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21.4Effector Mechanisms in Immune Responses

21.4.1

Mechanisms by which the immune system protects against parasites

The ultimate purpose of immune responses is to eradicate microinvaders such as viruses, microorganisms, and parasites. In most cases, the cellular and humoral immune responses work together to fight off infectious parasites. The cellular immune response is crucial for protecting the body against viruses and microorganisms living inside cells, whereas the humoral immune response is crucial for dealing with extracellular microorganisms and large parasites. The transfer of serum from an individual who has succeeded in eradicating the infection to non-exposed individuals was found to confer the recipient with protection against infection (termed “passive immunization”), which led to the discovery of immunoglobulins or antibodies. However, in cellular immune responses, for example, towards tuberculosis bacteria (an intracellular parasite), detected by tuberculin reaction, antigen-specific defense capability can be transferred through the transfer of lymphocytes rather than serum containing the antibody. This final-stage mechanism, which is involved in parasite eradication or tissue damage by immune responses, is called the effector mechanism. At the time of initiation of the acquired immune response, lymphocyte proliferation and activation are carried out in the secondary lymphoid organs, whereas the effector mechanisms characteristically function at the site of infection (Figure 21-3).

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Allergies

Allergy, also called hypersensitivity, generally refers to any undesirable state caused by immune responses. According to the classification of allergic reactions developed by Philip Gell and Robert Coombs, type I allergic reactions are mediated by immunoglobulin E (IgE), type II by cytotoxic antibodies, type III by crosslinking of antibodies to soluble antigens, and type IV by cellular immune responses. General allergies such as pollinosis and atopic dermatitis are type I allergic reactions. Most contact hypersensitivity reactions are type IV allergic reactions. Type II and III hypersensitivity reactions are mainly mechanisms related to the pathogenesis of autoimmune diseases.

Of the known immunoglobulins, IgE is found in the smallest amount in the serum. IgE is produced in trace amounts under the influence of Th2 cells. Receptors binding to IgE are found in basophils in the blood and mast cells in tissues. If an antigen encounters receptor-bound IgE, this can provoke undesirable events in the immediate phase (within several minutes) and late phase (after several hours). First, granules found abundantly in the basophils and mast cells are released. These granules contain mainly proteoglycan (highly stained with basic dye) and histamine. The histamine increases blood vessel permeability (e.g., skin becomes red), and causes secretion of mucus from the luminal surface of the airway and intestinal peristalsis. If the antigen has spread throughout the body, a severe symptom called anaphylactic shock accompanied by a rapid drop in blood pressure may occur. The late phase is especially a problem in mast cells localized in the tracheal epithelium. During this phase, leukotriene and Th2-type cytokines are secreted, triggering symptoms characteristic of asthma, due to the accumulation of neutrophils and tissue remodeling.

The so-called “allergic tendency” is related to the predisposition to initiate an immune response induced by Th2 cells, in which IgE is produced. Various types of polymorphism of multiple genes involved in the Th2-mediated response are suspected to be responsible for such allergic tendency.

Column Figure 21-2 Allergies triggered by interactions between allergens and IgE

Mast cells and basophils with granules containing amines such as histamine that act on blood vessels have receptors that bind specifically with the carboxy-terminal of immunoglobulin E (IgE). When IgE is cross-linked by an antigen (allergen), a domain in the receptor molecule is activated by phosphorylation in the cell. Through this phosphoenzyme activity, multiple pathways, including those related to the secretion of lipid mediator and regulation of cytokine transcription, are activated within a short period of time. Consequently, pathological changes occur in the blood vessel and epithelial tissue.

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21.4.2

Effector mechanisms in the cellular immune response

The cellular immune response is the mechanism that destroys cells infected by viruses and intracellular parasites. As mentioned earlier, in order to be recognized by T cell receptors, antigens need to be processed to peptides forming complexes with MHC gene products. Class II MHC products are expressed in restricted cell types (such as dendritic cells) that are involved in the activation of helper T cells. However, Class I MHC gene products, molecules similar to Class II MHC, are expressed in all types of nucleated cells. These cells monitor and degrade intracellularly produced proteins using the proteasome complex (see Chapter 12). The degradation products are then transported into the endoplasmic reticulum to form complexes with class I MHC gene products and are then presented on the cell surface. If proteins from virus genes or other intracellular parasites are produced in the cytoplasm, fragments of such protein are also presented at the cell surface in complexes with class I MHC gene products. They are then recognized by T cell receptors as foreign molecules, and killer T cells (CD8-positive) with such receptors become activated and destroy target cells presenting the foreign antigen (Figure 21-3).

