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Basic Components of the Immune System Explained
- 1. Basic Components of the Immune System Themba Hospital FCOG(SA) Part 1 Tutorials By Dr N.E Manana
- 2. INTRODUCTION • It is generally believed that the immune system evolved as the host’s defence against infectious agents • However, it may well play a larger role in the elimination of other foreign substances, tumour cells and antibodies that attack self. An immune response may be conveniently divided into two parts: (1) A specific response to a given antigen (2) A more nonspecific augmentation to that response
- 3. • Fig 1.1
- 4. Macrophages • Divided into two main groups: the dendritic cell and the mature macrophage. • The dendritic cell’s major function is to present antigen to the lymphocyte, and it is the earliest cell to recognize foreign antigen • There are two forms of dendritic cells: immature and mature • The induction of an adaptive immune response begins when a pathogen is ingested by an immature dendritic cell • This immature cell carries receptors on its surface that recognize common features of many pathogens such as cell wall carbohydrates of bacteria
- 5. Macrophages • The mature macrophage also derives from primitive stem cells in the bone marrow, but unlike the lymphocyte, it matures in the tissues • Thus monocytes, the precursors of mature macrophages, circulate for only a few hours before entering the tissues • Where they live for months as mature macrophages • There is great variety in the tissue macrophages; they are heterogeneous in appearance and metabolism. • The primary function of these mononuclear cells is to phagocytose invading organisms, dead cells, immune complexes, and antigens
- 6. Neutrophils • These cells produce adhesin molecule receptors, permitting them to adhere to and migrate from the blood vessels to the site of infection • They are attracted to the site by IL-8, C3a, and C3b, cytokines released by TH1 cells, and mast cells • These cells are also phagocytic cells, and the process of phagocytosis is similar to that seen in macrophages. • They are particularly effective when the invading organism becomes coated with antigen-specific antibodies (opsonins) along with activated complement components
- 7. Others • NK cells also can kill target cells in the absence of either antigen or antibody stimulation • Their lineage is not known, but they are probably in some manner related to T cells. • Unlike other cells, they can be non-specifically activated by mitogens, interferon, and IL-12. • These cells are particularly useful in the early response to viral infection • NK cells have a broad range of specificity and no real memory
- 8. INITIATION OF THE IMMUNE RESPONSE • The first step must involve modification of the antigen, and these specialized cells are called APCs (Antigen presenting cells) • Without such processing, T cells cannot recognize antigen • Secretion of cytokines by APCs activated by antigen presentation that further activates antigen specific T cells • Antigen is presented to the T cells in the MHC complex present on the surface of APCs • The most efficient APCs are the dendritic cells
- 9. CYTOKINES • They are secreted by macrophages (and T, B, epithelial cells and fibriblast) and may act as stimulatory or inhibitory signals between cells • Cytokines that initiate chemotaxis of leucocytes are called chemokines, other are interferons, interleukins, lymphokines and TNFs • Interleukins 1 (IL-1) and 2 (IL-2) are of particular importance secondary to their role in amplifying the immune response • IL-1 acts on a wide range of cells including T and B cells. • In contrast, IL-2 primarily acts on lymphocytes
- 10. Specific immune response The specific immune response may be divided into two parts (mediated through the lymphocyte) : (1) The humoral response (2) The cellular response to a given antigen. • Humoral responses are antibodies produced in response to a given antigen • These antibodies are proteins, have similar structures, and can be divided into various classes (immunoglobulins) • Cellular immune responses require an intact Thymus, and are mediated by T (Thymus) lymphocytes, • While antibody producing cells are dependent on the bone (bursa) marrow, are known as B cells.
- 11. Specific immune response • Antigens, both foreign and self, are substances that may or may not provoke an immune response • Both T cells and B cells have receptors that recognize these antigens. • In the case of B cells, antibodies on the surface are a major source of antigen recognition, and once activated, they differentiate into plasma cells that produce large quantities of antibodies • T cells have similar receptors known as T-cell receptors (TCR), and in the context of the major histocompatibility complex (MHC) molecules provide a means of self-recognition functions. • Some functions are carried out by messages transmitted between these cells (interleukins or cytokines)
- 12. ANTIBODY • FIG 1.2A 1.2B
- 13. Antibodies • The IgM molecule is the oldest class of immunoglobulins, and it is a large molecule consisting of five basic units held together by a J chain. • • The reason for this important physiological role is that it contains five complement-binding sites, resulting in excellent complement activation • Because of its size, it does not usually penetrate into tissues • In contrast, IgG is a smaller molecule that penetrates easily into tissues.
