Immune responses can be divided into two broad categories: innate and adaptive. Innate immune responses are also called nonspecific since they do not discriminate between most foreign substances. They are also not enhanced by previous exposure to a pathogen. In contrast, adaptive (also called acquired) immunity is highly specific to a particular pathogen and becomes more rapid and stronger with subsequent exposure to an antigen. Upon the initial encounter with an antigen, the adaptive immune response takes 4 or 5 days to become fully effective. During this period, the innate immune response plays a critical role in limiting and controlling infections. In addition, it is crucial in stimulating and directing the subsequent adaptive immune responses.
Phagocytosis Pathogens can cause infection only after they have breached the nonimmunological barriers of skin or mucosal surfaces. Generally, the first immune cells they come in contact with are macrophages. Among the many chemicals macrophages start to produce are chemokines, small proteins involved in the recruitment and activation of immune cells. The first cells to be recruited to the site of infection are neutrophils. Macrophages along with neutrophils are the major cell types involved in phagocytosis (i.e., the ingestion of foreign materials, including entire microorganisms). Phagocytosis is triggered via receptors on the surface of macrophages and neutrophils that recognize common cell wall components of bacteria. Killing of the ingested bacteria occurs via several different mechanisms involving the production of reactive oxygen and nitrogen species as well as the release of a variety of preformed antimicrobial substances.
Inflammation In addition to stimulating phagocytosis, the encounter of macrophages and neutrophils with bacteria frequently initiates an inflammatory response. The characteristics of inflammation are pain, redness, swelling, and heat. These symptoms are the consequence of the activities of cytokines and chemokines along with a variety of other vaso-active and inflammatory mediators, such as histamine, prostaglandins, and leukotrienes. They act mostly on local blood vessels, where their combined effect is to enhance blood flow, induce vasodilation, and increase the permeability of blood vessels. These changes allow leakage of fluids and plasma proteins, such as immunoglobulins, complement, and acute phase proteins, into the affected tissue. Cytokines also induce the expression of molecules that make it possible for immune cells to adhere to, and eventually pass between, the cells lining the blood vessels. Together, these alterations result in the infiltration of the site of inflammation by immune cells.
The major inflammatory cytokines are tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1, IL-6, and IL-12, all of which are produced mostly by macrophages. Among these, TNF-a, IL-1, and IL-6 are central to mediating the acute phase response, which is characterized by elevation of the body temperature (fever) and a marked shift in the types of proteins secreted by the liver into the bloodstream. Whereas the synthesis of some liver proteins, called acute phase proteins, is dramatically increased, that of others is decreased. Among the acute phase proteins, C-reactive protein, mannose-binding protein, and serum amyloid P component undergo the most striking increase in synthesis, whereas only moderate increases are observed in a number of other acute phase proteins. It appears that the diverse activities of these proteins are ultimately beneficial to the host since they not only enhance the inflammatory response and other immune cell activities, thereby boosting host resistance, but also promote tissue repair.
Natural killer cells All viruses are intracellular pathogens since they lack the ability to replicate on their own and need to penetrate cells of the host in order to take over their replication machinery. The killing of such infected cells before the virus has had a chance to reproduce can be accomplished by a variety of cell types but is one of the major functions of NK cells. NK cells are large granular lymphocytes with a morphology and lineage that are distinct from those of B and T lymphocytes. They are known to be able to distinguish between normal cells and virally infected or tumorous cells, but the exact mechanisms by which they do so remain to be fully established. The granules of NK cells contain perforin, a protein that can polymerize and form transmembrane pores in the infected cell, possibly providing an entry route for a variety of enzymes also stored in the granules. As a result, the infected cell initiates an active suicide program called programmed cell death or apoptosis.
Interferons Interferon-a and interferon-^ are proteins produced by many cells types in response to viral infection. They reduce the spread of viruses to uninfected cells by inhibiting protein synthesis and DNA replication in virus-infected cells and activating NK cells. In addition, they increase the expression of certain molecules and enhance certain cellular processes that are of great importance in activating components of the adaptive immune system involved in eliminating virally infected cells.