Figure 21-3 Effector mechanism serving as final phase of immune response

The effector mechanism in the immune response differs between cellular and humoral immune responses. Infectious parasites and infected cells are eradicated by killer T cells, NK cells, and macrophages in cellular immune response, and by NK cells, macrophages, and neutrophils that bind soluble immunoglobulin to the cell surface in humoral immune response. In these processes, it is vital that effector cells gather at the site of the parasite activity. Such migration of effector cells is regulated by chemokines, cytokines, and cell adhesion molecules. In most cases, cellular and humoral immune responses occur at the same time.

In the eradication mechanism, important molecules triggering cell destruction and cell death include perforin, a protein that perforates the target cell membrane; granzyme, a protease injected into pores made by perforin; and caspase, which becomes effective by partially degradation by granzyme and induces apoptosis in the target cell. The expression of class I MHC gene products in various nucleated cells is increased by cytokines secreted predominantly by activated T cells (especially Th1 cells). Here too, the immune system fights infection as an interrelated system.

On the other hand, cancer cells and viruses are known to eliminate or decrease the expression of class I MHC gene products, thereby escaping the cellular immune response. To prepare for such events, the immune system is equipped with a mechanism for recognition and cytotoxic response by NK cells. When receptors on the surface of NK cells bind to class I MHC gene products, signals inhibiting cytotoxic activity (resembles killer T cells in that these also use perforin and granzyme) are transduced into the cells, so that normal nucleated cells are not damaged by the NK cells. Macrophages also contribute directly to cellular immune response as an effector mechanism. Macrophages activated by cytokines exert cytotoxic activity via molecules found on the cell surface or nitric oxide release from themselves. These innate immune cells are therefore also important components of acquired immunity in vertebrates. Structure and functions of antigens

In the humoral immune response, the specific proliferation and differentiation of B cell clones is triggered by Th2 cells and antigens. The differentiation here includes a switch of the immunoglobulin from a membrane-bound form (i.e., membrane-bound immunoglobulin known as the B cell receptor) to a secretory form (i.e., soluble protein antibody); class switching of immunoglobulin; increased affinity of immunoglobulins due to genetic mutation; and formation of plasma cells, which secrete large amounts of immunoglobulin. All these processes occur at different sites within secondary lymphoid organs. Immunoglobulins are essentially composed of two approximately 50-kDa heavy chains and two approximately 30-kDa light chains. In humans and mice, the immunoglobulin is classified, depending on the type of heavy chains present, into five classes or isotypes (M, D, G, A, and E) (Figure 21-4). Immunoglobulin A (IgA) is secreted through the epidermis and functions on the mucous surface. Immunoglobulin E (IgE) activates basophils and mast cells that express its cognate receptors, which is associated with the development of allergies. Thus, class switching of immunoglobulins produces antibodies with more specific functions. In immunoglobulin molecules, the amino terminal region binds to antigens. As the amino acid sequence in this area of the molecule differs according to the particular antigen, this portion is called the variable region. The characteristic of its protein structure is that the variable regions of heavy chains and light chains have three loops each that constitute the antigen-binding site. These three loops complement antigens and are sometimes referred to as hyper variable regions or complementarity determining regions (CDR) because these regions have different sequences for each antibody. In particular, the amino acid near terminal approximate position 95 is equivalent to the third CDR. This site has the highest diversity, as immunoglobulin gene recombination occurs here. The carboxy terminus is class/isotype-specific and is called the constant region. It mediates characteristic functions such as interactions with the immunoglobulin receptor/Fc receptor on the cell surface, activation of complement, multimerization of secretory IgM and IgA, and transport of IgA to the lumen across the epidermis.

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21.4.3

Initiation of acquired immune responses and involvement of MHC gene products

If the body is exposed to antigens such as pathogenic microorganisms, a germinal center for B cell proliferation is formed at the follicle area, in which B cells gather. The follicular area can be found in the lymph nodes, pancreas, and MALT. In contrast, the process involved in the differentiation of B cells mentioned earlier is induced by direct contact between Th2 cells and B cells in the vicinity of the germinal center.

