A Single B Lymphocyte Can Recognize Multiple Antigenic Determinants.
Vertebrates inevitably die of infection if they are unable to brand antibodies. Antibodies defend u.s. confronting infection by binding to viruses and microbial toxins, thereby inactivating them (run into Figure 24-ii). The binding of antibodies to invading pathogens besides recruits diverse types of white blood cells and a system of blood proteins, collectively called complement (discussed in Chapter 25). The white blood cells and activated complement components piece of work together to set on the invaders.
Synthesized exclusively by B cells, antibodies are produced in billions of forms, each with a different amino acid sequence and a different antigen-binding site. Collectively chosen immunoglobulins (abbreviated as Ig), they are amidst the most abundant protein components in the blood, constituting most 20% of the total protein in plasma by weight. Mammals make five classes of antibodies, each of which mediates a feature biological response following antigen binding. In this department, we hash out the structure and function of antibodies and how they interact with antigen.
B Cells Brand Antibodies as Both Cell-Surface Receptors and Secreted Molecules
As predicted by the clonal pick theory, all antibiotic molecules made past an individual B cell have the aforementioned antigen-binding site. The first antibodies made by a newly formed B cell are not secreted. Instead, they are inserted into the plasma membrane, where they serve as receptors for antigen. Each B cell has approximately ten5 such receptors in its plasma membrane. Every bit we discuss later, each of these receptors is stably associated with a complex of transmembrane proteins that activate intracellular signaling pathways when antigen binds to the receptor.
Each B cell produces a single species of antibody, each with a unique antigen-binding site. When a naïve or memory B cell is activated past antigen (with the aid of a helper T cell), it proliferates and differentiates into an antibiotic-secreting effector cell. Such cells make and secrete large amounts of soluble (rather than membrane-bound) antibody, which has the same unique antigen-binding site every bit the cell-surface antibody that served before as the antigen receptor (Figure 24-17). Effector B cells can begin secreting antibody while they are still small lymphocytes, but the terminate stage of their maturation pathway is a big plasma prison cell (see Figure 24-7B), which continuously secretes antibodies at the astonishing rate of about 2000 molecules per second. Plasma cells seem to take committed so much of their protein-synthesizing mechanism to making antibiotic that they are incapable of further growth and segmentation. Although many dice afterwards several days, some survive in the bone marrow for months or years and go on to secrete antibodies into the claret.
Effigy 24-17
B prison cell activation. When naïve or memory B cells are activated by antigen (and helper T cells—not shown), they proliferate and differentiate into effector cells. The effector cells produce and secrete antibodies with a unique antigen-binding (more...)
A Typical Antibody Has Two Identical Antigen-Binding Sites
The simplest antibodies are Y-shaped molecules with ii identical antigen-binding sites, one at the tip of each arm of the Y (Figure 24-eighteen). Because of their two antigen-binding sites, they are described as bivalent. Every bit long as an antigen has 3 or more antigenic determinants, bivalent antibiotic molecules can cross-link it into a big lattice (Figure 24-19). This lattice can be rapidly phagocytosed and degraded by macrophages. The efficiency of antigen binding and cantankerous-linking is greatly increased by a flexible hinge region in virtually antibodies, which allows the altitude between the 2 antigen-bounden sites to vary (Figure 24-twenty).
Effigy 24-18
A simple representation of an antibody molecule. Annotation that its two antigen-binding sites are identical.
Figure 24-19
Antibody-antigen interactions. Because antibodies have two identical antigen-binding sites, they tin cross-link antigens. The types of antibody-antigen complexes that grade depend on the number of antigenic determinants on the antigen. Here a single species (more...)
Effigy 24-twenty
The hinge region of an antibody molecule. Considering of its flexibility, the swivel region improves the efficiency of antigen binding and cantankerous-linking.
The protective effect of antibodies is not due merely to their ability to demark antigen. They engage in a variety of activities that are mediated by the tail of the Y-shaped molecule. As we discuss later, antibodies with the aforementioned antigen-bounden sites tin can accept any one of several dissimilar tail regions. Each type of tail region gives the antibody different functional properties, such as the ability to activate the complement system, to bind to phagocytic cells, or to cantankerous the placenta from female parent to fetus.
