The structure and function of IgG.
By: Safinaz Kurreeman
Researcher
Molecular and Medical Microbiology Research Group
UOW
Email: bioanalyst@hotmail.com
Immunoglobulins
circulate in the plasma and lymph, are present in mucosal and lymphoid tissues
and can be found on the surfaces of B lymphocytes, where they function as
receptors for antigen. Some classes of
immunoglobulins can enter extravascular spaces and cross the placenta. They are secreted from B lymphocytes in
response to foreign antigenic stimulation and comprise the principal component
of the adaptive humoral immune response.
They are found in all 'jawed' vertebrates, including phylogenetically
ancient species such as sharks, and therefore represent an early evolutionary
solution to the problem of recognizing and eliminating extracellular microbial
pathogens and their products.
The basic
structure of all immunoglobulin (Ig) molecules is a four-chain unit consisting
of two identical heavy (H) polypeptide chains and two identical light (L)
polypeptide chains linked b y disulfide bonds.
The different polypeptide chains are composed of compact globular
domains, the light chain has two domains and the heavy chain four or five. Each domain is made up of about 110 amino
acid residues that share the same three-dimensional structure, a compressed
antiparallel ß barrel, referred to as the immunoglobulin fold. The amino acid sequence of the N-terminal
variable (V) domain of each polypeptide chain varies substancially, while the
sequence of the other domains, the constant (C) domains, is more conserved
within a given class or subclass.
The whole
Ig molecule, according to Padlan (1994), has a distorted Y shape with two
identical arms (Fab parts) joined to the stem (Fc part) by a flexible
hinge. The Fab fragments contain the
complete light chains paired with the VH and CH1 domains
of the heavy chains and are responsible for the binding of antigen. The antigen-binding sites, located at the
tips of the Fabs, are formed by six hypervariable polypeptide loops, the
complementarity determining regions (CDRs), three from VL and three
from VH. The Fc fragment
contains paired CH2, CH3 and CH4 domains from
both the heavy chains and is responsible for mediating the effector functions,
such as complement activation and interaction with Fc receptors, aiming at the
elimination of the antigen-antibody complexes.
There are
two types of light chains, Kappa (k) and lambda ( l), which are common to the different Ig classes, but
in a given immunoglobulin molecule both light chains are of the same type.
However, no functional differences have been found between antibodies with k and those with l light chains.Depending on the structural differences
in the constant (C) regions, immunoglobulins are divided into different classes. In mammalian species five classes namely
IgA, IgD, IgE, IgG and IgM have been detected.
The IgG class is evenly distributed between the intra- and extravascular
pools and is the major immunoglobulin class in normal serum, accounting for
70-75% of the total immunoglobulin population . IgG is divided into four subclasses (IgG1, IgG2, IgG3 and IgG4),
that occur in the proportions of 65, 23, 8 and 4%. IgG is a monomeric protein with a sedimentation coefficient of 7S
and a molecular weight of about 150 KDa.
IgG3 is slightly larger than the other subclasses due to a longer
hinge. IgG is the least glycosylated Ig
class (2-3%) and the carbohydrate content is the same for all the four
subclasses.
From a
structural point of view, IgG is the most well characterized Ig class and it is
used as a model for the basic four-chain unit described previously . The IgG subclasses display a 95% sequence
homology, with the major differences located in the hinge region. IgG3 has a very long extended hinge with
several more disulfide bonds compared to other IgG isotopes. Little is known about the three-dimensional
structure of the hinge due to its flexible properties. It allows the Fab arms to move relative to
one another, giving the antibody a variable reach and increased affinity for
antigen binding. This enables IgG to
attach to two antigens even though they are close together or far apart. The hinge also allows the Fc to move
relative to the Fab arms and this may be important in triggering the effector
molecules. However, this model is still
only a prediction.