- 14. Antibodies • The major mucosal immunoglobulin, IgA, consists of two basic units joined by a J chain • IgA2 is the major IgA molecule in secretions and is quite effective in neutralizing antigens that enter via these mucosal routes • IgD is synthesized by antigen-sensitive B cells and is involved in the activation of these cells by antigen • IgE is produced by plasma cells and binds to specific IgE receptors on most cells and basophiles
- 15. T CELLS AND THEIR RECEPTORS • Each T cell is also committed to a given antigen and recognizes it by one of two TCRs. • They may have TCR2s composed of gamma (γ) and delta (δ) chains or TCR2s composed of another heterodimer of alpha (α) and beta (β) chains • These TCR2s are associated with a group of transmembrane proteins on the CD3 molecule, which takes the antigen recognition signal inside the cell • The TCR complex recognizes small peptides presented to it by the MHC class I and II
- 16. MAJOR HISTOCOMPATIBILITY COMPLEX • Human histocompatibility antigens are also known as human leucocyte antigens (HLA), synonymous with the MHC complex. • These antigens are cell surface glycoproteins classified as type I or type II. • They can produce genetic polymorphism with multiple alleles at each site, thus permitting a great deal of genetic variability between given individuals • Recognition of antigen by T cells is MHC restricted.
- 18. • Table 1.1
- 19. ANTIBODY PRODUCTION • To achieve antibody production, at least four types of cells are required: APCs, B cells, and two types of regulating cells • Antibodies are produced by naïve B cells and are called plasma cells • In the early stages, B cells first show surface IgM • These cells can later express IgG, IgA, or IgE, a phenomenon known as isotype switching • Surface immunoglobulin act as its antigen-receptor site
- 20. ANTIBODY PRODUCTION • A number of these B cells become memory cells so that a greater number of antigen specific B cells are available on a secondary contact with the same antigen. • This phenomenon is known as clonal expansion and helps to account for the greater secondary response • B cells alone do not respond to antigen directly, even in the presence of APC cells. • They must have a second signal, normally provided by the T cells
- 21. Cellular Immunity • Cell-mediated responses are implemented by T lymphocytes • The major functions of T cells can be divided into two categories - the first (cytotoxicity) is to lyse cells expressing specific antigens (CD8+ cells is a potent killer of virally infected cells) -The second (delayed hypersensitivity) is to release cytokines, thereby triggering an inflammatory response
- 22. COMPLEMENT • The complement component system consists of a series of heat-liable proteins, and they normally exist as inactive precursors • However, once activated each component may act as an enzyme and cleaves the next component in the sequence • The control of the sequence relies on either spontaneous decay or specific inactivation • Minor fragments play a role chemotaxis • The major function of the complement system is to help in the opsonization of microorganisms and immune complexes
- 23. COMPLEMENT • The critical step in complement activation is the cleavage of the C3 component by complement-derived enzymes called C3 convertases. • This results in the presence of C3b, which mediates a number of vital biological activities • Individuals who are deficient in C3 are obviously predisposed to bacterial infections and immune complex disease
- 24. • Figure 1.9
- 25. Thank you
Editor's Notes
- An important feature of the specific response is that there is a quicker response to the antigen during a second exposure to that antigen. It is the memory of the initial response that provides the booster effect
- Once the bacterium is in contact with these receptors, the dendritic cell is stimulated to engulf the pathogen and degrade it intracellularly These cells reside in most tissues and are relatively long-lived. As seen in Figure 1.1, they are derived from the same cell myeloid precursor as the macrophage These cells also continue engulfing extracellular material (both viruses and bacteria) by a receptor-independent mechanism of macropinocytosis. Once accomplished, the main function of the “activated” dendritic cell is to carry pathogenic antigens to the peripheral lymphoid organs to present them to T lymphocytes. Once arrived, the dendritic cell matures into an APC, which now permits it to activate pathogen-specific lymphocytes. Another function of activated dendritic cells is to secrete cytokines that influence both the innate and adaptive immune responses
- They include mobile alveolar and peritoneal macrophages. There are also fixed cells in the liver called Kupffer cells and skin macrophages called Langerhans cells To do this, these cells are equipped with powerful lyososomal granules containing acid hydrolases and other degrading enzymes. Macrophages need activation to carry out these functions. These include cytokines, which can bind to IgG: Fc receptors or most importantly (as we shall see later) receptors for bacterial polysaccharides. In addition, they can be activated by soluble inflammatory products such as C5a. In turn, the macrophages can release monokines, such as TNF or IL-1, which increase the inflammation in inflamed tissues.
