Saturday, 27 July 2013



A. T-cell activation. Upon activation by antigen, signals from the TCR and coreceptors alter the pattern of gene transcription for proliferation and differentiation into effector T cells (TH1, TH2, or CTL). The effector activity of the T cell is accomplished through the cytokines that the T cell produces (see Table: MAJOR PROPERTIES OF SELECTED CYTOKINES). TCR binding to antigen and initial T-cell activation involves a cascade of signaling events that include the transcription factors NF kB, nuclear factor of activated T cells (NFAT), and activator protein 1 (AP-1). The production of IL-2 in response to T-cell activation is important for the initial proliferation and differentiation of the T cell. The immunosuppressive drugs cyclosporine A and tacrolimus (also called FK506) disrupt the signals from the TCR, thereby inhibiting the production of IL-2. Rapamycin inhibits the signaling from the IL-2 receptor.

B. T-cell effector functions
1. Nonviral intracellular parasites such as mycobacteria, Listeria, and certain protozoa are primarily eliminated by T-cell–macrophage immunity. Antigen-specific TH1 cell activation with the release of IFN-g and other macrophage-activating factors enhances effective immunity to these bacterial intracellular pathogens.

2. Viruses must be eliminated from both extracellular sites and infected cells.
a. Antibodies neutralize virus particles in blood and tissue fluids to prevent further infection of host cells. These antibodies also serve as opsonins to assist with phagocytosis. Antibodies are generally ineffective against infected cells.
b. CTL cells recognize infected cells via class I MHC presentation of viral peptides. The CTL then directly kills the infected cells in an antigen-specific manner and secretes lymphokines, such as IFN-g. Cytotoxic granule release (granulolysin, perforin, and granzymes) by the CTL is focused toward the infected cell, which is triggered to die by apoptosis; healthy, nearby cells are not affected. In addition, CTLs can induce apoptosis via FAS ligand binding to FAS on the target cells.
c. NK cells kill infected (and tumor) cells in a non–antigen-specific manner by binding to MHClike molecules using a variety of receptors. NK cells kill their target cells using mechanisms similar to those used by CTLs.
d. IFN-g (secreted by CTL, NK, and TH1 cells) and IFN-a and IFN-b (secreted by fibroblasts and other cells) provide additional antiviral immunity by binding to receptors on nearby uninfected cells to induce the synthesis of kinases and endonucleases (i.e., antiviral proteins), which inhibit viral and cellular growth. Interferons also upregulate MHC protein expression, which makes infected cells more visible to T cells.

3. Tumors are modified host cells and must be eliminated by the immune system, usually by cell mediated immunity via CTL and NK cells.

4. Graft rejection (will be discussed later)

C. T-cell memory. T-cell immune responses give rise to long-lived immunological memory (memory cells) and protective immunity.

A. Overview. The production of antibodies is the major focus of the B-cell portion of the immune system. The function of an antibody is to recognize and bind to its corresponding foreign antigen in order to prevent that antigen from functioning (neutralization) or to target the antigen to other components of the immune system. Most antibody responses involve the activation of both B and TH cells. T-independent responses to certain antigens do not require TH cells. These antigens tend to either interact with other PRRs (e.g., bacterial LPS) or are highly repetitive antigens (e.g., bacterial cell wall carbohydrates). T-cell–independent responses generally produce only IgM and do not produce a memory B-cell response.

B. Primary immune response. The first time a specific antigen is encountered, only naive B cells and naive TH cells are present to respond to the antigen. In the secondary lymph tissue, B cells and T cells are closely associated with each other such that proliferation and differentiation of antigen specific B and T cells can occur simultaneously. Germinal centers develop in secondary lymph tissue as a result of the lymphocyte proliferation during an immune response. Activated lymphocytes differentiate into short-lived effector cells and long-lived memory cells. Some of the activated B cells differentiate into plasma cells secreting IgM of low affinity. Later in the immune response, under the direction of the TH cells, B cells will undergo isotype switching such that plasma cells producing other classes of antibody will develop. The primary humoral immune response is detected in the serum after 4 days and peaks at 7 to 14 days.

C. Affinity maturation. Under the influence of TH cells, B cells undergo somatic hypermutation, which introduces point mutations into the immunoglobulin genes such that the expanding population of B cells will produce BCRs with altered antigen-binding sites. Only those B cells that have produced immunoglobulins with a greater affinity for the antigens, as demonstrated by the ability to interact with antigen present in the lymph tissue, will be allowed to mature. In this way, the antibody response matures to produce antibodies with increasing binding affinity.

D. Isotype switching. After B-cell activation, TH cells secrete cytokines to direct isotype switching to produce different classes (isotypes) of antibody. Antigen binding is unaffected by the isotype change. TH2 cytokines, chiefly IL-4, IL-5, and TGF-b, lead to the production of IgA and IgE, as well as weakly opsonizing antibody, such as IgG2 and IgG4. TH1 cells direct the production of opsonizing antibodies, chiefly IgG1 (see Table: MAJOR PROPERTIES OF SELECTED CYTOKINES).