By changing the variable region, immunoglobulins can bind to all kinds of antigens, regardless of the chemical composition of the antigens to help immune cells eradicate the antigens by inactivating them. Soluble immunoglobulins, called antibodies, are indispensable in medicine; in the past, they were used as active components of antiserums and antitoxins, while today, they are used in drugs containing recombinant proteins.

Macrophages, NK cells, and neutrophils, which efficiently engulf bacteria, express immunoglobulin receptors at the surface. Following the production of parasite-specific antibodies, their binding to infectious parasites allows these immune cells to eradicate bacteria more efficiently, which is called the opsonic effect.

Figure 21-4 Structure of secretory immunoglobulin (antibody)

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Allergies

Guillain-Barré syndrome is an autoimmune motor nerve disorder occurring after infections with organisms such as Campylobacter jejuni and cytomegalovirus, which cause digestive tract symptoms such as severe diarrhea. The syndrome is triggered by the mass production of antibodies reacting to gangliosides found abundantly in motor nerve axons, as part of an immune response to the lipooligosaccharide on the surface of C. jejuni. The importance of antibodies in the pathogenesis of this disease is underscored by the observations that serum substitution, administration of large doses of immunoglobulin, and administration of ganglioside all provide therapeutic effects. However, there are differing opinions. In fact, there are no other examples demonstrating that infections trigger the onset of autoimmune disorders. Some autoimmune diseases are evidently caused by humoral immune responses, including Guillain-Barré syndrome, myasthenia gravis, and systemic lupus erythematosus (SLE), whereas others are thought to be triggered by cellular immune responses, including multiple sclerosis, type 1 diabetes (insulin-dependent), and Chrohn’s disease.

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New influenza epidemic

Influenza is caused by the influenza virus, which consists of eight single-stranded RNAs and the encoded nine protein products. The virus has an envelope (capsule) and belongs to the myxovirus genus. It is spherical in shape and has a diameter of approximately 100 nm. It infects and replicates in the mucosal epithelial cells of, for example, the respiratory epithelium. Two proteins distributed on the surface of the capsule are hemagglutinin (HA) and neuraminidase (NA). The former binds to sugar chains that have terminal sialic acids (neuraminic acid), and is thought to be crucial for viral entry to cells (Column Figure 21-3). NA is an enzyme that hydrolyzes ether or glycosidic linkages between the terminal sialic acid of the sugar chain and the adjacent glycan (normally galactose or N-acetylgalactosamine), and is thought to be vital for proliferated viruses to exit from the cell. Humans infected by the virus mount an immune response in an attempt to eliminate it. This immune response is triggered by the proteins on the virus surface–HA and NA–as the main antigens. Specific sites of these proteins (combination of amino acid sequences) are recognized as the epitopes. HA and NA respectively has sialic acid-binding activity and sialidase activity, although they vary in antigenicity. Classification of the influenza virus strains is based on the antigenic differences, for example H1N1, H3N2, and H5N1, where the H and N represent the respective initials of the two proteins. The influenza virus gene tends to mutate easily, possibly because the replication process of RNA templates does not have a repair mechanism. As a result of this mutation, the initial epitope recognized in the immune response to the previous infection may be lost even in viruses of the same pathogenic type such as H1N1. This nullifies the immune memory acquired through the previous infection or vaccination. The immune system must then start from scratch in responding to and eliminating the virus. This increases the risk of proliferation of viruses, and thus the onset of symptoms once they enter the human body. In this situation, the extended time from infection to cure will allow large quantities of virus to be released over a longer period of time, thereby sharply increasing the risk of infecting others. This is the reason for the worldwide epidemic of the “novel” influenza virus seen since 2009. The purpose of vaccination is to create immune memory by administering new strains of viruses with the same immunogenicity (antigenicity) but no infectiveness. Existing treatments widely used in Japan are enzyme-inhibiting compounds that enter the catalytic pocket of neuraminidase, the enzyme required for viruses to exit cells.

Column Figure 21-3 Influenza virus and its binding to host cell via hemagglutinin

The only proteins present on virus surfaces are hemagglutinin and neuraminidase. Both are essential for viruses to invade and exit cells.

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