What is opsonization in immunology
Basics of adaptive immunity
We now come to the components of adaptive immunity, the antigen-specific lymphocytes. Unless otherwise stated, from here on we use the term lymphocytes exclusively for the antigen-specific lymphocytes. Lymphocytes are able to respond to a huge number of antigens from the various pathogens that a person may come into contact with in the course of their life, and an important property is that they develop an immunological memory. The lymphocytes make this possible together with the help of the highly variable antigen receptors on their surface, through which they can recognize and bind antigens. Each lymphocyte matures and carries a specific variant of an antigen receptor prototype, so that the population of lymphocytes express a huge repertoire of receptors. Of the roughly one billion lymphocytes circulating in the body at any one time, there will always be some who can recognize a particular foreign antigen.
A special property of the adaptive immune system is that it is a immunological memory can produce. This means that once a person has come into contact with a pathogen, the reaction to this pathogen will be faster and stronger if it occurs again. This person then has protective immunity against this pathogen. Figuring out how to create long-lasting immunity against pathogens that do not naturally do so is one of the greatest challenges in immunology today.
The interaction of antigens with their antigen receptors causes the lymphocytes to perform effector and memory functions
There are two groups of lymphocytes in the vertebrate immune system - B lymphocytes (B cells ) and T lymphocytes (T cells ), These express different types of antigen receptors and have very different functions in the immune system, as was discovered in the 1960s. Most of the lymphocytes that circulate in the body act as inconspicuous small cells with a few organelles in the cytoplasm and a condensed, apparently little active chromatin in the nucleus (Fig. 1.12). Lymphocytes show little functional activity until they encounter a specific antigen that interacts with the antigen receptor on their surface. Lymphocytes that have not yet been activated by an antigen are called naive (unembossed) Lymphocytes. Those who have come into contact with their antigen are activated and further differentiate into fully functional lymphocytes, known as Effector lymphocytes designated.
B cells and T cells differ in the structures of their antigen receptors that they express. The B cell antigen receptor or B cell receptor (B-cell receptor, BCR) is made by the same genes that make antibodies, a group of proteins known as Immunoglobulins (Ig) (Fig. 1.13). The antigen receptor of B lymphocytes is therefore also known as Membrane immunoglobulin (mIg) or Surface immunoglobulin (surface immunoglobulin, sIg). The T cell antigen receptor or T cell receptor (T-cell receptor, TCR) is related to immunoglobulins, but differs in structure and binding properties.
After an antigen binds to the B-cell antigen receptor or B-cell receptor (BCR), the lymphocyte forms through proliferation and differentiation Plasma cells . This is the effector form of B lymphocytes that produces antibodies. These are the secreted form of the B-cell receptor and have the same antigen specificity as the B-cell receptor of the plasma cell. The antigen that activates a particular B-cell becomes the target for the antibodies that are produced by the offspring of that cell.
When a T cell first comes into contact with an antigen that can bind to its receptor, it forms one of several types through proliferation and differentiation T effector lymphocytes. Subsequently, when effector T cells encounter the antigen, they can develop three general types of activities. Cytotoxic T cells kill other cells that are infected with viruses or other intracellular pathogens and that carry the antigen. T helper cells provide signals, often in the form of specific cytokines, that activate the functions of other cells, such as antibody production by B cells and the killing of pathogens by macrophages that have ingested these pathogens. Regulatory T cells suppress the activity of other lymphocytes and help control immune responses; they are discussed in Chap. 10.1007 / 978-3-662-56004-4_9, 10.1007 / 978-3-662-56004-4_11, 10.1007 / 978-3-662-56004-4_12 and 10.1007 / 978-3-662-56004-4_15.
Some of the B and T cells activated by the antigen differentiate into Memory cells . These lymphocytes are responsible for the long-lasting immunity that follows after exposure to disease or vaccination. Memory cells easily differentiate into effector cells on a second contact with their specific antigen. The immunological memory is discussed in Chap. 10.1007 / 978-3-662-56004-4_11.
Antibodies and T-cell receptors consist of constant and variable regions that are each responsible for specific functions
Antibodies were analyzed using conventional biochemical methods long before recombinant DNA technology made it possible to study the membrane-bound forms of the antigen receptors in B and T cells. It turned out that antibody molecules consist of two different regions. One is that constant region , which is also known as an Fc fragment (Fc for fragment crystallizable) and which only occurs in four or five biochemically different forms (Fig. 1.13). In contrast, the variable region can consist of a huge number of different amino acid sequences through which antibodies can recognize an almost as large number of different antigens. Due to the uniformity of the Fc region compared to the variable region, Gerald Edelman and Rodney Porter carry out an X-ray structure analysis at an early stage. You were awarded the Nobel Prize in 1972 for your work on the structure of antibodies.
