Immunoglobulins (Antibodies) Structure and Functions

Immunoglobulins (Antibodies)

Antibodies, the antigen-binding glycoproteins are synthesized exclusively by B cells and in trillions of forms, each with a different amino acid sequence and a different antigen binding site. Collectively called immunoglobulins (Ig). they are among the most abundant protein components in the blood, constituting about 20% of the total protein component the blood plasma. Antibodies (Ab) are present on the B-cell membrane and also are secreted by plasma cell.

Structure of antibody molecule

  • The simplest antibodies are Y-shaped molecules with two identical antigen-binding sites, one at the tip of each arm of the Y. Because of their two antigen-binding sites, they are described as bivalent.
  • Antibody has a common structure of 4 polypeptide chains. It is a heterodimer and consists of two identical light (L) chains (each containing about 220 amino acids residues, about 25000 MW) and two identical heavy (H) chains (each usually containing about 440 amino acids residues, about 50,000 MW). Each light chain is bound to heavy chain by disulfide bridges and other non-covalent linkages. Thus, antibody is a dimer of H—L chain.


Immunoglobulins (Antibodies)

  • All species studied have the two major classes of light chains: κ and λ. Any one individual of a species produces both types of light chain. However, in any one immunoglobulin molecule, the light chains are always either both κ or both λ, never one of each.

  • While there are two types of light chains, the immunoglobulins of virtually all species have been shown to consist of five different types of heavy chains- α, γ, δ, ε and μ. These five different types of heavy chains are called isotypes.
  • The heavy-chains of a given antibody molecule determine the class of that antibody: IgM (μ), IgG (γ), IgA (α), IgD (δ) or IgE (ε). Each class can have either κ or λ light chains. Any individual of a species makes all heavy chains, but in any one antibody molecule, both heavy chains are identical. Thus an antibody molecule of the IgG class could have the structure κ2γ2 with two identical κ light chains and two identical γ heavy chains. Alternatively, it could have the structure λ2γ2 with two identical λ light chains and two identical γ heavy chains.
  • Minor differences in the amino-acid sequences of the α and the γ heavy chains led to further classification of the heavy chains into subclasses. In humans, there are two subclasses of α heavy chains (α1 and α2) and four subclasses of γ heavy chains (γ1, γ2, γ3 and γ4).
  • Both light and heavy chains have a variable sequence at their N-terminal ends but a constant sequence at their C-terminal ends. Light chains have a constant region (CL) about 110 amino acids long and a variable region (VL) of the same size. The variable region (VH) of the heavy chains (at their N-terminus) is also about 110 amino acids long, but the heavy-chain constant region (CH) is about three to four times longer (330 or 440 amino acids), depending on the class. It is the N-terminal ends of the light and heavy chains that come together to form the antigen-binding site.
  • The diversity in the variable regions of both light and heavy chains is for the most part restricted to three small hypervariable regions (each ~10 amino acid residues long) in each chain called complementarity determining regions (CDR); the remaining parts of the variable region, known as framework regions, are relatively constant. Proceeding from either the VL or VH amino terminus, these regions are called CDR1, CDR2 and CDR3. The CDR3 is the most variable of the CDRs.

Classes of Immunoglobulin

There are five classes of immunoglobulins, according to their properties, They are:

  • Immunoglobulin G (IgG).
  • Immunoglobulin A (IgA).
  • Immunoglobulin M (IgM).
  • Immunoglobulin D (IgD).
  • Immunoglobulin E (IgE).

Immunoglobulins (Antibodies)

Immunoglobulin G (IgG)

Immunoglobulins (Antibodies)

  • Immunoglobulins of the IgG class have a MW of 150 kDa and are found both in vascular and extravascular spaces as well as in secretions.

  • IgG is the most abundant immunoglobulin in the blood.
  • It provides the bulk of immunity to most bloodborne infectious agents and is the only antibody class to cross the placenta to provide passive humoral immunity to the developing fetus and thus to the infant on its birth.
  • IgG has two H-chains (referred to as γ chains) with either two κ or two λ L-chains.
  • There are four subclasses of IgG isotypes in man (IgG1, IgG2, IgG3 and IgG4), each one is distinguished by a minor variation in the amino acid sequences in the C-region and by the numbers and location of disulfide bridges.
  • The four subclasses are distributed in human serum, IgG1 (65%), IgG2 (23%), IgG3 (8%) and IgG4 (4%).
  • The subtle amino acid differences between subclasses of IgG affect the biological activity of the molecule:-
    • IgG1, IgG3, and IgG4 readily cross the placenta and play an important role in protecting the developing fetus.
    • IgG3 is the most effective complement activator, followed by IgG1; IgG2 is less efficient, and IgG4 is not able to activate complement at all.
    • IgG1 and IgG3 bind with high affinity to Fc receptors on phagocytic cells and thus mediate opsonization. IgG4 has an intermediate affinity for Fc receptors, and IgG2 has an extremely low affinity.

