how B-lymphocyte activated to form antibody ?

Answer 1

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An antibody or immunoglobulin is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. This is because at the two tips of its "Y", it has structures akin to locks. Every lock only has one key, in this case, its own antigen. When the key is inserted into the lock, the antibody attaches, tagging the microbe or an infected cell for attack by other parts of the immune system or by directly neutralizing its target (i.e. blocking a part of the microbe that is essential for its invasion and survival). The production of antibodies is the main function of the humoral immune system.

Immunoglobulins are glycoproteins in the immunoglobulin superfamily that function as antibodies. The terms antibody and immunoglobulin are often used interchangeably. They are found in the blood and tissue fluids, as well as many secretions. In structure, they are globulins (in the γ-region of protein electrophoresis). They are synthesized and secreted by plasma cells that are derived from the B cells of the immune system. B cells are activated upon binding to their specific antigen and differentiate into plasma cells. In some cases, the interaction of the B cell with a T helper cell is also necessary.

Immunoglobulin isotypes

In mammals there are five types of antibody: IgA, IgD, IgE, IgG, and IgM, with 4 IgG and 2 IgA subtypes present in humans. (Ig stands for immunoglobulin, which is another name for antibody). These are classified according to differences in their heavy chain constant domains (see below for more information regarding the structural features of antibodies). Each immunoglobulin class differs in its biological properties and has evolved to deal with different antigens. IgA can be found in areas containing mucus (e.g. in the gut, in the respiratory tract or in the urinogenital tract) and prevents the colonization of mucosal areas by pathogens. IgD functions mainly as an antigen receptor on B cells. IgE binds to allergens and triggers histamine release from mast cells (the underlying mechanism of allergy) and also provides protection against helminths (worms). IgG (in its four forms) provides the majority of antibody-based immunity against invading pathogens. IgM is expressed on the surface of B cells and also in a secreted form with very high affinity for eliminating pathogens in the early stages of B cell mediated immunity (i.e. before there is sufficient IgG to do the job).

Immature B cells express only IgM on their cell surface (this is the surface bound form not the secreted form of immunoglobulin). Once the naive B cell reaches maturity, it can express both IgM and IgD on its surface - it is the co-expression of both these immunoglobulin isotypes that renders the B cell 'mature' and ready to respond to antigen. Following an engagement of the immunoglobulin molecule with an antigen, the B cell becomes activated, and begins to divide and differentiate into an antibody producing cell (sometimes called a plasma cell). In this activated form, the B cell will produce its immunoglobulin in a secreted form rather than a membrane-bound form. Some of the daughter cells of the activated B cells will undergo isotype switching, a mechanism by which the B cell begins to express the other heavy chains and thus produce IgD, IgA or (more commonly) IgG


Immunoglobulin diversity

Somatic recombination also known as V(D)J recombination is when genes are selected (variable (V), diversity (D) and joining (J) for heavy chains, and only V and J for light chains) to form countless combinations. Multiple copies of the V, D and J segments exist tandemly arranged in the genomes of mammals and their selection for recombination within the individual B cell is also called gene rearrangement. Following successful recombination of the immunoglobulin DNA segments, that B cell suppresses the expression of any other Variable region genes by a process known as allelic exclusion. At this stage, each individual B cell can now only generate antibodies with the same variable regions in the heavy and light chains, regardless of Ig class/constant chain. The main reason that the human immune system is capable of binding so many antigens is the diversity in the variable region of the heavy chain - to be specific, in the area where these V, D and J genes are found, otherwise known as the complementarity determining region 3 (CDR3). Isotype (or class) switching occurs after the process of recombination and following activation of the mature B cell (see above) to generate the different classes of antibody, all with the same variable domains as the original immunoglobulin generated in the immature B cell during recombination.

A further mechanism for generating antibody diversity exists for the mature B cell after antigen stimulation. Activated B cells are more prone to somatic mutations in their immunoglobulin variable chain genes. This generates slight changes in the amino acid sequence of the variable domains of both the Light and Heavy Chains between clones of the same activated B cell, and ultimately, differences in the affinity or strength of interaction that the B cell has with its specific antigen. Thus, B cells expressing immunoglobulins with higher affinity for the antigen will outcompete those with weaker immunoglobulin for function and survival in a process known as affinity maturation.