An Antibiotic Molecule Is Composed of Heavy and Light Chains
The basic structural unit of an antibiotic molecule consists of iv polypeptide bondage, two identical light (Fifty) chains (each containing most 220 amino acids) and ii identical heavy (H) bondage (each ordinarily containing about 440 amino acids). The four chains are held together past a combination of noncovalent and covalent (disulfide) bonds. The molecule is composed of 2 identical halves, each with the same antigen-binding site. Both light and heavy chains usually cooperate to course the antigen-binding surface (Figure 24-21).
Figure 24-21
A schematic drawing of a typical antibody molecule. Information technology is composed of four polypeptide chains—two identical heavy chains and ii identical light chains. The two antigen-bounden sites are identical, each formed by the N-terminal region of a lite (more than...)
There Are Five Classes of Heavy Chains, Each With Different Biological Properties
In mammals, in that location are v classes of antibodies, IgA, IgD, IgE, IgG, and IgM, each with its own class of heavy chain—α, δ, ε, γ, and μ, respectively. IgA molecules have α bondage, IgG molecules have γ chains, and then on. In addition, in that location are a number of subclasses of IgG and IgA immunoglobulins; for example, there are four human IgG subclasses (IgG1, IgG2, IgG3, and IgG4), having γ1, γtwo, γ3, andγfour heavy bondage, respectively. The diverse heavy chains give a distinctive conformation to the hinge and tail regions of antibodies, so that each form (and subclass) has characteristic properties of its ain.
IgM, which has μ heavy chains, is ever the starting time grade of antibiotic made by a developing B prison cell, although many B cells somewhen switch to making other classes of antibody (discussed below). The immediate precursor of a B prison cell, chosen a pre-B jail cell, initially makes μ chains, which associate with so-chosen surrogate light chains (substituting for genuine low-cal chains) and insert into the plasma membrane. The complexes of μ bondage and surrogate light chains are required for the jail cell to progress to the side by side stage of development, where information technology makes bona fide light chains. The light chains combine with the μ chains, replacing the surrogate light chains, to form four-chain IgM molecules (each with two μ chains and two lite chains). These molecules then insert into the plasma membrane, where they role as receptors for antigen. At this point, the cell is called an immature naïve B prison cell. Subsequently leaving the bone marrow, the cell starts to produce prison cell-surface IgD molecules also, with the same antigen-binding site as the IgM molecules. It is at present called a mature naïve B prison cell. It is this cell that tin can answer to strange antigen in peripheral lymphoid organs (Figure 24-22).
Figure 24-22
The main stages in B cell development. All of the stages shown occur independently of antigen. When they are activated by their specific foreign antigen and helper T cells in peripheral lymphoid organs, mature naïve B cells proliferate and differentiate (more...)
IgM is not only the first class of antibiotic to appear on the surface of a developing B jail cell. It is also the major class secreted into the blood in the early stages of a primary antibody response, on start exposure to an antigen. (Unlike IgM, IgD molecules are secreted in only pocket-size amounts and seem to function mainly as cell-surface receptors for antigen.) In its secreted form, IgM is a pentamer composed of five four-chain units, giving information technology a total of 10 antigen-binding sites. Each pentamer contains one copy of another polypeptide chain, called a J (joining) chain. The J chain is produced past IgM-secreting cells and is covalently inserted between two adjacent tail regions (Figure 24-23).
Figure 24-23
A pentameric IgM molecule. The five subunits are held together past disulfide bonds (cherry). A single J chain, which has a construction similar to that of a unmarried Ig domain (discussed later), is disulfide-bonded between the tails of 2 μ heavy chains. (more...)
The binding of an antigen to a single secreted pentameric IgM molecule can activate the complement system. As discussed in Affiliate 25, when the antigen is on the surface of an invading pathogen, this activation of complement can either mark the pathogen for phagocytosis or kill information technology directly.
