Antibodies, or immunoglobulins (Ig), are glycoproteins produced by the immune system to aid recognition of invading microorganisms. They coat foreign but not self antigen, allowing the immune system to differentiate between these to mount appropriate responses. All immunoglobulins share the following basic properties:
There are 5 classes of human immunoglobulin molecules:
(Useful mnenomic: GAMED)
Each immunoglobulin class can by distinguished by a unique amino acid sequence in the Heavy chain Constant region (CH) which confers their class-specific structural and functional properties. This governs how they stimulate the innate system to remove antigen.
Immunoglobulins are the archetypal members of the Immunoglobulin Gene Superfamily: a large family of proteins that are related by sequence as a result of their common ancestry (paralogs). Some examples of this family are:
(1) Multiprotein complexes:
(2) Single proteins:
The members of this superfamily contain a conserved immunoglobulin domain of two beta sheets stabilised by a disulphide bond. This conserved domain, which stabilises proteins in the extracellular milieu, provides antibodies with long half-lives.
All antibodies share a basic molecular H2L2structure:
which are joined together by intermolecular disulphide bonds
The molecule itself is classically described as Y-shaped: a hinge region that fulfills the role of a 'flexible tether' links the Fc (no antigen-binding activity) and Fab (antigen-binding) regions. This flexibility allows independent movement of the two Fab fragments.
There are 5 different classes of H chains that can be found in humans (designated by lower-case Greek letters)
2. Light Chains are of 2 types:
Both types of light chains can be found in all 5 classes, but a single immunoglobulin molecule can only contain one type of a light chain (i.e. it is either K-K or L-L)
Both Heavy (H) and Light (L) chains have repeating substructures known as domains.
Sequence variability is not evently distributed in VL and VH domains. Instead, variability is confined to three hypervariable regions on each chain. These regions are equally spaced between the framework regions that show less variability. Upon protein folding, the hypervariable regions are brought together at the N-terminus to form an antigen-binding site (paratope) that interacts with the antigen.
For this reason, hypervariable regions are also sometimes called the complementarity-determining regions (CDRs) because they are complementary in shape to an antigenic epitope.
Diversity of immunoglobulin repertoire.
Variability is a term that is used to describe the generation of immunoglobulins of different specificities.This is essential to their functioning as a recognition molecule. The extent of variablity in paratope structure is such that antibodies exist which could recognise pathogens from other planets.
Variability is partly due to different combinations of H and L chain V regions. Furthermore, the unique DNA sequences of each V region are generated by expression of one of a number of possible genome encoded segments. This is known as V(D)J recombination, and results in a DNA sequence containig one of each of:
The variability is also then further enhanced by the presence of Recombination Signal Sequences (RSSs) and, finally, faciliated by somatic hypermutation in mature B cells.
Antibody-antigen interaction is based on reversible non-covalent forces that are weak unless antibody and antigen are in good proximity determined by complementary surfaces. Extremes of pH, high salt concentrations, detergents and high epitope concentrations can all disrupt the antibody-antigen interaction.
There are 4 types of molecular forces involved:
The contribution of each depends on the particular antibody and antigen involved (i.e. their amino acid composition). This determines the affinity (i.e. the strength) of antibody-antigen interaction.
Selected properties of human immunoglobulins.
(Arranged in accordance with their corresponding serum concentrations: high->low)
IgG is the workhorse of the humoral immune response, with different subclasses produced to induce different types of immune effector function.
* The Complement cascade is one of the most powerful effector functions of antibody. Antibody is able to trigger activation of a group of serum proteins with several immune activities including cell lysis (proteins C5-C9), opsonisation (C3b), chemotaxis (C5a), inflammatory mediation (C3a-C5a), and clearence of immune complexes (C3b)
** Haemolytic Disease of the Newborn (Erythroblastosis Fetalis) is a disease which is caused by the unique ability of maternal IgG to cross the placenta to protect the foetus against infection.
Erythroblastosis fetalis develops when a Rh-negative mother makes IgG antibodies when exposed to paternally inherited Rh-positive foetal erythrocytes during childbirth. During a subsequent pregnancy, anti-Rh IgG coats foetal erythrocytes which become destroyed in foetal liver by phagocytosis, resulting in haemolytic anaemia and toxicity due to excess bilirubin (manifested as jaundice).
The disease can be prevented by sensitising the mother through administering her a preparation of anti-Rh IgG shortly after giving birth - this will remove foetal erythrocytes before they evoke maternal immune response
IgA is involved in protection of environmental/mucosal surfaces of the body and it has several interesting adaptations in line with this role.
Heavy chain: ALPHA
* J-chain is coded by the gene on a separated chromosome; reguired for proper polymerisation
** Secretory Piece is an additional protein that protects the molecule against proteolysis; is NOT made by a Ig-producing cell
IgM is a large, low affinity antibody which is produced by B cells as a first line of defence before class switching and somatic hypermutation have kicked in.
1st immunoglobulin to appear: IgM=iMMediate
IgD is present on naive B cell surfaces, allowing them to recognise antigen at the induction period of adaptive immunity.
IgE has adapted to deal with large, eukaryotic parasites. It is involved in allergy as an inappropriate anti-parasitic response.
Clinical significance: profound changes in globulin electrophoretic pattern almost always assumed to be due to changes in quantities of immunoglobulins - as they are most likely to affect the total globulin values.
(1) Wood, P. (2001). Understanding Immunology. Ch. 3. Specific Immune recognition: the antibody molecule. Pearson Education Limited. Essex, UK.
(2) Janeway, C.A., Travers, P., Walport, M. and Shlomchik, M.J. (2005). Immunobiology. The immune system in health and disease. Ch. 4 The generation of lymphocyte antigen receptors. Garland Science Publishing. New York. U.S.A.
(3) Peakman, M. and Vergani, D. (2010). Basic and Clinical Immunology. Churchill Livingstone. Edinburgh. UK.
(1) Schroeder, H. and Cavacini, L. (2010). Structure and function of immunoglobulins. Journal of allergy and clinical immunology. 125 (2): 41-52.
(2) Butler, J.E., Zhao, Y., Sinkora, M., Wertz, N. and Kasckovics, I. (2009). Immunoglobulins, antibody repertoire and B cell development. Developmental and Comparative Immunology. 33(3): 321-333.
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