Immunoglobulin A (IgA)

Immunoglobulins (Antibodies)
Fig:- IgA

  • Immunoglobulin A is the second most abundant class of immunoglobulin constitute about 10% to 13% of all serum immunoglobulins.
  • The normal serum level is 0.6 to 4.2 mg per mL. It has a half-life of 6 to 8 days. IgA is found in two forms in the body—in serum, where it occurs principally as monomer (160 kDa, 7S) and on secretory surfaces, where it exists as a dimeric molecule (385 kDa, 11S).
  • The dimeric form is known as secretory IgA (sIgA) and is found in association of J chain and with secretory component; the latter is involved in the transport of IgA to the secretory surfaces.
  • Secretory component is non-covalently associated with the IgA molecules in the sIgA complex. sIgA is the main Ig in the secretions such as milk, saliva and tears and in the secretions of respiratory, intestinal and genital tracts. It protects mucous membranes from attack by bacteria and viruses.
  • There are two subclasses of IgA; IgA1 and IgA2 distinguished by their distribution and arrangement of disulfide bonds. sIgA is the predominant form found in serum, where as IgA1 and IgA2 isotypes are present in roughly equal amounts in IgA.
  • Immunoglobulin A is the component of the secondary humoral response. The principal antigens that elicit an IgA response are microorganisms in the gut or on the airways. IgA cannot cross the placental barrier, but however, IgA can be passed to the neonate through milk. IgA does not fix complement, but can activate the alternative complement pathway. It promotes phagocytosis and intracellular killing of microorganisms.

Immunoglobulins (Antibodies)

Immunoglobulin M (IgM)

Immunoglobulins (Antibodies)

  • IgM is the first antibody produced by, and expressed on the surface of, a B cell.
  • It acts as an antigen receptor for these cells, and is also present as a soluble molecule in the blood.
  • Immunoglobulin M is the principal component of primary immune response. Because of its large size, it is located mainly in the bloodstream. As it is not transported across the placenta, the presence of IgM in the fetus indicates intrauterine infection and its detection is useful to the diagnosis of congenital infections such as syphilis, rubella, human immunodeficiency virus (HIV) infection and toxoplasmosis. IgM antibodies are relatively short lived, disappears earlier than IgG. Hence, their demonstration in serum indicates recent infection. Treatment of serum with 0.12 M 2-mercaptoethanol selectively destroys IgM without affecting IgG antibodies.
  • Immunoglobulin M constitutes 5% to 8% of serum Ig with a normal level of 0.5 to 2 mg per mL.
  • It has a half-life of about 5 days. It is a heavy molecule (19S; molecular weight 900,000 to 1,000,000, hence called the millionaire molecule).
  • It has a pentameric structure comprising five identical four chain units, i.e. it has 10 identical binding sites. The ‘mu’ heavy chains has five domains, VH plus 4 C regions (Cµ1, Cµ2, Cµ3, Cµ4) and lacks a hinge region. The pentameric structure is stabilized by disulfide bonding between adjacent Cµ3 domains and by the presence of Joinez (J) chain. Though theoretically 10 antigen-binding sites are there, only five antigen-binding sites react with antigen probably due to steric hindrance.
  • The isohemagglutinins (anti-A, anti-B) and many other natural antibodies to microorganisms are IgM. Antibodies to typhoid O antigen (endotoxin) and Wassermann reaction (WR) antibodies in syphilis are also of this class. It is efficient in both opsonization and complement fixation.

Immunoglobulins (Antibodies)

Immunoglobulin D (IgD)

Immunoglobulins (Antibodies)

  • IgD is present in low quantities in the circulation (0.3 mg/ml in adult serum).
  • Immunoglobulin D structurally resembles IgG.
  • It has a half-life of about 3 days.
  • Its primary function is that of an antigen receptor on B lymphocytes, but it is probably also involved in regulating B cell function when it encounters antigen. B cells thus can express both IgM and IgD and both are specific for the same antigen.
  • When IgM and IgD expressed on a B cell interact with an antigen for which they are specific, the antigen is internalized, and processed and presented to helper T cells which trigger the B cells to proliferate and differentiate into plasma cells, thus initiating the development of a humoral immune response.

Immunoglobulin E (IgE)

Immunoglobulins (Antibodies)

  • Immunoglobulin E is 8S molecule (molecular weight is about 190,000) with a half-life of 2 days.
  • It exhibits unique properties such as heat lability and affinity towards surface of mast cells.
  • Plays a significant role in enhancing acute inflammation, in protection from infection by worms, and in allergic reactions. Antibody mediated allergy is predominantly associated with IgE. After stimulation of the development of IgE-producing plasma cells by an antigen.
  • the IgE produced binds to receptors on mast cells which are specific for the Fc region of IgE.
  • When antigen is reintroduced into an individual with such ‘armed’ mast cells, it binds to the antigen-binding site of the IgE molecule on the mast cell, and as a result of this interaction, the mast cell is triggered to release pharmacologically active agents (e.g., histamine).
  • IgE antibodies are thus important components of immediate hypersensitivity syndromes such as hay fever and asthma.


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