How is antibody production stopped?

How is antibody production stopped?

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Once clonal selection is done, B cells would start dividing and producing antibodies. So, after an antigen is eliminated, what stops the division of B cells and antibody production?

Upon activation plasma B cells upregulate death receptors as part of being activated. Presence of the antigen overcomes the death signal, thus the cell survives. When antigen is lost, the death signals overcome the survival signals as there is no antigen, so the B cell dies via apoptosis.

Memory B cells don't do this. They survive and continue to produce antibodies for years, although this slowly wanes. Antibodies have to be produced as antibody mediated immune mechanisms are extremely important for memory and the reason why a subsequent infection is cleared so rapidly. Furthermore for the example of HPV, antibodies induced by the vaccine prevent the virus even infecting cells (so called neutralising antibodies).

You are right to say that Plasma Cells are terminally differentiated, so they don't become the memory cells, or calm back down or anything. But all Plasma Cells are not the same, there are Short-Lived Plasma Cells (SLPCs) that are less specific, but arise rapidly after stimulation, and there are Long-Lived Plasma Cells (LLPCs) that come about later and have more specific antigen binding. SLPCs are rapidly activated, but also rapidly lost. These are the cells that Android was talking about when s/he said that apoptotic programs are initiated as soon as cells become activated and are eventually eliminated by these mechanisms. LLPCs are the cells that stay in your body for a much longer time (theoretically for life, but probably not practically unless you get hit by a bus in a couple of years). When you get a vaccination, these are the cells that produce antibody that can be detected in the blood for a number of years (what testing your antibody titer looks for). These cells are in pretty limited supply, so we know less about them. My guess is that they are not actively eliminated, but may become eliminated over time by other mechanisms (purposely undefined here).

My understanding of this question is: Antibodies are produced by plasma cells which are terminally-differentiated B cells. Maturation of B cells to plasma cells is stimulated by the presence of antigen (T cells, cytokines, etc. etc).

In the absence of antigen the existing plasma cells undergo apoptosis, and the maturation of the cognate B cells will not be stimulated, so no more plasma cells will be produced.

I have found it surprisingly difficult to find references in support of these statements, although there is a large literature on the suppression of apoptosis in memory B cells.

How is antibody production stopped? - Biology

Variations in antibody structure allow great diversity of antigen recognition among different antibodies.

Learning Objectives

Differentiate among the classes of antibodies

Key Takeaways

Key Points

  • Antibodies contain four polypeptides: two identical (to each other) heavy chains in a “Y” formation and two idenitical (to each other) light chains on the outside of the top of the “Y” portion.
  • Each antibody has a unique variable region, which is responsible for antigen detection and specificity.
  • There are five classes of antibodies, each utilized by the body under different conditions, including IgM, IgG, IgA, IgD, and IgE Ig stands for immunoglobulin.
  • IgAs, secreted in the milk, tears and mucous, are the most numerous antibodies produced inside of the body, circulating IgGs are the most abundant.

Key Terms

  • immunoglobulin: any of the glycoproteins in blood serum that respond to invasion by foreign antigens and that protect the host by removing pathogens also known as an antibody
  • antigen: a substance that binds to a specific antibody may cause an immune response
  • B cell: a lymphocyte, developed in the bursa of birds and the bone marrow of other animals, that produces antibodies and is responsible for the immune system
  • epitope: that part of a biomolecule (such as a protein) that is the target of an immune response the part of the antigen recognized by the immune system

Antibody Structure

An antibody is a molecule that recognizes a specific antigen this recognition is a vital component of the adaptive immune response. Antibodies are composed of four polypeptides: two identical heavy chains (large peptide units) that are partially bound to each other in a “Y” formation, which are flanked by two identical light chains (small peptide units). The area where the antigen is recognized on the antibody is known as the variable domain or variable region. This is why there are numerous antibodies that can each recognize a different antigen. The antibody base is known as the constant domain or constant region. The portion of an antigen that is recognized by the antibody is known as the epitope.

Antibodies: (a) As a germ-line B cell matures, an enzyme called DNA recombinase randomly excises V and J segments from the light chain gene. Splicing at the mRNA level results in further gene rearrangement. As a result, (b) each antibody has a unique variable region capable of binding a different antigen.

