* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Antigen-presenting cells
Survey
Document related concepts
Gluten immunochemistry wikipedia , lookup
Anti-nuclear antibody wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Duffy antigen system wikipedia , lookup
Immunocontraception wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Complement system wikipedia , lookup
DNA vaccination wikipedia , lookup
Immune system wikipedia , lookup
Molecular mimicry wikipedia , lookup
Adaptive immune system wikipedia , lookup
Innate immune system wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Transcript
Immunology College of Dentistry Third stage Asst. Proff.Dina M.R. Alkhafaf IMMUNE SYSTEM. A. Specific and Nonspecific Defenses. The protection of the organism against infectious agents involves many different mechanisms, some nonspecific (i.e., generically applicable to many different pathogenic organisms), and others specific (i.e., their protective effect is directed to one single organism). 1. Nonspecific defenses, which as a rule are innate (i.e., all normal individuals are born with it), include: a. Mechanical barriers, such as the integrity of the epidermis and mucosal membranes. b. Physicochemical barriers, such as the acidity of the stomach fluid. c. Antibacterial substances (e.g., lysozyme) present in external secretions. d. Normal intestinal transit and normal flow of bronchial secretions and urine, which eliminate infectious agents from the respective systems. e. Ingestion and elimination of bacteria and particulate matter by granulocytes, which is independent of the immune response. 2. Specific defenses, as a rule, are induced during the life of the individual as part of the complex sequence of events designated as the immune response. B. Unique Characteristics of the Immune Response. The immune response has two unique characteristics: 1. Specificity for the eliciting antigen. For example, immunization with poliovirus only protects against poliomyelitis, not against the flu. The specificity of the immune response is due to the existence of exquisitely discriminative antigen receptors on lymphocytes. Only a single or a very limited number of similar structures can be accommodated by the receptors of any given lymphocyte. When those receptors are occupied, an activating signal is delivered to the lymphocytes. Therefore, only those lymphocytes with specific receptors for the antigen in question will be activated. 2. Memory, meaning that repeated exposures to a given antigen elicit progressively more intense specific responses. Most immunizations involve repeated administration of the immunizing compound, with the Immunology goal of establishing a long-lasting, protective response. The increase in the magnitude and duration of the immune response with repeated exposure to the same antigen is due to the proliferation of antigenspecific lymphocytes after each exposure. The numbers of responding cells will remain increased even after the immune response subsides. Therefore, whenever the organism is exposed again to that particular antigen, there is an expanded population of specific lymphocytes available for activation and, as a consequence, the time needed to mount a response is shorter and the magnitude of the response is higher. C. Stages of the Immune Response. To better understand how the immune response is generated, it is useful to consider it as divided into separate sequential stages (Table 1.1). The first stage (induction) involves a small lymphocyte population with specific receptors able to recognize an antigen or a fragment generated by specialized cells known as antigenpresenting cells (APC). The proliferation and differentiation of antigenresponding lymphocytes is usually enhanced by amplification systems involving APC and specialized T-cell subpopulations (T helper cells, defined below) and is followed by the production of effector molecules (antibodies) or by the differentiation of effector cells (cells which directly or indirectly mediate the elimination of undesirable elements). The final outcome, therefore, is the elimination of the microbe or compound that triggered the The Cells of the Immune System A. Lymphocytes and Lymphocyte Subpopulations. The peripheral blood contains two large populations of cells: the red cells, whose main physiological role is to carry oxygen to tissues, and the white blood cells, which have as their main physiological role the elimination of potentially harmful organisms or compounds. Among the white blood cells, lymphocytes are particularly important because of their primordial role in the immune response. Several subpopulations of lymphocytes have been defined: 1. B lymphocytes, which are the precursors of antibody-producing cells, known as plasma cells. 2. T lymphocytes, or T-cells, which are further divided into several subpopulations: a. Helper T lymphocytes (TH), which play a very significant amplification role in the immune responses. Two functionally distinct subpopulations of T helper lymphocytes have been well defined in mice. Immunology i. TH1 lymphocytes, which assist the differentiation of cytotoxic cells and also activate macrophages, which after activation play a role as effectors of the immune response. ii. TH2 lymphocytes, which are mainly involved in the amplification of B lymphocyte responses. These amplifying effects of helper T lymphocytes are mediated in part by soluble mediators— interleukins—and in part by signals delivered as a consequence of cell-cell contact. b. Cytotoxic T lymphocytes, which are the main immunological effector mechanisms involved in the elimination of non-self or infected cells. 