The major class of immunoglobulin in the blood is IgG, which is a four-chain monomer produced in large quantities during secondary allowed responses. Besides activating complement, the tail region of an IgG molecule binds to specific receptors on macrophages and neutrophils. Largely by means of such Fc receptors (so-named because antibody tails are called Fc regions), these phagocytic cells bind, ingest, and destroy infecting microorganisms that accept get coated with the IgG antibodies produced in response to the infection (Figure 24-24).
Figure 24-24
Antibody-activated phagocytosis. (A) An IgG-antibody-coated bacterium is efficiently phagocytosed past a macrophage or neutrophil, which has prison cell-surface receptors that demark the tail (Fc) region of IgG molecules. The bounden of the antibody-coated bacterium (more...)
IgG molecules are the simply antibodies that tin pass from mother to fetus via the placenta. Cells of the placenta that are in contact with maternal blood have Fc receptors that bind blood-borne IgG molecules and direct their passage to the fetus. The antibody molecules leap to the receptors are first taken into the placental cells by receptor-mediated endocytosis. They are then transported across the cell in vesicles and released past exocytosis into the fetal claret (a process called transcytosis, discussed in Affiliate 13). Because other classes of antibodies do non demark to these particular Fc receptors, they cannot pass across the placenta. IgG is besides secreted into the mother's milk and is taken up from the gut of the neonate into the blood, providing protection for the baby against infection.
IgA is the primary grade of antibody in secretions, including saliva, tears, milk, and respiratory and intestinal secretions. Whereas IgA is a four-concatenation monomer in the blood, it is an eight-chain dimer in secretions (Figure 24-25). It is transported through secretory epithelial cells from the extracellular fluid into the secreted fluid by another type of Fc receptor that is unique to secretory epithelia (Figure 24-26). This Fc receptor can also transport IgM into secretions (but less efficiently), which is probably why individuals with a selective IgA deficiency, the nigh common form of antibody deficiency, are only mildly afflicted past the defect.
Effigy 24-25
A highly schematized diagram of a dimeric IgA molecule found in secretions. In addition to the two IgA monomers, there is a single J chain and an additional polypeptide chain called the secretory component, which is thought to protect the IgA molecules (more than...)
Figure 24-26
The mechanism of transport of a dimeric IgA molecule across an epithelial cell. The IgA molecule, as a J-chain-containing dimer, binds to a transmembrane receptor protein on the nonlumenal surface of a secretory epithelial prison cell. The receptor-IgA complexes (more than...)
The tail region of IgE molecules, which are iv-chain monomers, binds with unusually loftier affinity (One thousand a ~ 1010 liters/mole) to nevertheless some other class of Fc receptors. These receptors are located on the surface of mast cells in tissues and of basophils in the blood. The IgE molecules bound to them function every bit passively acquired receptors for antigen. Antigen binding triggers the mast cell or basophil to secrete a multifariousness of cytokines and biologically active amines, particularly histamine (Figure 24-27). These molecules cause claret vessels to dilate and become leaky, which in turn helps white blood cells, antibodies, and complement components to enter sites of infection. The same molecules are also largely responsible for the symptoms of such allergic reactions equally hay fever, asthma, and hives. In improver, mast cells secrete factors that attract and activate white blood cells called eosinophils. These cells besides take Fc receptors that bind IgE molecules and tin can impale various types of parasites, especially if the parasites are coated with IgE antibodies.
Effigy 24-27
The function of IgE in histamine secretion past mast cells. A mast cell (or a basophil) binds IgE molecules after they are secreted by activated B cells. The soluble IgE antibodies bind to Fc receptor proteins on the mast cell surface that specifically recognize (more...)
In addition to the 5 classes of heavy chains found in antibody molecules, higher vertebrates have two types of low-cal bondage, κ and λ, which seem to be functionally duplicate. Either type of light chain may exist associated with whatsoever of the heavy chains. An private antibody molecule, however, always contains identical calorie-free bondage and identical heavy chains: an IgG molecule, for example, may have either κ or λ light bondage, but non one of each. As a result of this symmetry, an antibody's antigen-binding sites are always identical. Such symmetry is crucial for the cross-linking function of secreted antibodies (see Figure 24-nineteen).
