Antibody And Its Mode Of Action

Introduction
The first use of the term "antibody" occurred in a text by Paul Ehrlich.

Antibodies are heavy (~150 kDa) globular plasma proteins. The size of an antibody molecule
is about 10 nm. They have sugar chains (glycans) added to conserved amino acid residues.In
other words, antibodies are glycoproteins. The attached glycans are critically important to
the structure and function of the antibody

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-

shaped protein produced mainly by plasma cells that is used by the immune
system to neutralize pathogens such as pathogenic bacteria and viruses. The
antibody recognizes a unique molecule of the pathogen, called an antigen, via
the Fab's variable region. Each tip of the "Y" of an antibody contains
a paratope (analogous to a lock) that is specific for one particular epitope (similarly,
analogous to a key) on an antigen, allowing these two structures to bind together
with precision. Using this binding mechanism, an antibody can tag a microbe or an
infected cell for attack by other parts of the immune system, or can neutralize its
target directly (for example, by inhibiting a part of a microbe that is essential for its
invasion and survival). Depending on the antigen, the binding may impede the
biological process causing the disease or may activate macrophages to destroy the
foreign substance. The ability of an antibody to communicate with the other
components of the immune system is mediated via its Fc region (located at the base
of the "Y"), which contains a conserved glycosylation site involved in these
interactions. The production of antibodies is the main function of the humoral
immune system.

Antibodies are secreted by B cells of the adaptive immune system, mostly by

differentiated B cells called plasma cells. Antibodies can occur in two physical forms,
a soluble form that is secreted from the cell to be free in the blood plasma, and
a membrane-bound form that is attached to the surface of a B cell and is referred to
as the B-cell receptor (BCR). The BCR is found only on the surface of B cells and
facilitates the activation of these cells and their subsequent differentiation into either
antibody factories called plasma cells or memory B cells that will survive in the body
and remember that same antigen so the B cells can respond faster upon future
exposure. In most cases, interaction of the B cell with a T helper cell is necessary to
produce full activation of the B cell and, therefore, antibody generation following
antigen binding. Soluble antibodies are released into the blood and tissue fluids, as
well as many secretions to continue to survey for invading microorganisms.
Structure of Antibody
Antibodies are glycoproteins belonging to the immunoglobulin superfamily. They
constitute most of the gamma globulin fraction of the blood proteins. They are
typically made of basic structural units—each with two large heavy chains and two
small light chains. There are several different types of antibody heavy chains that
define the five different types of crystallisable fragments (Fc) that may be attached to
the antigen-binding fragments. The five different types of Fc regions allow
antibodies to be grouped into five isotypes. Each Fc region of a particular antibody
isotype is able to bind to its specific Fc Receptor (except for IgD, which is essentially
the BCR), thus allowing the antigen-antibody complex to mediate different roles
depending on which FcR it binds. The ability of an antibody to bind to its
corresponding FcR is further modulated by the structure of the glycan(s) present at
conserved sites within its Fc region.The ability of antibodies to bind to FcRs helps to
direct the appropriate immune response for each different type of foreign object they
encounter. For example, IgE is responsible for an allergicresponse consisting of mast
cell degranulation and histamine release. IgE's Fab paratope binds to
allergic antigen, for example house dust mite particles, while its Fc region binds to
Fc receptor ε. The allergen-IgE-FcRε interaction mediates allergic signal transduction
to induce conditions such as asthma.

Though the general structure of all antibodies is very similar, a small region at the
tip of the protein is extremely variable, allowing millions of antibodies with slightly
different tip structures, or antigen-binding sites, to exist. This region is known as
the hypervariable region. Each of these variants can bind to a different antigen.
Antibody genes also re-organize in a process called class switching that changes the
one type of heavy chain Fc fragment to another, creating a different isotype of the
antibody that retains the antigen-specific variable region. This allows a single
antibody to be used by different types of Fc receptors, expressed on different parts of
the immune system.
 1. Fab region
2. Fc region
3. Heavy chain (blue) with one variable (VH) domain followed by a constant
domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains
4. Light chain (green) with one variable (VL) and one constant (CL) domain
5. Antigen binding site (paratope)
6. Hinge regions

Immunoglobulin domains
The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two
identical heavy chains and two identical light chains connected by disulfide bonds. Each
chain is composed of structural domains called immunoglobulin domains. These domains
contain about 70–110 amino acids and are classified into different categories (for example,
variable or IgV, and constant or IgC) according to their size and function. They have a
characteristic immunoglobulin fold in which two beta sheets create a "sandwich" shape, held
together by interactions between conserved cysteines and other charged amino acids.

Heavy chain
There are five types of mammalian Ig heavy chain denoted by the Greek letters: α, δ, ε, γ,
and μ. The type of heavy chain present defines the class of antibody; these chains are found
in IgA, IgD, IgE, IgG, and IgM antibodies, respectively. Distinct heavy chains differ in size
and composition; α and γ contain approximately 450 amino acids, whereas μ and ε have
approximately 550 amino acids.