3. Antigen-presenting cells, such as the macrophages and macrophagerelated cells, play a very significant role in the induction stages of the immune response by trapping and presenting both native antigens and antigen fragments in a most favorable way for the recognition by lymphocytes. In addition, these cells also deliver activating signals to lymphocytes engaged in antigen recognition, both in the form of soluble mediators (interleukins such as IL-12 and IL-1) and in the form of signals delivered by cell-cell contact. 4. Phagocytic and cytotoxic cells, such as monocytes, macrophages, and granulocytes, also play significant roles as effectors of the immune response. Once antibody has been secreted by plasma cells and is bound by the microbes, cells, or compounds that triggered the immune response, it is able to induce their ingestion by phagocytic cells. If bound to live cells, antibody may induce the attachment of cytotoxic cells that cause the death of the antibody-coated cell (antibody-dependent cellular cytotoxicity; ADCC). The ingestion of microorganisms or particles coated with antibody is enhanced when an amplification effector system known as complement is activated. 5. Natural killer (NK) cells play a dual role in the elimination of infected and malignant cells. These cells are unique in that they have two different mechanisms of recognition: they can identify directly virus-infected and malignant cells and cause their destruction, and they can participate in the elimination of antibody-coated cells by ADCC. Antigens and Antibodies A. Antigens are non-self substances (cells, proteins, polysaccharides) that are recognized by receptors on lymphocytes, thereby eliciting the immune Immunology response. The receptor molecules located on the membrane of lymphocytes interact with small portions of those foreign cells or proteins, designated as antigenic determinants or epitopes. An adult human being has the capability of recognizing millions of different antigens, some of microbial origin, others present in the environment, and even some artificially synthesized. B. Antibodies are proteins that appear in circulation after immunization and that have the ability to react specifically with the antigen used to immunize. Because antibodies are soluble and are present in virtually all body fluids (“humors”), the term humoral immunity was introduced to designate the immune responses in which antibodies play the principal role as effector mechanisms. Antibodies are also generically designated as immunoglobulins. This term derives from the fact that antibody molecules structurally belong to the family of proteins known as globulins (globular proteins) and from their involvement in immunity. C. Antigen-Antibody Reactions, Complement, and Phagocytosis. The knowledge that the serum of an immunized animal contained protein molecules able to bind specifically to the antigen led to exhaustive investigations of the characteristics and consequences of the antigenantibody reactions. 1. If the antigen is soluble, the reaction with specific antibody under appropriate conditions results in precipitation of large antigen-antibody aggregates. 2. If the antigen is expressed on a cell membrane, the cell will be crosslinked by antibody and form visible clumps (agglutination). 3. Viruses and soluble toxins released by bacteria lose their infectivity or pathogenic properties after reaction with the corresponding antibodies (neutralization). 4. Antibodies complexed with antigens can activate the complement system. This system is composed of nine major proteins or components which are sequentially activated. Some of the complement components are able to promote ingestion of microorganisms by phagocytic cells (phagocytosis), while others are inserted into cytoplasmic membranes and cause their disruption, leading to cell death. Immunology 5. Antibodies can cause the destruction of microorganisms by promoting their ingestion by phagocytic cells or their destruction by cytotoxic cells. Phagocytosis is particularly important for the elimination of bacteria and involves the binding of antibodies and complement components to the outer surface of the infectious agent (opsonization) and recognition of the bound antibody and/or complement components as a signal for ingestion by the phagocytic cell. 6. Antigen-antibody reactions are the basis of certain pathological conditions, such as allergic reactions. Antibodymediated allergic reactions have a very rapid onset, in a matter of minutes, and are known as immediate hypersensitivity reactions. Characteristics of Immunogenicity Many different substances can induce immune responses. The following characteristics have an important influence in the ability that a substance has to behave as an immunogen. A. Foreigness. As a rule, only substances recognized as “non-self” will trigger the immune response. Microbial antigens and heterologous proteins are obviously “non-self” and are strongly immunogenic. B. Molecular Size. The most potent immunogens are macromolecular proteins [molecular weight (M.W.) > 100,000]. Molecules smaller than 10,000 daltons are weakly immunogenic. C. Chemical Structure and Complexity. Proteins and polysaccharides are among the most potent immunogens, although relatively small polypeptide chains, nucleic acids, and even lipids can, given the right circumstances, be immunogenic. 