The properties of the various classes of antibodies in humans are summarized in Table 24-1.
Table 24-1
Properties of the Major Classes of Antibodies in Humans.
The Strength of an Antibody-Antigen Interaction Depends on Both the Number and the Affinity of the Antigen-Binding Sites
The bounden of an antigen to antibiotic, similar the binding of a substrate to an enzyme, is reversible. Information technology is mediated by the sum of many relatively weak non-covalent forces, including hydrogen bonds and hydrophobic van der Waals forces, and ionic interactions. These weak forces are effective but when the antigen molecule is close plenty to allow some of its atoms to fit into complementary recesses on the surface of the antibody. The complementary regions of a four-chain antibody unit are its 2 identical antigen-binding sites; the corresponding region on the antigen is an antigenic determinant (Figure 24-28). Virtually antigenic macromolecules have many unlike antigenic determinants and are said to be multivalent; if ii or more of them are identical (as in a polymer with a repeating structure), the antigen is said to be polyvalent (Figure 24-29).
Effigy 24-28
Antigen bounden to antibody. In this highly schematized diagram, an antigenic determinant on a macromolecule is shown interacting with the antigen-bounden site of 2 dissimilar antibody molecules, one of high affinity and one of low affinity. The antigenic (more...)
Effigy 24-29
Molecules with multiple antigenic determinants. (A) A globular protein is shown with a number of different antigenic determinants. Unlike regions of a polypeptide chain unremarkably come up together in the folded structure to class each antigenic determinant (more...)
The reversible binding reaction betwixt an antigen with a single antigenic determinant (denoted Ag) and a unmarried antigen-binding site (denoted Ab) can be expressed as
The equilibrium point depends both on the concentrations of Ab and Ag and on the strength of their interaction. Clearly, a larger fraction of Ab volition get associated with Ag equally the concentration of Ag increases. The strength of the interaction is generally expressed as the affinity constant ( One thousand a ) (see Figure three-44), where
(the foursquare brackets indicate the concentration of each component at equilibrium).
The affinity constant, sometimes called the association constant, can exist adamant by measuring the concentration of costless Ag required to fill one-half of the antigen-binding sites on the antibody. When half the sites are filled, [AgAb] = [Ab] and K a = i/[Ag]. Thus, the reciprocal of the antigen concentration that produces half the maximum binding is equal to the affinity constant of the antibiotic for the antigen. Common values range from every bit low as 5 × 10iv to as loftier as 1011 liters/mole.
The affinity of an antibody for an antigenic determinant describes the strength of binding of a single copy of the antigenic determinant to a single antigen-binding site, and information technology is independent of the number of sites. When, nonetheless, a polyvalent antigen, carrying multiple copies of the same antigenic determinant, combines with a polyvalent antibody, the binding forcefulness is greatly increased because all of the antigen-antibody bonds must be cleaved simultaneously earlier the antigen and antibiotic can dissociate. As a result, a typical IgG molecule tin bind at least 100 times more strongly to a polyvalent antigen if both antigen-bounden sites are engaged than if simply one site is engaged. The total binding forcefulness of a polyvalent antibody with a polyvalent antigen is referred to as the avidity of the interaction.
If the affinity of the antigen-binding sites in an IgG and an IgM molecule is the same, the IgM molecule (with ten bounden sites) volition have a much greater avidity for a multivalent antigen than an IgG molecule (which has two binding sites). This difference in avidity, often 10four-fold or more, is important because antibodies produced early in an immune response usually have much lower affinities than those produced later. Because of its high total avidity, IgM—the major Ig class produced early on in immune responses—can function effectively even when each of its binding sites has only a low affinity.
And so far we have considered the general structure and part of antibodies. Next we look at the details of their construction, equally revealed past studies of their amino acid sequence and iii-dimensional structure.