IgG is
found in the blood and extracellular fluids and can neutralize toxins, viruses
and bacteria. The IgG subclasses
differ in their functional properties namely, IgG1 dominates in an immune
response against tetanus toxoid (toxin which has been sufficiently denatured to
destroy its toxic properties while still retaining its antigenic properties),
IgG2 against polysaccharides, IgG3 against rhesus-D and IgG4 against factor
VIII. There are three major classes of
Fc receptors (FcgRI, FcgRII and FcgRIII). The ability of the IgG to interact with these
receptors varies, IgG1 and IgG3 being the most efficient. The effector responses mediated via IgG's
interaction with these receptors include phagocytosis, endocytosis,
antibody-dependent-cell-mediated cytotoxicity (ADCC), the release of mediators
of inflammation, and the regulation of N cell activation and antibody
production.
The
primary function of the V site in IgG is to bind antigen by an energetically
favourable process. This allows the
antibody to perform protective functions.
Bacteria exert their effects by elaboration of exotoxins that interfere
directly with the cell and organ physiology.
Toxins initiate their destructive effects by binding to specific
receptors on host cells. Since IgG
antibodies can permeate extravascular spaces where many bacterial and viral
infections occur, they are able to block the interaction between the toxin and
the cells, therefore preventing pathogenic effects.
IgGs also
occur as cell-bound molecules on mature B lymphocytes and cooperate in
initiating immune responses by functioning as receptors for antigens
(Lanzavecchia, 1985). This occurs by complement activation. A complement is a term applied to a group of
plasma proteins that can interact with antibodies bound to the surface of
microbes. The components of the
complement system bind to the Fc portion of IgG antibodies and this initiates a
series of enzymatic reactions that ultimately produce three categories of
complement products namely (1) peptides that mediate inflammation and that
functions as signals to recruit phagocytes; (2) proteins that bind covalently
to the surface of the microbe and (3) a group of proteins that assemble into a
complex known as the membrane attack complex.
The
deposition of complement components on the bacterial surface promotes the
removal of the organisms by means of phagocytosis. Cells such as neutrophils and macrophages possess receptors (FcgR) for the complement components and receptors
specific to the Fc portion of IgG antibodies.
Phagocytosis is initiated by recognition of both the bound complement
component and the antibody Fc.
FcgR operates a protective mechanism via ADCC. ADCC involves the killing of antibody-coated
target cells by a class of lymphocytes known as natural killer (NK) cells. When host cells infected by pathogens
express antigens on their surface, the FcgRIII receptor on NK cells engage the cell-bound IgG
antibody resulting in cross-linking of the FcgRIII receptors and activation of the NK cells. These NK cells induce the release of
granules that contain cytotoxic substances such as perforin and granzymes. Exposure to these substances leads to lysis
and death of targeted cells. ADCC could
contribute to controlling viral infection by killing infected host cells. It has been
demonstrated in individuals infected with human immunodeficiency virus
(HIV). HIV-infected cells express viral
envelope proteins on their surface, and these cells can be killed by the
combined action of IgG antienvelope protein antibodies and effector cells (NK
cells or perhaps monocytes). Although
ADCC could serve as a mechanism to control viral infections or possibly
eliminate malignant cells, its role in protective immunity remains to be firmly
established.
Transplacental
transport of maternal IgG to the developing fetus is extremely important in the
protection of the newborn from infection.
According to Saji et al (1999), several known receptors for the Fc part
of IgG play a key role in the selective and active transfer of IgG across the
placental barrier and also demonstrate heterogeneous patterns in the
placenta. However, the exact mechanisms
of involvement of these IgG receptors are not fully understood.
IgG
antibodies have a wide spectrum of protective functions. The structure of the antibody is well
integrated with its dual function in antigen recognition and in providing the
ability to interact with complement and cells in removing infectious organisms
and their products. However in certain
cases it can also evolve against the host and produce autoimmunity and
immunopathological conditions. Immunosuppressive drugs are currently being used
against such hypersensitivity reactions.
The
functions associated to the main components of the IgG antibody have been
unveiled. However, certain aspects of
the antibody have to be researched to provide a profound understanding of its
mechanism of action.