- As in other cells, they have receptors on their surface that recognize particular ligands. For example, NKR-PI is a lectin-like receptor that recognizes carbohydrate moieties on target cells, which initiates killing. As in other cell systems, there is also an inhibiting receptor called KIR. This molecule binds to ligands on MHC class I ligands, and this prevents killing of the target cell NK deficiencies indicate that they have a greater incidence of viral infections and malignancies. This suggests that they have broad “immunological surveillance” properties but the exact mechanisms whereby they exert those properties are not known. The use of an antibody-coated target to destroy foreign target cells is called antibody-dependent cell-mediated cytotoxicity, or ADCC. This killing is dependent on the recognition by cells bearing Fc receptors and includes monocytes, neutrophils, and NK cells. These cells do not need simultaneous recognition by MHC molecules. The mechanisms of killing most likely involve the release of cytoplasmic components of the target cells and perforin, but additional factors are also probably involved.
- The effector cells are really divided into two types: B cells and T cells. B cells are primarily responsible for antibody production whereas T cells act as effector cells and may function as both helpers and suppressors, depending on the stimulus provided by APCs. This interaction between APCs and T cells is strongly influenced by a group of molecules called co-stimulators. For example, it is CD80 (B7-1) and CD86 (B7-2) on the APC cells with receptors CD28 and CTLA-4 on the T cell that provides this interaction The absence of these co-stimulators leads to T-cell unresponsiveness. dendritic cells. These cells have high concentrations of MHC class I and II antigens, co-stimulatory molecules, and adhesion molecules on their surface. The dendritic cells of the skin are called the Langerhans cells and play an important role in immune defenses since they are present in the largest protective organ of the body Because they are mobile, Langerhans cells can capture antigen in the periphery and migrate to secondary lymph nodes where they become mature dendritic cells and interact with naïve T cells In contrast, the follicular dendritic cells reside in the follicular germinal center (B-cell area) of a lymph node. These cells have receptors for complement and immunoglobulins and their function is to trap immune complexes and feed them to B cells. This processed immune complex containing antigen is closely associated with MHC class II molecules on the APC surface and thus activates B cells.
- This group of soluble molecules plays an extremely important role in clinical immunology Among the group of cytokines, there are a few of particular interest because of their stimulatory activity.
- Each chain is composed of domains of 110 amino acids and is connected in a loop by a disulfide bond between two cysteine residues in the chain. The amino acids of these variable domains vary between different antibody molecules and are thus known as the variable (V) regions When the hypervariable regions in each chain come together along with the counterparts on the other pair of H and L chains, they form the antigen-binding site. This part of the molecule is unique to the molecule and is known as the idiotype determinant In any individual, 106 to 107 different antibody molecules can be composed from 103 different heavy and light chains of the variable regions
- The major role IgM plays is the intravascular neutralization of organisms, especially viruses. This activation permits the segment removal of antigen–antibody complement complexes via complement receptors on phagocytic cells or complement-mediated lysis of the organism IgG1 and IgG3 activate complement efficiently and clear most protein antigens, including the removal of microorganisms by phagocytic cells. In contrast, IgG2 and IgG4 react mostly with carbohydrate antigens and are relatively poor opsonins.
- Thus,. IgE: This molecule plays an extremely important role in allergic reactions and expelling intestinal parasites, which is accomplished by increasing vascular permeability and inducing chemotactive factors following mast cell degranulation
- Signal transduction via the CD3 complex is regulated by a series of kinases, which are associated with the tails of the CD3–TCR complex and regulate phosphorylation. Deficiencies or blocks in the T-cell signaling pathways either at the cell-surface complex or at the level of the kinases may result in various forms of immunodeficiency. The genes for TCR chains are on different chromosomes with the β and α molecules on chromosome 7, while the α and δ are on chromosome 14. the four chains are made up of a variable region and a constant region similar to those observed with the immunoglobulins. The variable regions are also numerous and joined at D and J regions by RAG1 and RAG2. This permits a diversity of antigen recognition similar to that observed with immunoglobulin, but additional somatic mutation is not involved in T cells. Helper T cells (CD4) recognize class II antigens while suppressor cytotoxic T cells (CD8) recognize class I antigens. Because of the rather low affinity of the reactions, recognition of processed antigen alone is not sufficient to activate T cells. Soluble interleukins are needed to complete the picture and are generated during the antigen processing
- This extensive polymorphism is important when viewed in the context of an immune system that needs to cope with an ever-increasing range of pathogens These pathogens in turn are extremely adept at evading the immune system. Thus, the battle between invading microbe and immune recognition is constant and ever changing. The MHC class I antigens are divided into three groups (A, B, and C), and each group belongs on a different gene locus on chromosome 6 The MHC class I antigen differences are due to variations in the α chains, the β2 microglobulin being constant MHC class II antigens also exhibit a similar structure with the groove being formed by the α1 and β1 chains. Unlike class I antigens present on most nucleated cells, the class II antigens are restricted to a few types: macrophages, B cells, and activated T cells. In humans, there are three groups of class II antigens: namely, HLADP, HLA-DQ, and HLA-DR. Depending on the nature of the antigen (endogenous or exogenous), the MHC response is different. For example, endogenous antigens (including viral antigens) are presented by MHC class I antigen cells exclusively to CD8 cells. The endogenous antigen is first broken down into small peptides and transported by shuttle proteins called Tap I and Tap II to the endoplasmic reticulum. There they complex with MHC class I molecules and are delivered to the cell surface for further processing to the CD8 cells. In contrast, MHC class II molecules are held in the endoplasmic reticulum and are protected from binding to peptides in the lumen (not human) by a protein called MHC class II associated invariant chain.