Structure of the antibody

Immunoglobulins are heavy plasma proteins, often with added sugar chains (see glycosylation) on N-terminal (all antibodies) and occasionally O-terminal (IgA1 and IgD) amino acid residues. In other words, they are glycoproteins. The basic unit of each antibody is a monomer (one immunoglobulin unit) but the secreted antibody can also be dimeric (with 2 Ig units as with IgA), tetrameric (with 4 Ig units like teleost fish IgM), or pentameric (with 5 Ig units, like mammalian IgM). The monomer is a "Y"-shape molecule that consists of four polypeptide chains: two identical heavy chains and two identical light chains connected by disulfide bonds. [1]



Heavy Chain

Mammalian immunoglobulin heavy chains

There are five types of heavy chain: γ, δ, α, μ and ε. They define classes of immunoglobulins. Heavy chains α and γ have approximately 450 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has a constant region (which is the same for all immunoglobulins of the same class but differs between each class of immunoglobulins) and a variable region of different B cells, but is the same for all immunoglobulins produced by the same B cell. Heavy chains γ, α and δ have a constant region composed of three tandem (in a line next to each other) immunoglobulin domains but also have a hinge region for added flexibility; the constant region of heavy chains μ and ε is composed of four immunoglobulin domains. The variable domain of any heavy chain is composed of a single immunoglobulin domain. These domains are about 110 amino acids long. There are also some amino acids between constant domains.

Fish immunoglobulin heavy chains

Jawed fish appear to be the most primitive animals that are able to make antibodies like those described for mammals. However, fish do not have the same repertoire of antibodies that mammals possess. Three distinct Ig heavy chains have so far been identified in bony fish. The first identified was the μ (or mu) heavy chain that is present in all jawed fish and is the heavy chain for what is thought to be the primordial immunoglobulin. The resulting antibody, IgM, is secreted as a tetramer (containing four polypeptide chains) in teleost fish instead of the typical pentamer (containing five polypeptide chains) found in mammals and sharks. The heavy chain (δ) for IgD was identified initially from the channel catfish and Atlantic salmon and is now well documented for many teleost fish. The third teleost Ig heavy chain gene was identified very recently and does not resemble any of the heavy chains so far described for mammals. This heavy chain, identified in both rainbow trout (τ) and zebrafish (ζ), could potentially form a distinct antibody isotype (IgT or IgZ) that may precede IgM in evolutionary terms. Similar to the situation observed for bony fish, three distinct Ig heavy chain isotypes have been identified in cartilaginous fish. With the exception of IgM, these Ig heavy chain isotypes appear to be unique to cartilaginous fish and are designated IgM, IgW (also called IgX or IgNARC) and IgNAR. See references 1-3 for a review of the literature concerning fish immunoglobulins.



Light Chain


There are only two types of light chain: λ and κ. In humans, they are similar, but only one type is present in each antibody. Each light chain has two successive domains: one constant and one variable domain. The approximate length of a light chain is from 211 to 217 amino acids.

Fun fact about immunoglobulin light chains: Camelids (see camel) are unique among all other mammals in that they have fully functional immunoglobulins which consist of two heavy chains, but lacking the light chains usually paired with each heavy chain (they also have classical four-chain antibodies). The functional role of this separate repertoire is unknown as yet. Apart from providing insight into immunglobulin structure and antigen recognition in absence of light chain CDR's, these unusual antibodies can also be exploited to generate antibody fragments smaller yet than scFv's, but also much more stable


Fc region

The Fc region (Fragment, crystalizable), is derived from the stem of the "Y," and is composed of two heavy chains that each contribute two to three constant domains (depending on the class of the antibody). Fc binds to various cell receptors and complement proteins. In this way, it mediates different physiological effects of antibodies (opsonization, cell lysis, degranulation of mast cells, basophils and eosinophils and other processes

Fab region

Each half of the forked end of the "Y" of the antibody is called the Fab (Fragment, antigen binding) region. It is composed of one constant and one variable domain of each the heavy and the light chain, which together shape the antigen binding site at the amino terminal end of the monomer. The two variable domains bind their specific antigens.

Generating the Fc and Fab fragments in the laboratory. In an experimental setting, the enzyme papain can be used to cleave an immunoglobulin monomer into two Fab fragments and an Fc fragment. The enzyme pepsin cleaves below hinge region, so a F(ab')2 fragment and a Fc fragment is formed. The variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv), which is only half the size of the Fab fragment yet retains the original specificity of the parent immunoglobulin.


Function

Since antibodies exist freely in the bloodstream or bound to cell membranes, they are said to be part of the humoral immune system. The circulating antibodies are produced by clonal B cells that are specific to only one antigen (e.g., a virus hull protein fragment). In binding their specific antigens, the antibodies can cause agglutination and precipitation of antibody-antigen products primed for phagocytosis by macrophages and other cells, block viral receptors, and stimulate other immune responses, such as the complement pathway. Here are some of those functions in more detail.

Neutralization: Antibodies that recognize viruses can block these directly. The virus will be unable to dock to its preferred receptor on a cell to infect it, hindered by the antibody. Antibodies (e.g. IgA) can also directly bind microbes in mucus, preventing the colonization of mucosal tissues. They also neutralize toxins by binding with them.

Agglutination: Antibodies specific for specific antigen on insoluble particles (e.g. whole viruses or cells) can link these particles together causing them to agglutinate so phagocytes can capture them.