Low-cal and Heavy Chains Consist of Abiding and Variable Regions
Comparison of the amino acid sequences of different antibiotic molecules reveals a striking characteristic with important genetic implications. Both light and heavy bondage have a variable sequence at their N-concluding ends but a constant sequence at their C-terminal ends. Consequently, when the amino acrid sequences of many different κ chains are compared, the C-final halves are the same or prove only minor differences, whereas the N-terminal halves are all very dissimilar. Light chains accept a constant region most 110 amino acids long and a variable region of the aforementioned size. The variable region of the heavy bondage (at their N-terminus) is also about 110 amino acids long, but the heavy-concatenation abiding region is near three or four times longer (330 or 440 amino acids), depending on the class (Figure 24-30).
Effigy 24-30
Abiding and variable regions of immunoglobulin bondage. Both low-cal and heavy chains of an antibody molecule have distinct constant and variable regions.
It is the N-terminal ends of the light and heavy chains that come together to form the antigen-binding site (see Figure 24-21), and the variability of their amino acrid sequences provides the structural footing for the diversity of antigen-bounden sites. The diversity in the variable regions of both light and heavy chains is for the virtually part restricted to three small hypervariable regions in each concatenation; the remaining parts of the variable region, known as framework regions, are relatively constant. But the 5–10 amino acids in each hypervariable region grade the antigen-binding site (Effigy 24-31). As a result, the size of the antigenic determinant that an antibiotic recognizes is more often than not comparably pocket-size. It tin can consist of fewer than 25 amino acids on the surface of a globular protein, for example.
Figure 24-31
Antibiotic hypervariable regions. Highly schematized drawing of how the three hypervariable regions in each light and heavy chain together form the antigen-bounden site of an antibody molecule.
The Light and Heavy Chains Are Composed of Repeating Ig Domains
Both light and heavy chains are made up of repeating segments—each about 110 amino acids long and each containing one intrachain disulfide bond. These repeating segments fold independently to form compact functional units called immunoglobulin (Ig) domains. As shown in Figure 24-32, a light chain consists of one variable (5L) and ane abiding (CL) domain (equivalent to the variable and abiding regions shown in the top one-half of Figure 24-thirty). These domains pair with the variable (VH) and start abiding (CHi) domain of the heavy chain to form the antigen-bounden region. The remaining constant domains of the heavy chains course the Fc region, which determines the other biological properties of the antibody. Most heavy chains have three abiding domains (CH1, CHii, and CH3), but those of IgM and IgE antibodies have four.
Figure 24-32
Immunoglobulin domains. The lite and heavy bondage in an antibody molecule are each folded into repeating domains that are similar to ane another. The variable domains (shaded in blue) of the light and heavy bondage (VFifty and FiveH) make up the antigen-binding (more than...)
The similarity in their domains suggests that antibody bondage arose during evolution by a series of gene duplications, showtime with a primordial gene coding for a unmarried 110 amino acrid domain of unknown function. This hypothesis is supported past the finding that each domain of the constant region of a heavy chain is encoded by a carve up coding sequence (exon) (Effigy 24-33).
Figure 24-33
The organization of the DNA sequences that encode the constant region of an antibody heavy chain. The coding sequences (exons) for each domain and for the hinge region are separated by noncoding sequences (introns). The intron sequences are removed past (more...)
An Antigen-Binding Site Is Synthetic From Hypervariable Loops
A number of fragments of antibodies, besides equally intact antibody molecules, accept been studied by x-ray crystallography. From these examples, we can sympathise the fashion in which billions of dissimilar antigen-binding sites are constructed on a common structural theme.
As illustrated in Figure 24-34, each Ig domain has a very similar three-dimensional structure based on what is called the immunoglobulin fold, which consists of a sandwich of 2 β sheets held together by a disulfide bail. We shall see after that many other proteins on the surface of lymphocytes and other cells, many of which function as prison cell-cell adhesion molecules (discussed in Chapter 19), incorporate similar domains and hence are members of a very large immunoglobulin (Ig) superfamily of proteins.