Antibody variation

In B cells, the variable region of the light chain gene has 40 variable (V) and five joining (J) segments. An enzyme called DNA recombinase randomly excises most of these segments out of the gene, splicing one V segment to one J segment. During RNA processing, all but one V and J segment are spliced out. Recombination and splicing may result in over 10 6 possible VJ combinations. As a result, each differentiated B cell in the human body typically has a unique variable chain. The constant domain, which does not bind to an antibody, is the same for all antibodies. The large diversity of antibody structure translates into the large diversity of antigens that antibodies can bind and recognize.

Similar to TCRs (T cell receptors) and BCRs (B cell receptors), antibody diversity is produced by the mutation and recombination of approximately 300 different gene segments encoding the light and heavy chain variable domains in precursor cells that are destined to become B cells. The variable domains from the heavy and light chains interact to form the binding site through which an antibody can bind a specific epitope on an antigen. The numbers of repeated constant domains in Ig classes (discussed below) are the same for all antibodies corresponding to a specific class. Antibodies are structurally similar to the extracellular component of the BCRs. The maturation of B cells into plasma cells occurs when the cells gain the ability to secrete the antibody portion of its BCR in large quantities.

Antibody Classes

Antibodies can be divided into five classes (IgM, IgG, IgA, IgD, and IgE) based on their physiochemical, structural, and immunological properties. Ig stands for immunoglobulin, another term for an antibody. IgGs, which make up about 80 percent of all antibodies in circulation, have heavy chains that consist of one variable domain and three identical constant domains. IgA and IgD also have three constant domains per heavy chain, whereas IgM and IgE each have four constant domains per heavy chain. The variable domain determines binding specificity, while the constant domain of the heavy chain determines the immunological mechanism of action of the corresponding antibody class. It is possible for two antibodies to have the same binding specificities, but be in different classes and, therefore, to be involved in different functions.

After an adaptive defense is produced against a pathogen, typically plasma cells first secrete IgM into the blood. BCRs on naïve B cells are of the IgM class and, occasionally, the IgD class. IgM molecules comprise approximately ten percent of all antibodies. Prior to antibody secretion, plasma cells assemble IgM molecules into pentamers (five individual antibodies) linked by a joining (J) chain. The pentamer arrangement means that these macromolecules can bind ten identical antigens. However, IgM molecules released early in the adaptive immune response do not bind to antigens as stably as do IgGs, which are one of the possible types of antibodies secreted in large quantities upon re-exposure to the same pathogen. The properties of immunoglobulins and their basic structures are shown in the table.

Classes of antibodies: Immunoglobulins (antibody classes) have different functions, but all are composed of light and heavy chains that form a Y-shaped structure.

IgAs populate the saliva, tears, breast milk, and mucus secretions of the gastrointestinal, respiratory, and genitourinary tracts. Collectively, these bodily fluids coat and protect the extensive mucosa (4000 square feet in humans). The total number of IgA molecules in these bodily secretions is greater than the number of IgG molecules in the blood serum. A small amount of IgA is also secreted into the serum in monomeric form. Conversely, some IgM is secreted into bodily fluids of the mucosa. Similarly to IgM, IgA molecules are secreted as polymeric structures linked with a J chain. However, IgAs are secreted mostly as dimeric molecules, not pentamers.

IgE is present in the serum in small quantities and is best characterized in its role as an allergy mediator. IgD is also present in small quantities. Similarly to IgM, BCRs containing the IgD class of antibodies are found on the surface of naïve B cells. This class supports antigen recognition and subsequent maturation of B cells to plasma cells.

Adaptive Immunity

E. John Wherry , David Masopust , in Viral Pathogenesis (Third Edition) , 2016

2.1 Measures of Antibody

There are many methods to measure antibody to viruses, and both the kinetics of the response and its biological significance depend upon the assay used. The canonical assay is the neutralization test, in which antibody is tested for its ability to reduce viral infectivity. This test depends on the availability of a convenient method to measure viral infectivity, often a plaque assay. One common technique involves the use of a single viral inoculum, such as 100 PFU (plaque forming units) serial dilutions of a test antibody are tested to determine the highest dilution that will reduce the plaque count by 50%. However, neutralization tests cannot be used for some important viruses, such as hepatitis B and C viruses, that cannot readily be grown in cell culture.