Complement The complement system consists of a group of proteins synthesized by the liver and released into the bloodstream in inactive form. It is part of the nonspecific immune response but can also be triggered by antigen-antibody complexes (i.e., it forms part of the humoral response in adaptive immunity). The latter pathway of activation is called the classical pathway and constitutes one of the three different pathways of complement activation. All three pathways involve a series of cleavage reactions converting inactive proteins into their active forms and ultimately converge at the formation of C3 convertase, an enzyme that cleaves complement component C3 into the large fragment C3b, on the one hand, and a group of smaller peptides consisting of C3a, C4a, and C5a, on the other hand. These smaller peptides mediate certain inflammatory processes and participate in the recruitment of phagocytes. C3b binds to the surface of pathogens and, in the presence of simultaneous coating with antibodies, stimulates phagocytes to engulf and ultimately destroy the microorganism. In addition, further cleavage of C3b yields a group of terminal complement components that form a membrane attack complex able to damage the cell membrane and causing the lysis of certain pathogens.
The cells of the innate immune system are vital as a first line of defense, but they are not always able to completely neutralize or eliminate infectious organisms. The adaptive immune system is thought to have evolved later in evolutionary history and now provides not only more specificity and versatility but also has added immunological memory as a further level of protection against reinfection with the same pathogen.
Adaptive immune responses can be classified as either antibody- or cell-mediated. Antibody-mediated, or humoral, responses are accomplished by plasma cells derived from B cells; cellular immune responses are mediated by activated T lymphocytes. Although they use vastly different effector mechanisms, the activation and subsequent differentiation of B and T lymphocytes nonetheless have many features in common.
In adaptive immunity, antigen alone is generally insufficient to activate naive antigen-specific lymphocytes. Naive T cells require a costimulatory signal from antigen presenting cells; naive B cells usually require accessory signals from an activated helper T cell, but in some cases the signal can be provided directly by microbial constituents. T cell help for B cells has to come from activated helper T cells that respond to the same antigen as the B cell, although the epitope—the specific part of the antigen that is recognized—is generally not identical. Upon recognition of its specific antigen in the context of the appropriate costimulatory signals, the previously small lymphocyte enlarges and undergoes a variety of changes in preparation for vastly increased RNA and protein synthesis. The activated cell is called a lymphoblast. This lymphoblast then begins to divide, duplicating every 6-12 h, thereby giving rise to ^1000 daughter cells, each exhibiting specificity that is identical to that of the parent. Thus, this group of cells constitutes a clone, defined as a population of identical cells that derive from the same ancestral line. Note that most antigens stimulate many different lymphocyte clones, making the resulting response polyclonal. The process of clonal expansion is followed by differentiation into either effector cells or memory cells.
Memory cells, unlike effector cells, do not participate in the initial immune response but can become activated cells when they encounter the same antigen at a later time point, in some cases years or even decades later. This, along with other changes in memory cells compared to virgin (or naive) cells, accounts for the fact that the primary immune response is characterized by a lag phase of several days (the period during which lymphocytes undergo clonal expansion and differentiation) and is relatively weak, whereas a second exposure to the same antigen results in a much more rapid and stronger response.
B cells The primary function of B cells is the production of antibodies, or immunoglobulins. There are five major classes (isotypes) of antibodies: IgA, IgD, IgE, IgG, and IgM, with IgA and IgG having two and four subclasses, respectively. Resting B cells express IgM and IgD on their cell surface as antigen receptors. Their function is to capture antigen so that it can then be processed and displayed to helper T cells specific for peptide fragments of the same antigen. In response to binding antigen and receiving the necessary accessory signal from helper T cells in the form of cell-cell interactions along with secreted molecules, B cells start to produce a secreted version of IgM. Under the influence of certain cytokines produced predominantly by activated helper T cells, B cells undergo isotype switching, also called class switching, meaning that they start to produce other types of immunoglobulins. The types and combinations of immunoglobulin isotypes depend on the nature and relative amounts of these cytokines. In B cell activation and initiation of antibody production, a subclass of helper T cells called Th2 plays the major role; the Th1 subclass of helper T cells, however, participates in isotype switching via the production of interferon-7, a cytokine that induces switching to specific subclasses of IgG, namely IgG2a and IgG3.
