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Original Author(s): Emilia O'Connor
Last updated: 29th November 2020
Revisions: 13

Original Author(s): Emilia O'Connor
Last updated: 29th November 2020
Revisions: 13

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Antibodies, or immunoglobulins, are Y-shaped glycoproteins produced by differentiated B-cells called plasma cells. They are present in bodily fluids, secretions and on the surface of specialised cells. Antibodies recognise and bind unique epitopes, which are molecular structures on the surface of their specific antigens.

In this article, we will consider antibody structure, function, classes and some clinical relevance.

Structure

Antibody molecules consist of two identical heavy chains and two identical light chains, which give the antibody two antigen-binding sites. The two heavy chains are connected by disulphide bonds, which also bind the heavy chains to the light chains. The heavy and light chains both consist of a series of amino-acid sequences, each corresponding to a protein domain. Each light chain has two domains (one variable and one constant), and each heavy chain has four domains (one variable and three constant).

There are five heavy chain types: μ (Mu), γ (Gamma), α (Alpha), ε (Epsilon) and δ (Delta), which classify IgM, IgG, IgA, IgE and IgD respectively.

There are two light chain types: κ (kappa) and λ (lambda). Each antibody can have either two κ or two λ chains but not one of each. The ratio of κ and λ is 2:1, but there are no functional differences between the types.

Each antibody contains two variable regions and one constant region.

The variable or Fab regions (fragment antigen binding) involve the variable domains of the light and heavy chains. Fab regions give the antibody its antigen specificity, and therefore, differ between antibodies.

The constant or Fc region (fragment crystallisable), is made up of the constant domains. It determines antibody class and is the same for all antibodies in the same class.

Antibodies; Structure; Heavy chains; Light chains; variable regions; constant regions; antigen-binding sites.

Fig 1 – Structure of antibodies.

IgA and IgG antibodies also have hinge regions, which are flexible amino-acid chains in the central part of the heavy chains.

Classification

Antibodies are classified according to heavy chain type, which is encoded by a gene on chromosome 14. The different classes are IgG, IgA, IgM, IgD and IgE; in descending order of abundance in serum.

IgG

IgG is the most abundant antibody class. It is expressed on the surface of mature B-cells and in serum. There are four subclasses: IgG1, IgG2, IgG3 and IgG4; in order of serum concentration. IgG is the only antibody to cross the placenta and consequently, it transfers passive immunity from mother to foetus. Newborns, therefore, have high IgG concentrations in the first 3-6 months of life.

IgA

IgA is the most prevalent antibody in secretions, such as saliva and mucous. There are two subclasses, IgA1 and IgA2. IgA forms a dimer, where a joining chain connects 2 Y-shaped molecules, giving it four antigen-binding sites in total. IgA antibodies are resistant to enzymatic digestion and act principally as neutralising antibodies. They are secreted in breastmilk and so can protect a breastfed newborn from infections. They also protect mucosal surfaces from pathogenic invasion; examples include nose, lungs, and intestines

IgM

IgM antibodies are expressed on the surface of B-cells as monomers but secreted as pentameters. A pentameter has five antibodies connected by a joining chain, with ten antigen-binding sites in total. It is the first immunoglobulin produced during foetal development and the first produced by B-cells against a new infection. IgM has high avidity, meaning the antibody-antigen complex is strong, but low affinity, so the strength of a single epitope-antibody interaction is weak. Along with IgD, IgM is expressed by all naïve B-cells.

Figure 2 – IgM pentamer structure

IgD

IgD is present on the surface of B-cells. It has a role in B-cell and antibody production. Along with IgM, IgD is expressed by all naïve B-cells.

IgE

IgE is found mainly on mast cells but is present at low levels in the blood and extracellular fluid. IgE is associated with allergy, particularly type I hypersensitivity reactions such as atopic disease (e.g. asthma and dermatitis) and anaphylaxis. It triggers histamine release from mast cells and basophils. It is also involved in the body’s response to parasitic infections.

Function

The Fc region binds different immune cell receptors (e.g. on phagocytes) and mediates various effector functions.

Opsonisation

Antibodies (mainly IgG1 and IgG3) can act as opsonins by binding to the pathogen, which allows better recognition by phagocytes. Phagocytes then bind to the antibodies via their Fc receptors and initiate phagocytosis.

Opsonisation; Antibodies; Phagocytosis.

Fig 3- opsonisation by multiple antibodies.

Neutralisation

Antibodies can prevent pathogens accessing cells by blocking different parts of the bacterial or viral cell surface. Consequently, this neutralises certain viruses and bacterial toxins. Neutralising antibodies must have high affinity to be effective; IgG and IgA antibodies have the greatest effect.

Complement activation

The classical complement pathway can be activated by IgM or IgG antibodies when they bind microbial surfaces. This releases C3b, which acts as an opsonin, and other complement components which form membrane-attack complexes. These can punch holes in the pathogen plasma membrane and cause cell lysis.

Immune complexes

The binding of multiple antigens and antibodies together can form immune complexes. Complex formation limits the antigens’ diffusing ability. Ultimately, complexes will be targeted for phagocytosis.

Antibody-dependent cell-mediated cytotoxicity

Antibodies bind and opsonise target cells. Natural killer cells then recognise the Fc portion of the antibody and release cytotoxic granules (perforin and granzymes) into the target cell which trigger apoptosis, and interferon, which attracts phagocytes.

Clinical Relevance

Autoantibodies

Autoantibodies are antibodies that react with the body’s antigens when the immune system cannot distinguish between self and non-self. Autoantibodies are found in healthy people. However, they can lead to autoimmune disease in some individuals. Below are common examples of autoimmune disease.

Autoantibody Antibody target Disease
Rheumatoid factor (RF) Fc portion of IgG Rheumatoid arthritis
Anti-thyrotropin receptor antibodies (TRAbs) TSH receptor of thyroid Graves’ disease
Anti-tissue transglutaminase antibodies (anti-tTG) Tissue transglutaminase enzyme Coeliac disease


Monoclonal Antibodies

Monoclonal antibodies are man-made molecules designed to act as antibodies. In cancer treatment, monoclonal antibodies can bind to cancer-specific antigens and therefore, induce a specific immune response against cancer cells. An example of this, is trastuzumab (aka Herceptin), which is used to treat HER2 receptor-positive breast cancer. Monoclonal antibodies can also be used to treat autoimmune diseases.