The antibody molecule consists of two identical ones heavy chains and two identical light chains . Heavy and light chains contain variable and constant regions. The variable regions of a heavy and a light chain together form the antigen binding site, which determines the antigen specificity of the antibody. Both the heavy and light chains contribute to the antigen specificity of the antibody molecule. Each antibody also has two identical variable regions and thus two identical antigen binding sites. The constant region determines the effector function of the antibody, i.e. how the antibody interacts with the various immune cells and acts with the antigen once it is bound.
The T-cell receptor is similar in many ways to the B-cell receptor and the antibody (Fig. 1.13). It consists of two chains, the TCRα- and the TCRβ-Chain . These are roughly the same size and span the membrane of the T cell. Like the antibody, the T-cell receptor chain also has a variable and a constant region, and through the combination of the variable α- and βChain creates a single antigen binding site. The structures of the antibodies and T-cell receptors are discussed in Chap. 10.1007 / 978-3-662-56004-4_4 discussed in more detail, the functional properties of the constant regions of the antibodies in Chap. 10.1007 / 978-3-662-56004-4_5 and 10.1007 / 978-3-662-56004-4_10.
Antibodies and T-cell receptors recognize antigens in fundamentally different ways
In principle, the adaptive immune system can recognize any chemical structure as an antigen, but the antigens that usually appear in an infection are proteins, glycoproteins and polysaccharides of the pathogens. A single antigen receptor, or antibody, recognizes a small portion of the molecular structure of an antigen molecule known as a Antigen determinant or Epitope labeled (Fig. 1.14). Proteins and glycoproteins usually contain many different epitopes that can be recognized by different antigen receptors.
Antibodies and B-cell receptors recognize epitopes of native antigens in serum or in the extracellular space. It is possible for different antibodies to recognize an antigen at the same time by its different epitopes; the removal or neutralization of the antigen is thereby more effective.
While antibodies can recognize almost any type of chemical structure, T-cell receptors usually only bind protein antigens and are therefore very different from antibodies. The T-cell receptor recognizes a peptide epitope that comes from a partially degraded protein, but only if the peptide is bound to special glycoproteins on the cell surface, the MHC molecules (Fig. 1.15). The members of this large family of glycoproteins are encoded by a group of genes known as the Major histocompatibility complex (major histocompatibility complex, MHC) designated. The antigens recognized by T cells can originate from proteins from intracellular pathogens, for example viruses, or from extracellular pathogens. Another difference to the antibody molecule is that there is no secreted form of the T cell receptors. The function of the T cell receptor is only to signal the T cell that it has bound an antigen. The subsequent immunological effects are based on the activities of the T cells themselves. We will look at it in Chap. 10.1007 / 978-3-662-56004-4_6 deal in more detail with how epitopes of antigens are bound to MHC proteins, and in Chap. 10.1007 / 978-3-662-56004-4_9 is about how T cells carry out their other functions.
The genes of the antigen receptors are reassembled by somatic gene rearrangements of incomplete gene segments
The innate immune system recognizes signals of inflammation with the help of a relatively limited number of sensors, such as TLR or NOD proteins; there are fewer than 100 different species in total. Antigen-specific receptors of the adaptive immune system comprise an almost unlimited number of specificities, but which are encoded by a limited number of genes. The basis for this extraordinary variety of specificities was established in 1976 by Susumu Tonegawa discovered, for which he received the Nobel Prize in 1987. The variable regions of the immunoglobulins are called groups of Gene segments inherited, each of which encodes part of the variable region in one of the immunoglobulin chains. During the development of the B cells in the bone marrow, these gene segments are irreversibly linked to one another by a process known as DNA recombination. This creates a stretch of DNA that encodes a complete variable region. For the genes for the T cell receptors, there is a similar mechanism during the development of the T cells in the thymus.
Only a few hundred different gene segments can be linked together in different ways, but this creates thousands of different chains of receptors. Through this combinatorial diversity it is possible that a small amount of genetic material can encode a truly impressive range of receptors. During the recombination process, nucleotides are added or removed at the juncture sites of the gene segments in a random process; this creates an additional one junctional diversity . The diversity is further enhanced by the fact that each antigen receptor contains two different variable chains, each encoded by a different group of gene segments. We deal with this process of gene rearrangement, from which the complete antigen receptors emerge, in Chap. 10.1007 / 978-3-662-56004-4_5.
Lymphocytes are activated by antigens, creating clones of antigen-specific cells that are responsible for adaptive immunity
The development of lymphocytes is characterized by two characteristics that distinguish adaptive immunity from innate. On the one hand, the process described above, which assembles the antigen receptors from incomplete gene segments, takes place in a way that ensures that each developing lymphocyte expresses only a single receptor specificity. While the cells of the innate immune system express many different pattern recognition receptors and recognize features that many pathogens have in common, the expression of the antigen receptors in the lymphocytes takes place “clonally”. As a result, each matured lymphocyte differs from the other lymphocytes due to the specificity of its antigen receptor. On the other hand, since the process of gene rearrangement changes the DNA irreversibly, all descendants of the lymphocytes inherit the same receptor specificity. Therefore, due to the proliferation of a single lymphocyte, a clone with identical antigen receptors.