Antibody structure and diversity It is estimated that even in the absence of antigen stimulation, the human body contains B cells capable of producing approximately 1015 different antibody molecules. This enormous diversity is generated through a variety of mechanisms.
The basic structure of an antibody is a Y shape (Figure 2) consisting of two heavy chains and two light chains, with each arm containing a specific antigen binding site formed by parts of the respective heavy and light chain. The light and the heavy chain each have a constant region and a variable region. Within the variable region three small i-binding site
hypervariable regions containing 5-10 amino acids form the antigen binding site. A different pool of gene segments encodes the constant and variable regions and, in addition, there is another pool for joining (J) segments for both heavy and light chains and a pool for diversity (D) segments in the case of heavy chains. The exact number of gene segments in these pools is not known, but the mouse genome is estimated to contain approximately 300 variable (V) segments for one of the two possible light chains, and these can be joined to any of 4 different J segments, yielding at least 1200 different V regions. In addition, there are approximately 500 V segments in the heavy-chain pool of the mouse, which can be combined with 4 J segments and at least 12 D segments to encode 24 000 different heavy-chain V regions. Thus, a total of at least 2.5 x 107 different antigen binding sites can be generated by combinatorial diversification, as the combining of V, J, and D segments is called.
The joining process further increases this diversity via two mechanisms. One operates in heavy- and light-chain segments and is the loss of 1 or more nucleotides from the ends of recombining gene segments. Heavy-chain gene segments can additionally be modified through the random insertion of up to 20 nucleotides. Although it is not uncommon for this junctional diversification to result in the production of nonfunctional genes, it nonetheless increases the number of different B cells in the mouse to an estimated 5 x 108.
After the assembly of functional antibody genes is completed, an additional mechanism for increasing diversity takes place when a B cell is stimulated by antigen. This process is called somatic hypermutation since it involves the insertion of point mutations at a rate that is approximately 1 million times greater than the spontaneous mutation rate in other genes. A few of these point mutations confer increased affinity for the antigen to the antigen receptors, ultimately resulting in the production of antibodies with progressively increasing affinity during the course of an immune response.
The function of antibodies The coating of pathogens and toxins with antibodies helps protect the host from infection in three main ways: neutralization, opsonization, and complement activation. Neutralization refers to the ability of antibodies to inhibit the adherence of pathogens to cells they might invade and destroy. Opsonization is defined as the coating of pathogens with antibodies in order to increase their susceptibility to ingestion by phagocytes. As discussed previously, antibodies com-plexed with antigen can also trigger the classical pathway of complement, thereby either enhancing opsonization or directly killing some bacteria through the formation of membrane attack complexes. Not all of the secreted antibody isotypes participate in all of these functions, and the extent to which they do so also differs. Certain additional functions are restricted to specific isotypes. For example, only some IgG subclasses can bind to certain viral proteins displayed on virally infected cells and, through interaction with specific receptors, signal NK cells to destroy these cells. Another example is IgE, which is the only isotype capable of sensitizing mast cells, resulting in a local inflammatory response mediated by the release of histamine and other inflammatory mediators. Allergic reactions are the consequence of such a response directed against innocuous antigens.
T cells Whereas B cells recognize and bind directly to extracellular antigens, generally native protein structures, T cells recognize partially degraded protein antigens—that is, peptide fragments that result from intracellular processing and are then carried to the cell surface for display there. The generation of peptide fragments is called antigen processing and the display is called antigen presentation.