There are many alternative assays that measure the ability of the antibody to bind to viral antigens, including hemagglutination inhibition, immunofluorescence, Western blot, and ELISA (enzyme linked immunosorbent assay). Of these, the most commonly used is the ELISA assay, which can readily be adapted to quantitation, automation, and rapid throughput. An antigen, either whole virus, a viral protein, or a viral peptide, is bound to a substrate, and then incubated with serial dilutions of test antibody adherence of the test antibody is determined with a conjugated antiserum directed against immunoglobulin of the species under test.

In contrast to the ELISA, the Western blot is a qualitative test that provides information about the specificity of the test antibody. Proteins from a viral lysate are separated, often using polyacrylamide gel electrophoresis, and crosslinked to a cellulose strip. An unknown serum is tested for its ability to bind to any of the proteins on the strip, and the reaction is “developed” with a labeled antisera against immunoglobulin, as for the ELISA.

Antibody production can also be measured at a cellular level. In the ELISPOT assay, cells—including plasma cells—are prepared from blood or lymphoid tissues, and overlaid on a surface to which a target antigen has previously been bound. Antigen-specific antibody released by specific plasma cells binds to the cognate antigen, and the “focus” is developed using a variation of the method used in ELISA assays. This assay permits the counting of antibody-secreting cells (ASCs) and can be employed for studies of the dynamics of the antibody response.

How does the adaptive response counter the two different states of a virus, the extracellular infectious virion versus the intracellular replicating virus?


Regulation of the immune response is perchance mediated in several ways. First, a specific group of T-cells, suppresser T-cells, are thought to be involved in turning down the immune response. Like helper T-cells, suppresser T-cells are stimulated by antigen but alternatively of let go ofing lymphokines that activate B-cells (and other cells), suppressor T-cells release factors that suppress the B-cell response. While immunosuppression is non wholly understood, it appears to be more complicated than the activation tract, perchance affecting extra cells in the overall tract.

Other agencies of ordinance involve interactions between antibody and B-cells. One mechanism, “ antigen blocking ”, occurs when high doses of antibody interact with all of the antigen ‘s antigenic determinants, thereby suppressing interactions with B-cell receptors. A 2nd mechanism, “ receptor cross associating ”, consequences when antibody, edge to a B-cell via its Fc receptor, and the B-cell receptor both combine with antigen. This “ cross-linking ” inhibits the B-cell from bring forthing farther antibody.

Another agency of ordinance that has been proposed is the idiotypic web hypothesis. This theory suggests that the idiotypic determiners of antibody molecules are so alone that they appear foreign to the immune system and are, hence, antigenic. Therefore, production of antibody in response to antigen leads to the production of anti-antibody in response, and anti-anti-antibody and so on. Eventually, nevertheless, the degree of [ anti ] n-antibody is non sufficient to bring on another unit of ammunition and the cascade ends.


Antibodies are host proteins that are produced by the immune system in response to foreign molecules that enter the body. These foreign molecules are called antigens, and their molecular recognition by the immune system results in selective production of antibodies that are able to bind the specific antigen. Antibodies are made by B-lymphocytes and circulate throughout the blood and lymph where they bind to their specific antigen, enabling it to be cleared from circulation.

This ability of animal immune systems to produce antibodies capable of binding specifically to antigens can be harnessed to manufacture probes for detection of molecules of interest in a variety of research and diagnostic applications. Certainly, no other current technology allows researchers to design and manufacture such highly specific molecular recognition tools. Several important features besides their high specificity make antibodies particularly conducive to development as probes. For example, except in those portions that determine antigen binding, antibodies share a relatively uniform and well-characterized protein structure that enables them to be purified, labeled and detected predictably and reproducibly by generalized methods.

Procedures for generating, purifying and modifying antibodies for use as antigen-specific probes were developed during the 1970s and 1980s and have remained relatively unchanged since Harlow and Lane published their classic Antibodies: A Laboratory Manual in 1988.