E. Memory immune responses. The creation of memory B and T cells establishes immunological memory. Long-lived memory B cells retain surface immunoglobulin with the selected antigen affinity and of the selected isotype, in the event the same antigen is encountered again. Memory cells more rapidly respond to the presence of the antigen (2 to 3 days after reencountering the antigen), and the absolute amount of specific antibody is greater. For some immune responses, but not all, memory is lifelong.

F. Immunoglobulins: Antigen binding and class-specific functions. In this chapter, the terms antibody and immunoglobulin are used interchangeably.
1. Structure.
The standard immunoglobulin unit has four polypeptide chains that are held together by disulfide bonds: two identical light (L) chains and two identical heavy (H) chains. Each chain can be divided into a C-terminal constant region and an N-terminal variable region of amino acids. The N-terminal variable regions formed from the H- and L-variable domains combined are responsible for antigen binding by the immunoglobulin. The C-terminal constant regions of the H chain (Fc, or fragment crystallizable) determine the class of the immunoglobulin.
The mechanism for generating diversity in the variable portion of the H and L chains is based on the requirement for gene rearrangement of the antibody gene segments during lymphocyte development. The germ line H and L chain genes are nonfunctional until gene segments are rearranged during B-cell development to create a functional gene. The number of different immunoglobulin gene segments, coupled with junctional and insertional variability during DNA recombination, accounts for an enormous number of different potential immunoglobulin sequences, and thus antigen binding for antibodies.

2. Class. There are five general heavy-chain, constant-region amino acid sequences. These determine the five general classes of immunoglobulins: IgM, IgG, IgE, IgA, and IgD. Within some classes, variants of heavy-chain amino acid sequence yield subclasses: IgG1–4 and IgA1–2. The class of an immunoglobulin defines the transport of the antibody throughout the body, as well as the ability of the antibody to interact with other components of the immune system.
a. IgM is the first antibody produced in response to a new infection. The IgM is present on the surface of the mature naive B cells as a monomer, whereas IgM is secreted from the plasma cell as a pentamer. As the first antibody produced, IgM tends to have low binding affinity; however, it is able to bind strongly because it has 10 antigen-binding sites. IgM is present in the blood and tissues, although it does not penetrate tissues well because of its large size. IgM is the most potent activator of the complement system via the classical pathway. Its serum half-life is 9 to 11 days.
b. IgD is produced on the surface of mature naive B cells simultaneously with IgM and serves as a marker for maturation. It is present in very small amounts in the serum and does not appear to be produced as a secreted antibody by plasma cells.
c. IgG is the predominant serum immunoglobulin secreted at the end of the primary immune responses and during memory responses. There are four subclasses of IgG in humans, each with differences in function. IgG has the longest lasting serum half-life (21 days for most subclasses) and is the most plentiful antibody in the serum. IgG (especially IgG3) is able to activate complement via the classical pathway. IgG1, IgG2, and IgG3 are opsonic and enhance the phagocyte’s ability to engulf the pathogen when it is coated in IgG. The FcRn receptor transports IgG across endothelial cells into the tissues and can also selectively transport IgG across the placenta into the fetus during the last trimester of pregnancy.
d. IgA can be expressed as either a monomer (in the blood and tissues) or a dimer (at mucosal surfaces). Dimeric IgA is secreted in large quantities across mucosal surfaces into gastrointestinal, respiratory, lachrymal, mammary, and genitourinary secretions, where it protects the mucosa from colonization.
e. IgE is the least plentiful antibody in the serum. IgE is made in small quantities and is rapidly bound irreversibly to the high affinity FceRI receptors present on mast cells, basophils, and eosinophils. Antigen binding to the IgE on the surface of the mast cell signals activation and degranulation of the mast cell.

3. Specificity. The specificity of each immunoglobulin for antigen binding resides in the two identical antigen-binding sites, each formed by the combination of the variable regions of heavy and light chains.

4. Quantitation of immunoglobulin: Antigen binding and cross-reactivity. Between 108 and 1011, unique immunoglobulins with different antigen-binding specificities are formed by the immune system. B cells are constantly being replaced at a rate of about 2.5 billion per day in a healthy, young adult by production in the bone marrow.
a. Cross-reactive antibodies are those that are able to bind to different, but closely structurally related, antigens. Cross-reactivity may also occur through the sharing of some, but not all, antigens by two strains of bacteria, viruses, or other microorganisms.
b. Each antigen has the potential to activate multiple B cells, and microorganisms have several antigens; therefore, each immune response will elicit the production of multiple antibodies with unique specificities. This response is known as a polyclonal response.

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