Intracellular pathogens can be located in two different compartments of a cell, the cytosol or the vesicular compartment, which is separated from the cytosol by membranes. Depending on the cellular location of the microorganism, one of two different classes of T cells is activated, either cytotoxic T cells or helper T cells. Cells infected with cytosolic pathogens, such as viruses and some bacteria, are eliminated by cytotoxic T cells via mechanisms closely resembling those described for NK cells. Cells containing foreign material or microorganisms in their vesicular compartment stimulate helper T cells.
These do not kill cells but enhance the activity of the very cells stimulating them (i.e., macrophages and B cells). Although macrophages can phagocytose and kill many infectious agents without T cell help, there are certain situations in which such help is indispensable. For example, the mycobacteria responsible for tuberculosis and leprosy have developed mechanisms to survive the process of phagocytosis and can replicate inside vesicular structures. However, they can be eliminated when the macrophage is activated by a helper T cell. T lymphocytes providing help for macrophages belong to a subclass of helper T cells characterized mainly by the types of cytokines it produces and designated as Th1. Another subclass, Th2, activates B cells to make antibody.
Cytotoxic and helper T cells have the same kind of antigen receptors, designated as T cell receptors. This indicates that the ability of the different classes of T cells to distinguish between peptide fragments coming from the cytosolic or the vesicular compartment must involve other molecules. The most important of these are major histocompatibility complex (MHC) molecules.
The MHC is a cluster of genes encoding not only two different classes of MHC molecules but also a variety of other proteins that participate in immune responses. 'Histo' means tissue, and the name 'major histocompatibility complex' reflects the fact that the proteins encoded by this group of genes were first identified as the target of the immune reaction that can result in graft rejection after organ transplantation. In humans, MHC molecules are called human leukocyte-associated antigen (HLA) molecules. In addition to being polygenic (having several genes encoding proteins with the same function), the MHC genes are strikingly polymorphic, meaning that there are multiple alleles, or copies, of each gene.
T cells recognize antigen only when presented as peptide fragments by a MHC molecule. Furthermore, a T cell recognizing a peptide fragment bound by a MHC molecule encoded by a particular allele will not recognize the same peptide bound to another type of MHC molecule, an effect called MHC restriction. Together with the polymorphism of the MHC genes, this limits the ability of a pathogen to put entire populations or even species at risk since the individuals within the population will vary in their susceptibility to the pathogen.
There are two classes (I and II) of MHC molecules that are structurally similar, though distinct, but differ functionally. Class I MHC molecules present foreign peptides to cytotoxic T cells; class II MHC molecules present foreign peptides to helper T cells.
Since viruses can infect any cell containing a nucleus, virtually all nucleated cells express MHC class I molecules, although the levels at which they do so can differ considerably. In contrast, the main function of helper T cells is to activate other cells of the immune system. Thus, MHC class II molecules are constitutively expressed on B lymphocytes, macrophages, and other antigen presenting cells, but they are inducible on many other cell types via certain cytokines.
Since MHC molecules insert themselves into the cell membrane once they have picked up processed antigen fragments inside the cell and the T cell receptor is also a cell surface molecule, T lymphocytes must make direct contact with their target cells. This cell-cell interaction is enhanced by so-called coreceptors, designated CD4 on helper T cells and CD8 on cytotoxic T cells. CD4 proteins recognize an invariable part of the class II MHC molecule, whereas CD8 proteins bind to a nonvariable region of the class I MHC molecule, and both play a vital role in ensuring that a T cell recognizes only those target cells bearing the correct type of MHC molecule.
As in the case of B cells, antigen alone is insufficient to activate T cells. For helper T cells, the accessory signal is provided either by a secreted signal such as IL-1 or by a specific plasma membrane molecule on the surface of an antigen presenting cell. The major cell type presenting antigen to T cells is the dendritic cell found in lymphoid organs, but macrophages and, under certain conditions, B cells can also act as antigen presenting cells. Antigen presenting cells with strong costimulatory activity also provide the secondary signal for cytotoxic T cells, but in some cases the presence of CD4 T cells seems to be required as well.
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