Antibody production and purification guide

The updated Antibody Production and Purification Technical Handbook is an essential resource for any laboratory working with antibodies. The handbook provides an overview of antibody structure and types, as well as technical information on the procedures, reagents and tools used to produce, purify, fragment and label antibodies.

Biology 151 - Chapter 21

Proteins are broken into fragments, transported to the rough endoplasmic reticulum, fuse with a Golgi vesicle containing class II MHCs, and this complex is transported to the plasma membrane.

Proteins are broken into fragments within a vesicle, which fuses with a Golgi vesicle containing class I MHCs, and this complex is transported to the plasma membrane.

Proteins are broken into fragments within a vesicle, which fuses with a Golgi vesicle containing class II MHCs, and this complex is transported to the plasma membrane.

Proteins are broken into fragments, transported to the rough endoplasmic reticulum, combined with class II MHCs, move to the Golgi apparatus, then to the plasma membrane.

Proteins are broken into fragments, transported to the rough endoplasmic reticulum, fuse with a Golgi vesicle containing class II MHCs, and this complex is transported to the plasma membrane.

Proteins are broken into fragments within a vesicle, which fuses with a Golgi vesicle containing class I MHCs, and this complex is transported to the plasma membrane.

Proteins are broken into fragments within a vesicle, which fuses with a Golgi vesicle containing class II MHCs, and this complex is transported to the plasma membrane.

Proteins are broken into fragments, transported to the rough endoplasmic reticulum, combined with class II MHCs, move to the Golgi apparatus, then to the plasma membrane.

There Are Five Classes of Heavy Chains, Each With Different Biological Properties

In mammals, there are five 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 chains, IgG molecules have γ chains, and so on. In addition, there 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, γ2, γ3, andγ4 heavy chains, respectively. The various heavy chains give a distinctive conformation to the hinge and tail regions of antibodies, so that each class (and subclass) has characteristic properties of its own.

IgM, which has μ heavy chains, is always the first class of antibody made by a developing B cell, although many B cells eventually switch to making other classes of antibody (discussed below). The immediate precursor of a B cell, called a pre-B cell, initially makes μ chains, which associate with so-called surrogate light chains (substituting for genuine light chains) and insert into the plasma membrane. The complexes of μ chains and surrogate light chains are required for the cell to progress to the next stage of development, where it 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 light chains). These molecules then insert into the plasma membrane, where they function as receptors for antigen. At this point, the cell is called an immature naïve B cell. After leaving the bone marrow, the cell starts to produce cell-surface IgD molecules as well, with the same antigen-binding site as the IgM molecules. It is now called a mature naïve B cell. It is this cell that can respond to foreign 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 antibody to appear on the surface of a developing B cell. It is also the major class secreted into the blood in the early stages of a primary antibody response, on first exposure to an antigen. (Unlike IgM, IgD molecules are secreted in only small 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 it 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 by 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 by disulfide bonds (red). A single J chain, which has a structure similar to that of a single Ig domain (discussed later), is disulfide-bonded between the tails of two μ heavy chains. (more. )

The binding of an antigen to a single secreted pentameric IgM molecule can activate the complement system. As discussed in Chapter 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 it directly.

The major class of immunoglobulin in the blood is IgG, which is a four-chain monomer produced in large quantities during secondary immune 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 have become 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 by a macrophage or neutrophil, which has cell-surface receptors that bind the tail (Fc) region of IgG molecules. The binding of the antibody-coated bacterium (more. )

IgG molecules are the only antibodies that can 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 bound 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 by exocytosis into the fetal blood (a process called transcytosis, discussed in Chapter 13). Because other classes of antibodies do not bind to these particular Fc receptors, they cannot pass across the placenta. IgG is also 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 principal class of antibody in secretions, including saliva, tears, milk, and respiratory and intestinal secretions. Whereas IgA is a four-chain 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 most common form of antibody deficiency, are only mildly affected by the defect.

