Antibody
From DrugPedia: A Wikipedia for Drug discovery
Antibody are immune system-related proteins called immunoglobulins. Soluble, or secreted, antibody is structurally slightly different than the antibody on the surface of B cells but the antigen recognition sites are similar. The ability of antibodies to recognize specific antigen is an important characteristic .
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Antigen recognition and binding allows antibodies to perform three important functions.
- opsonization
- activating complement
- neutralizing toxins and toxic organisms
Contents |
[edit] Antibody Structure
Each antibody consists of four polypeptides– two heavy chains and two light chains linked by disulphide bonds to form a "Y" shaped molecule.
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The amino acid sequence in the tips of the "Y" varies greatly among different antibodies. This variable region, composed of 110-130 amino acids, give the antibody its specificity for binding antigen. The variable region includes the ends of the light and heavy chains. Treating the antibody with a protease can cleave this region, producing Fab or fragment antigen binding that include the variable ends of an antibody. Material used for the studies shown below originated from Fab.
The constant region determines the mechanism used to destroy antigen.
The light chain has two domains and the heavy has four. The N-terminal domain at the tip of the arms of the "Y" on both the heavy and light chain are known to be variable in amino acid sequence composition and are thus called variable domains (VL and VH). The other domains are called constant for a similar reason (CL, CH1, CH2, CH3).
The variable domains show three regions of hypervariability in sequence called the complementarity determining regions (CDRs). They differ in length and sequence between different antibodies and are mainly responsible for the specificity (recognition) and affinity (binding) of the antibodies to their target markers. Proteolytic digestion of antibodies releases different fragments termed Fv (Fragment variable), Fab (Fragment antigen binding) and Fc (Fragment crystallisation).
The linear protein chain in each of the domains folds into a characteristic 3D structure called the immunoglobulin fold. It consists of two sheets, formed by the protein chain, packed against each other. In the constant domains, each sheet consists of three and four strands respectively. The constant domains of the Fc fragment are responsible for mediating the effector functions of the antibody. The variable domain has a similar structure, except that there are nine strands; four and five in each sheet respectively.
[edit] Antibody Classes
Based on their constant region structure and immune function, antibodies are divided into five major classes:
- IgM : Mu heavy chains
- IgG : Gamma heavy chains
- IgA : Alpha heavy chains
- IgD : Delta heavy chains
- IgE : Epsilon heavy chains
They are each named with an "Ig" prefix that stands for immunoglobulin, another name for antibody, and differ in their biological properties, functional locations and ability to deal with different antigens.
[edit] IgM
This type of antibody can be found as "surface antibody" on the surface membrane of B cells (sIgM) or as a 5-subunit macromolecule secreted into the blood by plasma cells. The surface IgM is structurally different in the Fc region from the secreted form since it must bind through the membrane. Surface IgM binds directly as an integral membrane protein, it does not bind to an IgM Fc receptor like IgE does.
Secreted IgM is found as a "pentameric" molecule. The five IgM subunits are held together providing multiple binding sites in each molecule. Because of its shape and size, IgM is particularly good at activating complement and causing agglutination. IgM is the first antibody to be produced in response to infection since it does not require "class switch" to another antibody class.
[edit] IgG
IgG is the most abundant form (class) of antibody in the blood (serum concentration is 13 mg/ml !). There are four subclasses of IgG which are all monomeric and they usually have a very high affinity for antigen. Unlike IgM, IgG is able to leave the blood stream and enter tissues.
IgG is also the only class of antibody to pass the placental barrier. Therefore IgG provides the only antibody protection for newborns until their own immune system is able to contribute to antibody production.
[edit] IgA
In the circulation IgA is found, in low levels, in the monomeric form (concentration is usually around 3.5 mg/ml) but IgA is most common and most active at mucosal surfaces where it appears as a dimeric protein. The two IgA are held together by a J chain.
[edit] IgD
This type of antibody is found on the surface of most B lymphocytes just like sIgM. So far, the function of this antibody is unknown but it has been suggested that it acts as an antigen receptor and that it is needed for B cell activation. A very small amount of IgD is secreted, and its functions as a secreted antibody are unclear.
[edit] IgE
Like IgA, this class of antibody is particularly effective at mucosal surfaces. It is also active in the blood and in the tissues. The serum concentration of this antibody is normally very low as most IgE is tightly bound to its receptors on mast cells and basophils. The production of IgE is controlled by cytokines and this class is responsible for Type I hypersentitivity reactions (allergic and anaphylactic). IgE is found to increase greatly in response to parasitic infection. It is also involved in inflammatory reponses through its role in mast cell degranulation.
[edit] Functions
Since antibodies exist freely in the bloodstream, they are said to be part of the humoral immune system. Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen, a virus hull protein fragment, for example. Antibodies contribute to immunity in three main ways: they can prevent pathogens from entering or damaging cells by binding to them; they can stimulate removal of a pathogen by macrophages and other cells by coating the pathogen; and they can trigger direct pathogen destruction by stimulating other immune responses such as the complement pathway.
[edit] Activation of complement
Antibodies that bind to surface antigens on, for example a bacterium, attract the first component of the complement cascade with their Fc region 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 certain complement molecules generated in the complement cascade. Secondly, some complement system components form a membrane attack complex to assist antibodies to kill the bacterium directly.
[edit] Activation of effector cells
To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody has at least two paratopes it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region.
Those cells which recognize coated pathogens have Fc receptors which, as the name suggests, interacts with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of the invading microbe. The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens.
[edit] Antigen-Antibody Interaction
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The antibodies on the surface of B cells and the soluble antibodies in the blood and lymphatics recognize antigens in the native form. This means that the antigens don't have to be digested or degraded in order for the antibodies to recognize them. For example, B cells can recognize some viral capsid proteins which may be released by an infected cell prior to viral assembly. Each epitope of an antigen binds to one of the Fab regions of antibodies. The interaction between the two proteins involves noncovalent bonding forces. The binding, therefore, is reversible and the strength of the interaction depends on how well the antigen and the antibody 'fit' together as well as if there is a second epitope for the other Fab to bind.