- The final type of surface immunoglobulin determines the class of antibody secreted. Isotype switching is mediated through two important protein interactions: CD40 on the B cell interacts with CD40L on activated T cells (IL-4 induced) to stimulate B cells to switch from IgM molecules to other isotypes Deficiencies in either molecule lead to severe immunodeficiency states with only IgM produced but no IgG or IgA antibodies. This syndrome is called the hyper-IgM syndrome, and in this case of CD40L deficiency, it is an X-linked immunodeficiency Perhaps more important is that the secondary response of antibodies has a higher affi nity binding for these antigens. These latter antibodies will bind to antigen even when complexed to antibody and help clear the antigen more effectively from the circulation
- Cytotoxic T cells lyse cells infected with viruses. This cytotoxicity is virus specific, and only cells expressing those proteins on the surface of the infected cell are killed As stated before, this destruction occurs only in the presence of the same MHC class I molecules. This combination directly activates CD8+ cells and is a potent killer of virally infected cells Cytotoxic T cells also play a role in graft rejection In contrast, delayed-type hypersensitivity reactions are mediated by specific T cells that produce TH1-type cytokines upon exposure to antigen An example of this type of reaction is the PPD reaction, or tuberculin test.
- Each precursor is cleaved into two or more components, and the major fragment (designated “b”) has two biologically active sites. One is for binding to cell membranes and the other is for enzymatic cleavage of the next component These components plus antibody are more readily recognized by macrophages and more readily bound and phagocytosed through IgG: Fc and C3b receptors. Individuals who lack one of the classical pathway components are prone to immune complex disease The minor complement fragments contribute to the immune response by activating the inflammatory response. For example, some increase vascular permeability (C3a); others are chemotactins for neutrophils and macrophages (C5a) and not only promote leucocytosis in the bone marrow but attract these cells to the site of infl ammation
- The cleavage of C3b can be initiated by three routes (classical, alternative, and lectin), but each route is in response to different stimuli Classical pathway: As its name implies, this is the usual pathway whereby antigen–antibody complexes in the presence of complement destroy the invading organism. The antibody (either IgM or IgG) causes a conformational change in the Fc portion of the antibody to reveal a binding site for the first component of complement C1q. This component consists of six subunits and reacts with the Fc via its globular heads. The activation of this component requires the binding of two globular heads for activation. The alternative pathway is phylogenetically older than the classical but was not generally accepted until the 1960s. Again, the control reaction is the activation of C3. In contrast to the classical pathway, however, this pathway by passes antibody, C1, C4, and C2, and it is bacterial cell walls or endotoxin that activates C3. C3b here is unstable and, if an appropriate receptor is not found, it decays and the molecule becomes inactive.
- 3. Lectin pathway: The third pathway of complement activation is created by the mannose-binding lectin MBL, a circulating protein that binds to carbohydrate on the surface of many microorganisms. MBL (structurally related to C1q) activates complement through a serine protease known as MBL associated serine protease. Deficiencies in circulating levels of MBL are associated with frequent infections in childhood Once these components are activated, that is, C3b, 4b2b or C3bBb, and properdin, these molecules trigger sequentially C5, C6, C7, C8, and C9, which leads to the final lytic pathway and lysis of the target cell. The target can be a red cell, a virally infected cell, or a bacterium Electron microscopy has shown that this complex binds to the cell membrane and actually punches a hole in the cell. Salts and water pass through the hole and the water fills the cell, eventually leading to swelling and destruction of the cell control is executed in the following ways. First, many of the activated components are unstable and will decay rapidly if the next sequence is not present. Second, there are specific inhibitors of each component, such as C1 esterase, which inhibits factors I and H. Finally, the cells themselves contain proteins that increase the rates of breakdown of these products