Figure 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. )

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 cell. The receptor-IgA complexes (more. )

The tail region of IgE molecules, which are four-chain monomers, binds with unusually high affinity (Ka

10 10 liters/mole) to yet another 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 as passively acquired receptors for antigen. Antigen binding triggers the mast cell or basophil to secrete a variety of cytokines and biologically active amines, especially histamine (Figure 24-27). These molecules cause blood 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 as hay fever, asthma, and hives. In addition, mast cells secrete factors that attract and activate white blood cells called eosinophils. These cells also have Fc receptors that bind IgE molecules and can kill various types of parasites, especially if the parasites are coated with IgE antibodies.

Figure 24-27

The role of IgE in histamine secretion by 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 five classes of heavy chains found in antibody molecules, higher vertebrates have two types of light chains, κ and λ, which seem to be functionally indistinguishable. Either type of light chain may be associated with any of the heavy chains. An individual antibody molecule, however, always contains identical light chains and identical heavy chains: an IgG molecule, for instance, may have either κ or λ light chains, but not 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 24-19).

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.

  • When B cells and T cells are first activated by a pathogen, memory B-cells and T- cells develop.
  • Throughout the lifetime of an animal these memory cells will &ldquoremember&rdquo each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again. This type of immunity is both active and adaptive.
  • Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system.
  • secondary response: the immune response occurring on second and subsequent exposures to an antigen, with a stronger response to a lesser amount of antigen, and a shorter lag time compared to the primary immune response
  • primary response: the immune response occurring on the first exposure to an antigen, with specific antibodies appearing in the blood after a multiple day latent period
  • adaptive immunity: the components of the immune system that adapt themselves to each new disease encountered and are able to generate pathogen-specific immunity.

The immune system is a system of biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, from viruses to parasitic worms, and distinguish them from the organism&rsquos own healthy tissue. Pathogens can rapidly evolve and adapt to avoid detection and neutralization by the immune system. As a result, multiple defense mechanisms have also evolved to recognize and neutralize pathogens. Even simple unicellular organisms such as bacteria possess a rudimentary immune system, in the form of enzymes that protect against bacteriophage infections. Other basic immune mechanisms evolved in ancient eukaryotes and remain in their modern descendants, such as plants and insects. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates, including humans, have even more sophisticated defense mechanisms, including the ability to adapt over time to recognize specific pathogens more efficiently. Adaptive (or acquired) immunity creates immunological memory after an initial response to a specific pathogen, leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination.

Figure: The Time Course of an Immune Response: Immune reactants, such as antibodies and effector T-cells, work to eliminate an infection, and their levels and activity rapidly increase following an encounter with an infectious agent, whether that agent is a pathogen or a vaccine. For several weeks these reactants remain in the serum and lymphatic tissues and provide protective immunity against reinfection by the same agent. During an early reinfection, few outward symptoms of illness are present, but the levels of immune reactants increase and are detectable in the blood and/or lymph. Following clearance of the infection, antibody level and effector T cell activity gradually declines. Because immunological memory has developed, reinfection at later times leads to a rapid increase in antibody production and effector T cell activity. These later infections can be mild or even inapparent.

Disorders of the immune system can result in autoimmune diseases, inflammatory diseases and cancer. Immunodeficiency occurs when the immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or the use of immunosuppressive medication. In contrast, autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto&rsquos thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus. Immunology covers the study of all aspects of the immune system.

The immune system protects organisms from infection with layered defenses of increasing specificity. In simple terms, physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all plants and animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered. Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non- self molecules. In immunology, self molecules are those components of an organism&rsquos body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (short for antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.

When B cells and T cells are first activated by a pathogen, memory B-cells and T- cells develop. Throughout the lifetime of an animal these memory cells will &ldquoremember&rdquo each specific pathogen encountered, and are able to mount a strong response if the pathogen is detected again. This type of immunity is both active and adaptive because the body&rsquos immune system prepares itself for future challenges. Active immunity often involves both the cell-mediated and humoral aspects of immunity as well as input from the innate immune system. The innate system is present from birth and protects an individual from pathogens regardless of experiences, whereas adaptive immunity arises only after an infection or immunization and hence is &ldquoacquired&rdquo during life.

How are Antibodies Produced?

How are Antibodies Produced?
Although detailed mechanics of the immune response are beyond the scope of this site, it is useful, in the context of developing a custom antibody, to have an overview of how antibodies are produced by the immune system.