Effigy 24-34
The folded structure of an IgG antibiotic molecule, based on ten-ray crystallography studies. The structure of the whole protein is shown in the center, while the construction of a constant domain is shown on the left and of a variable domain on the right. Both (more...)
The variable domains of antibody molecules are unique in that each has its detail set up of three hypervariable regions, which are arranged in three hypervariable loops (see Figure 24-34). The hypervariable loops of both the low-cal and heavy variable domains are clustered together to form the antigen-bounden site. Considering the variable region of an antibody molecule consists of a highly conserved rigid framework, with hypervariable loops attached at one end, an enormous diversity of antigen-binding sites can be generated past irresolute just the lengths and amino acrid sequences of the hypervariable loops. The overall three-dimensional structure necessary for antibody role remains abiding.
X-ray analyses of crystals of antibody fragments bound to an antigenic determinant reveal exactly how the hypervariable loops of the light and heavy variable domains cooperate to form an antigen-bounden surface in particular cases. The dimensions and shape of each different site vary depending on the conformations of the polypeptide chain in the hypervariable loops, which in plough are determined past the sequences of the amino acid side chains in the loops. The shapes of binding sites vary greatly—from pockets, to grooves, to undulating flatter surfaces, and even to protrusions—depending on the antibody (Figure 24-35). Smaller ligands tend to bind to deeper pockets, whereas larger ones tend to bind to flatter surfaces. In addition, the binding site can modify its shape after antigen binding to ameliorate fit the ligand.
Figure 24-35
Antigen-bounden sites of antibodies. The hypervariable loops of different FiveL and VH domains can combine to form a large variety of bounden surfaces. The antigenic determinants and the antigen-binding site of the antibodies are shown in red. Simply ane antigen-binding (more than...)
Now that we have discussed the structure and functions of antibodies, we are ready to consider the crucial question that puzzled immunologists for many years—what are the genetic mechanisms that enable each of us to brand many billions of different antibody molecules?
Summary
Antibodies defend vertebrates against infection by inactivating viruses and microbial toxins and by recruiting the complement organization and various types of white blood cell to kill the invading pathogens. A typical antibody molecule is Y-shaped, with 2 identical antigen-binding sites at the tips of the Y and binding sites for complement components and/or various cell-surface receptors on the tail of the Y.
Each B cell clone makes antibody molecules with a unique antigen-binding site. Initially, during B cell development in the bone marrow, the antibody molecules are inserted into the plasma membrane, where they serve as receptors for antigen. In peripheral lymphoid organs, antigen binding to these receptors, together with costimulatory signals provided by helper T cells, activates the B cells to proliferate and differentiate into either memory cells or antibody-secreting effector cells. The effector cells secrete antibodies with the same unique antigen-binding site equally the membrane-bound antibodies.
A typical antibody molecule is composed of four polypeptide bondage, two identical heavy bondage and ii identical light chains. Parts of both the heavy and light chains normally combine to form the antigen-bounden sites. At that place are five classes of antibodies (IgA, IgD, IgE, IgG, and IgM), each with a distinctive heavy chain (α, δ, ε, γ, and μ, respectively). The heavy chains also form the tail (Fc region) of the antibody, which determines what other proteins will bind to the antibiotic and therefore what biological properties the antibody class has. Either type of light chain (κ or λ) can be associated with any form of heavy chain, simply the type of light chain does non seem to influence the properties of the antibiotic, other than its specificity for antigen.
Each light and heavy chain is equanimous of a number of Ig domains—β sail structures containing about 110 amino acids. A light chain has one variable (Five50) and one constant (CFifty) domain, while a heavy chain has one variable (5H) and three or iv constant (CH) domains. The amino acrid sequence variation in the variable domains of both low-cal and heavy chains is mainly bars to several small hypervariable regions, which protrude as loops at one finish of the domains to form the antigen-binding site.
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Source: https://www.ncbi.nlm.nih.gov/books/NBK26884/
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