A single person has at least 10 at any given point in time8 different specificities that put together the Lymphocyte receptor repertoire form. These lymphocytes constantly go through a process that is similar to natural selection: only those lymphocytes that come into contact with an antigen that binds to their receptor are activated, causing them to proliferate and differentiate into effector cells. This selection mechanism was formulated for the first time Frank Macfarlane Burnet in the 1950s and he postulated the presence of many different cells that are potentially capable of producing antibodies. Each of these cells can produce antibodies of a different specificity, which are present in membrane-bound form on the cell surface. The antibody serves as a receptor for an antigen. When an antigen binds, the cell is stimulated to divide and in this way it produces many identical offspring, a process known as clonal expansion designated. This clone from identical cells can now clonotypical Release antibodies with the same specificity as the surface receptor that triggered the activation and clonal expansion at the beginning (Fig. 1.16). Burnet called this the Clonal selection theory the production of antibodies. Its four basic hypotheses are shown in Fig. 1.17.
Lymphocytes with autoreactive receptors are usually eliminated or inactivated during development
When Burnet formulated his theory, neither antigen receptors nor how the lymphocytes themselves were known. Discovered in the early 1960s James Gowans that removing the small lymphocytes from rats resulted in a loss of all known adaptive immune responses. If the small lymphocytes were replaced, the immune responses were also restored. This led to the realization that the lymphocytes are the basic units of clonal selection. The biology of these cells became the focus of the new research area of cellular immunology .
The clonal selection of lymphocytes with different receptors provided an elegant explanation for the adaptive immunity, but caused a significant intellectual problem: If the antigen receptors of the lymphocytes arise at random during the life of an organism, there is a possibility that some receptors on the body's own antigens (Autoantigens ) respond. How can you then prevent the lymphocytes from recognizing and attacking antigens in the body's own tissues? Ray Owen had already shown in the late 1940s that genetically different twin calves with a common placenta and thus with a common bloodstream against the tissue of the other animal tolerant were. Peter Medawar then showed in 1953 that mice that were brought into contact with foreign tissues during their embryonic development became immunologically tolerant to these tissues. Burnet postulated that developing lymphocytes, which are potentially autoreactive, are destroyed before maturation; this process is known today under the name clonal deletion . Medawar and Burnet shared the Nobel Prize in 1960 for their work on immunological tolerance. In the late 1980s, this process could also be demonstrated in experiments. Some lymphocytes that receive either too strong or too weak signals through their antigen receptors during their development are eliminated by a mechanism of suicide. This process is known as Apoptosis (after the Greek word for the fall of leaves from trees) or as programmed cell death. Since then there have been other mechanisms of the immunological tolerance discovered that are based on the fact that an inactive state is created, the so-called Anergy . Mechanisms are now also known which bring about an active suppression of autoreactive lymphocytes. Cape. 10.1007 / 978-3-662-56004-4_8 deals with lymphocyte development and the tolerance mechanisms that determine the receptor repertoire of lymphocytes. In chap. 10.1007 / 978-3-662-56004-4_14 and 10.1007 / 978-3-662-56004-4_15 we then discuss how the innate mechanisms of immune tolerance can also fail.
Lymphocytes mature in the bone marrow or thymus and then collect in lymphatic tissues throughout the body
Lymphocytes circulate in the blood and in the lymphatic fluid, and they come into the in large numbers lymphoid tissues or lymphoid organs in front. These are structured collections of lymphocytes in a network of non-lymphatic cells. The lymphatic organs can be roughly divided into the central or primary lymphoid organs where the lymphocytes originate and the peripheral or secondary lymphoid organs , in which mature naive lymphocytes are stabilized and adaptive immune responses are triggered. The central lymphatic organs are the bone marrow and the Thymus (a large organ in the upper chest area). The peripheral lymphoid organs include the Lymph nodes , the spleen and the mucosal lymphoid tissues of the intestine, nasal and respiratory tract, urogenital tract, and other mucous membranes. The location of the most important lymphatic tissues is shown schematically in Fig. 1.18; the individual lymphatic organs are described in more detail later in this chapter. Lymph nodes are connected to one another by a system of lymph vessels that drain extracellular fluid from the tissues via the lymph nodes and return it to the blood.
The progenitor cells from which the B and T lymphocytes arise come from the bone marrow. B lymphocytes also mature there. The "B" of the B-lymphocytes originally stood for
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