Antibody

An antibody, or immunoglobulin, is a large protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that cause disease. Each individual antibody recognizes one or more specific antigens, and antigens of virtually any size and chemical composition can be recognized. Each of the branching chains comprising the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" the antigen for attack by cells of the immune system, or can neutralize it directly.
Antibodies may be borne on the surface of an immune cell, as in a B cell receptor, or they may exist freely by being secreted into the extracellular space. The term antibody generally refers to the free form, while the term immunoglobulin can refer to either forms. Since they are, broadly speaking, the same protein, the terms are often treated as synonymous.
To allow the immune system to recognize millions of different antigens, the antigen-binding paratopes at each tip of the antibody come in an equally wide variety. The rest of an antibody's structure is much less variable; in humans, antibodies occur in five classes or isotypes: IgA, IgD, IgE, IgG, and IgM. Human IgG and IgA antibodies are also divided into discrete subclasses. The class refers to the functions triggered by the antibody, in addition to some other structural features. Antibodies from different classes also differ in where they are released in the body and at what stage of an immune response. Between species, while classes and subclasses of antibodies may be shared, their function and distribution throughout the body may be different, which complicates the use of animal models in studying antibodies. For example, mouse IgG1 is closer to human IgG2 than to human IgG1 in terms of its function.
The term humoral immunity is often treated as synonymous with the antibody response, describing the function of the immune system that exists in the body's humors in the form of soluble proteins, as distinct from cell-mediated immunity, which generally describes the responses of T cells. In general, antibodies are considered part of the adaptive immune system, though this classification can become complicated. For example, natural IgM, which are made by B-1 cells that have properties more similar to innate immune cells than adaptive, refers to IgM antibodies made independently of an immune response that demonstrate polyreactivity—i.e. they recognize multiple distinct antigens. These can work with the complement system in the earliest phases of an immune response to help facilitate clearance of the offending antigen and delivery of the resulting immune complexes to the lymph nodes or spleen for initiation of an immune response. Hence in this capacity, the functions of antibodies are more akin to that of innate immunity than adaptive. Nonetheless, in general, antibodies are regarded as part of the adaptive immune system because they demonstrate exceptional specificity, are produced through genetic rearrangements, and are a manifestation of immunological memory.

Structure

Antibodies are heavy proteins of about 10 nm in size,
arranged in three globular regions that roughly form a Y shape.
In humans and most other mammals, an antibody unit consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds.
Each chain is a series of domains: somewhat similar sequences of about 110 amino acids each.
These domains are usually represented in simplified schematics as rectangles.
Light chains consist of one variable domain V_L and one constant domain C_L, while heavy chains contain one variable domain V_H and three to four constant domains C_H1, C_H2,...
Structurally an antibody is also partitioned into two antigen-binding fragments, containing one V_L, V_H, C_L, and C_H1 domain each, as well as the crystallisable fragment, forming the trunk of the Y shape.
In between them is a hinge region of the heavy chains, whose flexibility allows antibodies to bind to pairs of epitopes at various distances, to form complexes, and to bind effector molecules more easily.
In an electrophoresis test of blood proteins, antibodies mostly migrate to the last, gamma globulin fraction.
Conversely, most gamma-globulins are antibodies, which is why the two terms were historically used as synonyms, as were the symbols Ig and γ.
This variant terminology fell out of use due to the correspondence being inexact and due to confusion with γ heavy chains which characterize the IgG class of antibodies.

Antigen-binding site

The variable domains can also be referred to as the F_V region. It is the subregion of Fab that binds to an antigen.
More specifically, each variable domain contains three hypervariable regions – the amino acids seen there vary the most from antibody to antibody.
When the protein folds, these regions give rise to three loops of β-strands, localized near one another on the surface of the antibody.
These loops are referred to as the complementarity-determining regions, since their shape complements that of an antigen.
Three CDRs from each of the heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen.
Typically though, only a few residues contribute to most of the binding energy.
The existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen, as well as to form antibody complexes and larger antigen-antibody complexes.
The structures of CDRs have been clustered and classified by Chothia et al.
and more recently by North et al.
and Nikoloudis et al. However, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities.
In the framework of the immune network theory, CDRs are also called idiotypes. According to immune network theory, the adaptive immune system is regulated by interactions between idiotypes.

Fc region

The Fc region is composed of constant domains from the heavy chains. Its role is in modulating immune cell activity: it is where effector molecules bind to, triggering various effects after the antibody Fab region binds to an antigen. Effector cells bind via their Fc receptors to the Fc region of an antibody, while the complement system is activated by binding the C1q protein complex. IgG or IgM can bind to C1q, but IgA cannot, therefore IgA does not activate the classical complement pathway.
Another role of the Fc region is to selectively distribute different antibody classes across the body. In particular, the neonatal Fc receptor binds to the Fc region of IgG antibodies to transport it across the placenta, from the mother to the fetus. In addition to this, binding to FcRn endows IgG with an exceptionally long half-life relative to other plasma proteins of 3-4 weeks. IgG3 in most cases has mutations at the FcRn binding site which lower affinity for FcRn, which are thought to have evolved to limit the highly inflammatory effects of this subclass.
Antibodies are glycoproteins, that is, they have carbohydrates added to conserved amino acid residues. These conserved glycosylation sites occur in the Fc region and influence interactions with effector molecules.

Protein structure

The N-terminus of each chain is situated at the tip.
Each immunoglobulin domain has a similar structure, characteristic of all the members of the immunoglobulin superfamily:
it is composed of between 7 and 9 β-strands, forming two beta sheets in a Greek key motif.
The sheets create a "sandwich" shape, the immunoglobulin fold, held together by a disulfide bond.

Antibody complexes

Secreted antibodies can occur as a single Y-shaped unit, a monomer.
However, some antibody classes also form dimers with two Ig units, tetramers with four Ig units, or pentamers with five Ig units. IgG can also form hexamers, though no J chain is required. IgA tetramers and pentamers have also been reported.
Antibodies also form complexes by binding to antigen: this is called an antigen-antibody complex or immune complex.
Small antigens can cross-link two antibodies, also leading to the formation of antibody dimers, trimers, tetramers, etc.
Multivalent antigens can form larger complexes with antibodies.
An extreme example is the clumping, or agglutination, of red blood cells with antibodies in blood typing to determine blood groups: the large clumps become insoluble, leading to visually apparent precipitation.

B cell receptors

The membrane-bound form of an antibody may be called a surface immunoglobulin or a membrane immunoglobulin. It is part of the B cell receptor, which allows a B cell to detect when a specific antigen is present in the body and triggers B cell activation. The BCR is composed of surface-bound IgD or IgM antibodies and associated Ig-α and Ig-β heterodimers, which are capable of signal transduction. A typical human B cell will have 50,000 to 100,000 antibodies bound to its surface. Upon antigen binding, they cluster in large patches, which can exceed 1 micrometer in diameter, on lipid rafts that isolate the BCRs from most other cell signaling receptors.
These patches may improve the efficiency of the cellular immune response. In humans, the cell surface is bare around the B cell receptors for several hundred nanometers, which further isolates the BCRs from competing influences.