional lymph nodes. Dendritic cells are found in the paracortical area of lymph nodes. This group of cells also includes interdigitating cells of the thymus and Langerhans cells of the skin. Follicular dendritic cells are accessible to B cells in the germinal centres of lymph nodes. They are similar cells which are able to bind antibody-antigen complexes to their surface without prior processing.
APC function is shown on the right side of diagram (a). Antigen (e.g. a bacterium B) is taken up by APCs into an early endosome EE that fuses with a lysosome containing major histocompatibility complex class II molecules MHC II. The antigen is broken down into short antigenic peptides AP that bind to MHC II and the peptide-MHC II complex is transported to the plasma membrane. After fusion of the phagolysosome PL with the plasma membrane PM, the MHC II-peptide complex is exposed on the cell surface where it may come into contact with helper T cells TH. If the T cell receptor TCR on the TH cell can bind to that particular peptide-MHC II complex, activation will occur and the adaptive immune response will proceed. Obviously, processing of a bacterium will generate many different antigenic peptides, but only one peptide and one TH cell is shown here for simplicity.
In general, TH cells recognise peptide bound to MHC II and cytotoxic T cells TC recognise antigen bound to MHC class I MHC I. On the left of diagram (a), processing of intrinsic viral antigen in a virus-infected cell is shown. The viral protein VPr is chopped into short peptides VP by a proteasome (an organelle that breaks down abnormal proteins). The peptides bind to MHC I and are presented on the cell surface for interaction with a TC. Almost all body cells express MHC I but usually only APCs express MHC II.
Micrograph (b) illustrates several lymphocytes and an APC in a lymph node. Lymphocytes and APCs exhibit similar features in other lymphoid tissues. The lymphocytes L are relatively small with round nuclei and condensed chromatin that tends to be clumped around the periphery of the nucleus. Cell outlines are fairly regular with occasional surface projections. The scanty cytoplasm contains plentiful free ribosomes and a few mitochondria but little endoplasmic reticulum, lysosomes or secretory granules.
The centre of the field is occupied by the large cell body of an antigen presenting cell APC, in this case a dendritic cell. These have numerous long branched cytoplasmic extensions CE reaching out between the surrounding lymphocytes so that a single dendritic cell can be in contact with many different lymphocytes. Its nucleus is deeply indented with dispersed chromatin; in this example, the plane of section has resulted in a small nuclear extension appearing to be separate from the main part of the nucleus. Typically, the APC cytoplasm contains numerous small lysosomes Ly and larger phagosomes P.



AP antigenic peptide APC antigen presenting cell B bacterium CE cytoplasmic extension EE early endosome ER endoplasmic reticulum L lymphocyte Ly lysosome MHC I major histocompatibility complex class I MHC II major histocompatibility complex class II P phagosome PL phagolysosome PM plasma membrane TC cytotoxic T cell TCR T cell receptor TH T helper cell VP viral peptide VPr viral protein



Thymus


The thymus is a flattened lymphoid organ located in the upper anterior mediastinum and lower part of the neck. The thymus is most active during childhood, reaching a weight of about 30 to 40 g at puberty, after which it undergoes slow involution so that in the middle-aged or older adult it may be difficult to differentiate from adipose tissue macroscopically.


In the embryo, the thymus originates from epithelial outgrowths of the ventral wing of the third pharyngeal pouch on each side. These merge in the midline, forming a single organ subdivided into numerous fine lobules. The epithelium develops into a sponge-like structure containing a labyrinth of interconnecting spaces that become colonised by immature T lymphocytes derived from haematopoietic tissue elsewhere in the developing embryo. Towards the centre of the organ, the epithelial framework has a coarser structure with smaller interstices and a much smaller lymphocyte population, so that on microscopic examination, the gland has a highly cellular outer cortex and a less cellular central medulla.


The epithelial cells of the thymus provide a mechanical supporting framework for the lymphocyte population. Cortical epithelial cells also promote T cell differentiation and proliferation. Furthermore, the epithelial cells secrete a number of different hormones that regulate T cell maturation and proliferation within the thymus and in other lymphoid organs and tissues. The inner surfaces of the thymic capsule and septa are invested by a continuous layer of thymic epithelial cells resting on a basement membrane. The epithelium also forms sheaths around the blood vessels, creating a barrier to the entry of antigenic material into the thymic parenchyma. This is known as the blood-thymus barrier.


The functions of the thymus include:




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FIG. 11.4 Thymus
(a) Infant, H&E (LP) (b) Adult, H&E (LP)
The infant thymus (a) is a lobulated organ invested by a loose collagenous capsule C from which interlobular septa S containing blood vessels radiate into the substance of the organ. The thymic tissue is divided into two distinct zones, a deeply basophilic outer cortex Cx and an inner eosinophilic medulla M; distinction between the two is most marked in early childhood, as in this specimen.
In the adult (mid-30s in this case), the thymus (b) is already well into the process of involution, which involves two distinct processes, fatty infiltration and lymphocyte depletion. Fat cells (adipocytes) first begin to appear at birth, their numbers slowly rising until puberty when the rate of fatty infiltration increases markedly. Fatty infiltration of the interlobular septa occurs first, spreading out into the cortex and later the medulla. Thus, in the mature thymus islands of lymphoid tissue L are separated by areas of adipose tissue A. At this age, the cortex and medulla can still be differentiated. In the elderly, the thymus can be very difficult to detect both macroscopically and microscopically, with only small islands of lymphoid tissue lost in a sea of adipose tissue. Lymphocyte numbers begin to fall from about 1 year of age, the process continuing thereafter at a constant rate. Despite this, the thymus continues to provide a supply of mature T lymphocytes to the circulating pool and peripheral tissues. Lymphocyte depletion results in collapse of the epithelial framework. However, cords of epithelial cells persist and continue to secrete thymic hormones throughout life.
The normal process of slow thymic involution associated with aging should be distinguished from acute thymic involution, which may occur in response to severe disease and metabolic stress associated with pregnancy, lactation, infection, surgery, malnutrition, malignancy and other systemic insults. Stress involution is characterised by greatly increased lymphocyte death and is probably mediated by high levels of corticosteroids; thus the size and activity of the adult thymus are often underestimated if examined after prolonged illness.
Numerous small branches of the internal thoracic and inferior thyroid arteries enter the thymus via the interlobular septa, branching at the corticomedullary junction to supply the cortex and medulla. Postcapillary venules in the corticomedullary region have a specialised cuboidal endothelium similar to that of the high endothelial venules of the lymph node (see Fig. 11.11), which allows passage of lymphocytes into and out of the thymus. The venous and lymphatic drainage follow the course of the arterial supply; there are no afferent lymphatics. Sympathetic and parasympathetic nerve fibres derived from the sympathetic chain and phrenic nerves, respectively, accompany the blood vessels into the thymus.

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Aug 22, 2016 | Posted by in HISTOLOGY | Comments Off on Immune system

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