Activation of complement: Antibodies that bind to surface antigens on, for example a bacterium, will bind the first component of the complement system with their Fc region (see above) and initiate activation of the classical complement system. This results in the killing of bacteria in two ways. First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization. These phagocytes are attracted by some of the complement molecules that are generated in the complement cascade. Secondly, some complement components form a membrane attack complex to assist the antibodies to kill bacteria directly.

Activation of effector cells: Some cells (e.g. Mast cells and phagocytes) have specific receptors on their cell surface for binding antibodies. These are called Fc receptors, and, as the name suggests, these receptors interact with the Fc region of some antibodies (e.g. IgA, IgG, IgE). The engagement of a particular antibody with the Fc receptor on a particular cell will trigger the effector function of that cell (e.g. phagocytes will phagocytose, mast cells will degranulate) that will ultimately result in destruction of the invading microbe. The Fc receptors are isotype-specific, which gives a great flexibility to the immune system, because different situations require only certain immune mechanisms to respond to antigens.

It is important to note that antibodies cannot attack pathogens within cells, and certain viruses "hide" inside cells (as part of the lysogenic cycle) for long periods of time to avoid them (such as HIV and HBV). This is the reason for the chronic nature of many minor skin diseases (such as cold sores); any given outbreak is quickly suppressed by the immune system, but the infection is never truly eradicated because some cells retain viruses that will resume the apparent symptoms later.



Affinity vs Avidity


Depending on the structure of the antibody (which varies with the isotype) and that of the antigen, an antibody may have only one binding interaction with the antigen (monovalent) or multiple simultaneous interactions (multivalent).

Affinity is the binding strength of a single antibody - antigen interaction.
Avidity is the compound affinity of multiple antibody - antigen interactions when more than one takes place between the two molecules. That is, avidity is the apparent affinity of the antigen - antibody binding in these cases, not the true affinity.
Avidity can be orders of magnitude greater than affinity, helping for instance poorly affinity maturated but highly multivalent IgM still bind antigen efficiently.


Practical Applications

Medical Applications


Detection of particular antibodies is a very common form of medical diagnostics. Serology depends on these methods. Autoimmune disorders can often be traced to antibodies that bind the body's own epitopes; many can be detected through blood tests. Antibodies directed against RBC surface antigens in immune mediated hemolytic anemia can be detected with the Coombs test. The Coombs test is also used for antibody screening in blood transfusion preparation and also for antibody screening in antenatal women.

"Designed" monoclonal antibody therapy is already being employed in a number of diseases (including rheumatoid arthritis) and in some forms of cancer. Presently, many antibody-related therapies are undergoing extensive clinical trials for use in practice.

Some immune deficiencies result in partial or complete lack of antibodies, such as X-linked agammaglobulinemia and hypogammaglobulinemia


Liver disease

Elevations in the different classes of immunoglobulins are sometimes useful in determining the cause of liver damage in patients whom the diagnosis is unclear:

total IgA is elevated in alcoholic cirrhosis;
total IgM is elevated in viral hepatitis and primary biliary cirrhosis;
total IgG is elevated in viral hepatitis, autoimmune hepatitis and cirrhosis

RHOGAM antibodies

RHOGAM antibodies are used in Rhesus-negative mothers who have a Rhesus-positive fetus. The Rhesus factor (a.k.a. D antigen) is an antigen found in blood. It is the second most important thing to consider in a blood transfusion, next to blood type. People that are Rh+ have this antigen on their blood cells. People that are Rh- don't have this antigen on their blood cells.

When the mother is Rh-, her body has B cells primed to produce antibodies that are specific to the Rh antigen, which essentially means that if the Rhesus antigen is injected into her blood, in about a week, all the antigen will be destroyed. This is a problem for babies that are Rhesus-positive, because if childbirth has complications, and blood from the baby enters the mother, then the mother will treat the baby's blood cells as foreign enemies with Rhesus antigens sticking out, and will counter the invader with antibodies. The next time this mother has a baby with Rhesus-positive blood, the mother will actively attack the fetus, causing a serious condition where the baby will have massive red blood cell destruction, known as hemolysis. However, this can be prevented by an injection of RHOGAM antibodies.

RHOGAM antibodies are specific to Rh, i.e. that they were built to connect to the Rhesus antigen. They are used normally every time that a Rhesus-negative mother has a fetus that is Rhesus-positive. They will destroy the antigen before it can stimulate the mother's B cells to make anti-Rh antibodies. Therefore, her humoral immune system will never have to make anti-Rh antibodies, and will not attack the baby's Rhesus antigen.



I THOUGHT THIS INFO IS ENOUGH....

Answer 2

I was curious about your question so I pulled out my old Human Phis textbook. B-lymphocyes are transformed into plasma cells which secrete antibodies. So they are released.