Each heavy chain has two regions, the constant region and the variable region. The constant
region is identical in all antibodies of the same isotype, but differs in antibodies of different
isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem (in a
line) Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a
constant region composed of four immunoglobulin domains. The variable region of the
heavy chain differs in antibodies produced by different B cells, but is the same for all
antibodies produced by a single B cell or B cell clone. The variable region of each heavy
chain is approximately 110 amino acids long and is composed of a single Ig domain.

Light chain
In mammals there are two types of immunoglobulin light chain, which are called lambda (λ)
and kappa (κ). A light chain has two successive domains: one constant domain and one
variable domain. The approximate length of a light chain is 211 to 217 amino acids. Each
antibody contains two light chains that are always identical; only one type of light chain, κ
or λ, is present per antibody in mammals. Other types of light chains, such as the iota (ι)
chain, are found in other vertebrates like sharks (Chondrichthyes) and bony fishes
(Teleostei).

Antibody–Antigen interactions
The antibody's paratope interacts with the antigen's epitope. An antigen usually
contains different epitopes along its surface arranged discontinuously, and
dominant epitopes on a given antigen are called determinants.

Antibody and antigen interact by spatial complementarity (lock and key). The
molecular forces involved in the Fab-epitope interaction are weak and non-specific –
for example electrostatic forces, hydrogen bonds, hydrophobic interactions, and van
der Waals forces. This means binding between antibody and antigen is reversible,
and the antibody's affinity towards an antigen is relative rather than absolute.
Relatively weak binding also means it is possible for an antibody to cross-react with
different antigens of different relative affinities.

Often, once an antibody and antigen bind, they become an immune complex, which
functions as a unitary object and can act as an antigen in its own right, being
countered by other antibodies. Similarly, haptens are small molecules that provoke
no immune response by themselves, but once they bind to proteins, the resulting
complex or hapten-carrier adduct is antigenic.

Antibody Classes (types)

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.
Mode of Action
Differentiated plasma cells are crucial players in the humoral immunity response. The
antibodies they secrete are particularly significant against extracellular pathogens and
toxins. Once secreted, antibodies circulate freely and act independently of plasma cells.
Sometimes, antibodies can be transferred from one individual to another. For instance, a
person who has recently produced a successful immune response against a particular
disease agent can donate blood to a non-immune recipient, confering temporary immunity
through antibodies in the donor’s blood serum. This phenomenon, called passive immunity,
also occurs naturally during breastfeeding, which makes breastfed infants highly resistant to
infections during the first few months of life.

Antibodies coat extracellular pathogens and neutralize them by blocking key sites on the
pathogen that enhance their infectivity, such as receptors that “dock” pathogens on host
cells. Antibody neutralization can prevent pathogens from entering and infecting host cells,
as opposed to the cytotoxic T-cell-mediated approach of killing cells that are already infected
to prevent progression of an established infection. The neutralized antibody-coated
pathogens can then be filtered by the spleen and eliminated in urine or feces.

The main categories of antibody action include the following:

1) Antibodies (A) and pathogens (B) free roam in the blood. 2) The antibodies bind to pathogens, and can do so in different

formations such as: opsonization (2a), neutralisation (2b), and agglutination (2c). 3) A phagocyte (C) approaches the pathogen,

and the Fc region (D) of the antibody binds to one of the Fc receptors (E) of the phagocyte. 4) Phagocytosis occurs as the

pathogen is ingested.

Neutralisation, in which neutralizing antibodies block parts of the surface of a

bacterial cell or virion to render its attack ineffective
Agglutination, in which antibodies "glue together" foreign cells into clumps that are
attractive targets for phagocytosis

Precipitation, in which antibodies "glue together" serum-soluble antigens, forcing

them to precipitate out of solution in clumps that are attractive targets
for phagocytosis
Complement activation (fixation), in which antibodies that are latched onto a
foreign cell encourage complement to attack it with a membrane attack complex,
which leads to the following:

Lysis of the foreign cell

Encouragement of inflammation by chemotactically attracting inflammatory cells

Mechanisms of antibody action: Antibodies may inhibit infection by (a) preventing the antigen from
binding to its target, (b) tagging a pathogen for destruction by macrophages or neutrophils, or (c)
activating the complement cascade.
Antibodies also mark pathogens for destruction by phagocytic cells, such as macrophages or
neutrophils, because they are highly attracted to macromolecules complexed with
antibodies. Phagocytic enhancement by antibodies is called opsonization. In another
process, complement fixation, IgM and IgG in serum bind to antigens, providing docking
sites onto which sequential complement proteins can bind. The combination of antibodies
and complement enhances opsonization even further, promoting rapid clearing of
pathogens.
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