1. Proteins. Large heterologous proteins expressing a wide diversity of antigenic determinants are potent immunogens. a. The immunogenicity of a protein is strongly influenced by its chemical composition. Positively charged (basic) amino acids, such as lysine, arginine, and histidine are repeatedly present in the antigenic sites of lysozyme and myoglobin, while aromatic amino acids (such as tyrosine) are found in two of albumin's six antigenic sites. Therefore, it appears that basic and aromatic amino acids may contribute more strongly to immunogenicity than other amino acids; basic proteins with clusters of positively charged amino acids are strong immunogens. Immunology b. There appears to be a direct relationship between antigenicity and chemical complexity: aggregated or chemically polymerized proteins are much stronger immunogens than their soluble monomeric counterparts. 2. Polysaccharides. Polysaccharides are among the most important natural antigens, since either pure polysaccharides or the sugar moieties of glycoproteins, lipopolysaccharides, glycolipid-protein complexes, etc., are immunogenic. Many microorganisms have polysaccharide-rich capsules or cell walls, and a variety of mammalian antigens, such as the erythrocyte antigens (A, B, Le, H), are short-chain polysaccharides (oligosaccharides). 3. Nucleic acids. Nucleic acids usually are not immunogenic, but can induce antibody formation if coupled to a protein to form a nucleoprotein. The autoimmune responses characteristic of some of the so-called autoimmune diseases (e.g., systemic lupus erythematosus) are often directed to DNA and RNA that may have stimulated the immune system as nucleoproteins. 4. Polypeptides. Hormones such as insulin and other polypeptides, although relatively small in size (M.W. 1500), are usually immunogenic when isolated from one species and administered over long periods of time to an individual of a different species. Antigens An antigen is a substance that reacts with an antibody. Immunogens induce an immune response and most antigens are also immunogens. There are a wide variety of features that largely determine immunogenicity. They include the following: (1) Recognition of foreignness: Generally, molecules recognized as “self” are not immunogenic. To be immunogenic, molecules must be recognized as foreign (“nonself”). (2) Size: The most potent immunogens are usually large, complex proteins. Molecules with a molecular weight less than 10,000 are weakly immunogenic, and as expected very small molecules are nonimmunogenic. Some small molecules, called haptens, become immunogenic only when linked to a carrier protein. Immunology An example is seen with lipids and amino acids that are nonimmunogenic haptens. They require conjunction with a carrier protein or polysaccharide before they can be immunogenic or generate an immune response (3) Chemical and structural complexity: Chemical complexity is another key feature of immunogenicity. For example, amino acid homopolymers are less immunogenic than heteropolymers that contain two or more different amino acids (4) Genetic constitution of the host: Because of differences in MHC alleles, two strains of the same species of animal may respond differently to the same antigen. (5) Dosage, route, and timing of antigen administration: Other factors that affect immunogenicity include concentration of antigen administered, route of administration, and timing of antigen administration. These concepts of immunogenicity are important for designing vaccines in which enhancing immunogenicity is key. However, methods to reduce immunogenicity are also a consideration in protein drug design. This can be seen in an individual who may respond to a certain drug and produce anti-drug antibodies. These anti-drug antibodies may inhibit drug efficacy. Finally, it should be noted that it is possible to enhance the immunogenicity of a substance by combining it with an adjuvant. Adjuvants are substances that stimulate the immune response by facilitating uptake into APCs. I. General Structure of Immunoglobulins A. Information concerning the precise structure of the antibody molecule started to accumulate as technological developments were applied to the study of the general characteristics of antibodies. By the early 1940s antibodies had been characterized electrophoretically as gamma globulins (Fig. 5.1) and also classified into large families by their sedimentation coefficient determined by analytical ultracentrifugation (7S and 19S antibodies). It also became evident that plasma cells were responsible for immunoglobulin synthesis and that a malignancy known as multiple myeloma was a malignancy of immunoglobulin-producing plasma cells. B. As protein fractionation techniques became available, complete immunoglobulins and their fragments were isolated in large