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The structure and function of IgG.


By: Safinaz Kurreeman

Molecular and Medical Microbiology Research Group


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 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.


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