When an organism’s immune system encounters a foreign molecule (typically a protein) for the first time, specialized cells such as macrophages and dendritic cells capture the molecule and begin breaking it down so that it can present these antigens to B cell lymphocytes.

Once Antigen Presentation to the B cell lymphocytes has occurred, a process known as Somatic Hypermutation allows the B cell to begin coding for a new antibody that will contain a unique Antigen Binding Site in the variable region that is capable of binding specifically to an epitope from the antigen.

Each B cell lymphocyte produces one unique antibody against one unique epitope.

Once antibodies with sufficient specificity to the epitope can be encoded, the B cell begins to release antibodies into the bloodstream. These antibodies then bind specifically with the foreign molecule and allow the immune system to eliminate the molecule from the system.

In some cases, these antibodies can disable pathogens such as viruses directly due to the binding action. In other cases, such as with bacterial pathogens, these antibodies bind to surface proteins on the bacterium’s surface, thereby signaling to the rest of the immune system that the pathogen should be destroyed.

After the foreign molecule has been eliminated, B cells remain in the bloodstream ready to produce antibodies if the antigen is encountered again.

From the perspective of developing a custom antibody against a protein antigen, the immune system captures the protein, breaks it down into individual epitopes and presents these epitopes to the B cells so that development of antibodies specific to those epitopes can begin. These antibodies can then be collected directly in the serum or by isolating the individual B cells that produce antibody against the epitope of interest. With a full-length protein antigen, there will typically be multiple B cells generating antibodies against multiple epitopes from different regions of the protein.

Primary and Secondary Phases

Now we know the various components of the humoral immune system, it is easy to picture the two phases.

In the primary phase of the humoral immune response that takes several days to take effect, the following occurs:

  • First contact with a foreign pathogen by APCs
  • Digestion of antigen by APCs and conversion of antigen fragments into MHC II surface proteins
  • Recognition of MHC II surface protein by T helper cell
  • Production of cytokines by T helper cell
  • Naïve B cells activated by T helper cell cytokines
  • Naïve B cells differentiate into plasma or memory B cells
  • Plasma cells produce and secrete IgM antibodies where necessary, IgG or IgA antibodies are secreted if the pathogen population remains active after peak IgM secretion.
  • This process requires 7 to 10 days to produce peak antibody levels.

In the secondary humoral immune response, the body has previously been in contact with a specific pathogen and memory B cells produced during the initial attack are still present. Memory B cells can live for weeks, months, or even years.

The steps of the secondary phase only involve thymus-dependent antibodies (memory B cells):

  • Memory B cells recognize the antigens of the microorganism
  • Memory B cells divide to produce highly-specific plasma cells
  • Plasma cells produce primarily IgG but also IgM, IgA, and IgE immunoglobulins
  • Antibodies are produced in quantities of over 1000 times the primary response
  • Peak antibody levels are achieved within 3 to 5 days.

Somatic Hypermutation

The second stage of recombination occurs after the B cell is activated by an antigen. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation, by a process called somatic hypermutation (SHM). SHM is a cellular mechanism by which the immune system adapts to the new foreign elements that confront it and is a major component of the process of affinity maturation. SHM diversifies B cell receptors used to recognize antigens and allows the immune system to adapt its response to new threats during the lifetime of an organism. Somatic hypermutation involves a programmed process of mutation affecting the variable regions of immunoglobulin genes. SHM results in approximately one nucleotide change per variable gene, per cell division. As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains. This serves to increase the diversity of the antibody pool and impacts the antibody&rsquos antigen-binding affinity. Some point mutations will result in the production of antibodies that have a lower affinity with their antigen than the original antibody, and some mutations will generate antibodies with a higher affinity. B cells that express higher affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with lower affinity antibodies will not, and will die by apoptosis. Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival. The process of generating antibodies with increased binding affinities is called affinity maturation. Affinity maturation occurs after V(D)J recombination, and is dependent on help from helper T cells.

Antibody genes also re-organize in a process called class switching, which changes the base of the heavy chain to another. This creates a different isotype of the antibody while retaining the antigen specific variable region, thus allowing a single antibody to be used by several different parts of the immune system.