amounts, particularly from the serum and urine of patients with multiple myeloma. These proteins were used both for studies of chemical structure and for immunological studies that led to the definition of antigenic differences Immunology between proteins from different patients; this was the basis for the initial identification of the different classes and subclasses of immunoglobulins and the different types of light chains. Immunoglobulin G (IgG): The Prototype Immunoglobulin Molecule. A. General Considerations. IgG, a 7S immunoglobulin, is the most abundant immunoglobulin in human serum and in the serum of most mammalian species. It is also the immunoglobulin most frequently detected in large concentrations in multiple myeloma patients. For this reason, it was the first immunoglobulin to be purified in large quantities and to be extensively studied from the structural point of view. The basic knowledge about the structure of the IgG molecule was obtained from two types of experiments: 1. Proteolytic digestion. The incubation of purified IgG with papain, a proteolytic enzyme extracted from the latex of Carica papaya, results in the splitting of the molecule into two fragments that differ both in charge and antigenicity. These fragments can be easily demonstrated by immunoelectro The Minor Immunoglobulin Classes: IgD and IgE A. General Concepts. IgD and IgE were the last immunoglobulins to be identified due to their low concentrations in serum. Both are monomeric immunoglobulins, similar to IgG, but their heavy chains are larger than chains. IgE has five domains in the heavy chain (one variable and four Immunology constant); IgD has four heavy-chain domains (as most other monomeric immunoglobulins). B. IgD and IgM are the predominant immunoglobulin classes in the B lymphocyte membrane, where they are the antigen-binding molecules in the antigen-receptor complex. The B-cell antigen complex is composed of membrane Ig Immunoglobulin Classes A. IgG IgG is the major class of immunoglobulin present in the serum. The IgG molecule consists of two L chains and two H chains (H2L2) (Figure 8-5). There are four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. Each subtype contains a distinct but related H chain and each differs somewhat regarding their biological activities. IgG1 represents 65% of the total IgG. IgG2 is directed against polysaccharide antigens and may be an important host defense against encapsulated bacteria. IgG3 is an effective activator of complement due to its rigid hinge region, whereas IgG4 does not activate complement due to its compact structure. IgG is the only immunoglobulin class to cross the placenta and therefore is the most abundant immunoglobulin in newborns. Isotype-specific transport of IgG across the placenta occurs with preference for IgG1 and IgG3 subclasses. IgG also mediates opsonization of antigen through binding of antigenantibody complexes to Fc receptors on macrophages and other cells. B. IgM The first immunoglobulin produced in response to an antigen is IgM. IgM is secreted as a pentamer and is composed of five H2L2 units (similar to one IgG unit) and one molecule of a J chain (Figure 8- in the fetus or newborn provides evidence of intrauterine infection. C. IgA IgA is the major immunoglobulin responsible for mucosal immunity. The levels of IgA in the serum are low, consisting of only 10–15% of total serum immunoglobulins present. In contrast, IgA is the predominate class of immunoglobulin found in extravascular secretions. Thus, plasma cells located in glands and mucous membranes mainly produce IgA. Therefore, IgA is found in secretions such as milk, saliva, and tears, and in other secretions of the respiratory, intestinal, and genital tracts. These locations place IgA in contact with the external environment and therefore can be the first line of defense against bacteria and viruses. The properties of the IgA molecule are different depending on where IgA is Immunology located. In serum, IgA is secreted as a monomer resembling IgG. In mucous secretions, IgA is a dimer and is referred to as secretory IgA. This secretory IgA consists of two monomers that contain two additional polypeptides: the J chain that stabilizes the molecule and a secretory component that is incorporated into the secretory IgA when it is transported through an epithelial cell. There are at least two IgA subclasses: IgA1 and IgA2. Some bacteria (eg, Neisseria spp.) can destroy IgA1 by producing a protease and can thus overcome antibodymediated resistance on mucosal surfaces. D. IgE The IgE immunoglobulin is present in very low quantities in the serum. The Fc region of IgE binds to its high-affinity receptor on the surface of mast cells, basophils, and eosinophils. This bound IgE acts as a receptor for the specific antigen that stimulated its production and the resulting antigen– antibody complex triggers allergic responses of the immediate (anaphylactic) type through the release of inflammatory mediators such as histamine. E. IgD Serum IgD is present only in trace amounts. However, IgD is the major surface bound immunoglobulin on mature B lymphocytes that have not yet encountered antigen. These B cells contain IgD and IgM at a ratio of 3 to 1. At the present time, the function of IgD is unclear. Immunology